Datasets:

GleghornLab

/

abstract_domain_autoimmune

like 0

A variety of islet autoantibodies (AAbs) can predict and possibly dictate eventual type 1 diabetes (T1D) diagnosis.,Upwards of 75% of those with T1D are positive for AAbs against glutamic acid decarboxylase (GAD65 or GAD), a producer of gamma-aminobutyric acid (GABA) in human pancreatic beta cells.,Interestingly, bacterial populations within the human gut also express GAD and produce GABA.,Evidence suggests that dysbiosis of the microbiome may correlate with T1D pathogenesis and physiology.,Therefore, autoimmune linkages between the gut microbiome and islets susceptible to autoimmune attack need to be further elucidated.,Utilizing in silico analyses, we show that 25 GAD sequences from human gut bacterial sources show sequence and motif similarities to human beta cell GAD65.,Our motif analyses determined that most gut GAD sequences contain the pyroxical dependent decarboxylase (PDD) domain of human GAD65, which is important for its enzymatic activity.,Additionally, we showed overlap with known human GAD65 T cell receptor epitopes, which may implicate the immune destruction of beta cells.,Thus, we propose a physiological hypothesis in which changes in the gut microbiome in those with T1D result in a release of bacterial GAD, thus causing miseducation of the host immune system.,Due to the notable similarities we found between human and bacterial GAD, these deputized immune cells may then target human beta cells leading to the development of T1D.

The relationship between maternal gluten intake in pregnancy, offspring intake in childhood, and offspring risk of type 1 diabetes has not been examined jointly in any studies.,Our aim was to study the relationship between maternal and child intake of gluten and risk of type 1 diabetes in children.,We included 86,306 children in an observational nationwide cohort study, the Norwegian Mother and Child Cohort Study (MoBa), with recruitment from 1999 to 2008 and with follow-up time to April 15, 2018.,We used registration of type 1 diabetes in the Norwegian childhood diabetes registry as the outcome.,We used Cox proportional hazard regression to estimate hazard ratios (HRs) for the mother’s intake of gluten up to week 22 of pregnancy and offspring gluten intake when the child was 18 months old.,The average time followed was 12.3 years (0.70-16.0).,A total of 346 children (0.4%) children were diagnosed with type 1 diabetes, resulting in an incidence rate of 32.6/100,000 person-years.,Mean gluten intake per day was 13.6 g for mothers and 8.8 g for children.,There was no association between the mother’s intake of gluten in pregnancy and offspring type 1 diabetes, with an adjusted HR (aHR) of 1.02 (95% confidence interval [CI] 0.73-1.43, p = 0.91) for each 10-g-per-day increment.,There was an association between offspring intake of gluten and a higher risk of type 1 diabetes, with an aHR of 1.46 (95% CI 1.06-2.01, p = 0.02) for each 10-g-per-day increment.,Among the limitations are the likely imprecision in estimation of gluten intake and that we only had information regarding gluten intake at 2 time points in early life.,Our results show that, while the mother’s intake of gluten in pregnancy was not associated with type 1 diabetes, a higher intake of gluten by the child at an early age may give a higher risk of type 1 diabetes.,Nicolai A Lund-Blix et al report the relationship between maternal gluten intake during pregnancy, gluten intake in children and the development of Type I diabetes in the children.

The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive.,A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs).,These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression.,The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively.,Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases.,Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches.

We have investigated the role of human endogenous retroviruses in multiple sclerosis by analyzing the DNA of patients and controls in 4 cohorts for associations between multiple sclerosis and polymorphisms near viral restriction genes or near endogenous retroviral loci with one or more intact or almost-intact genes.,We found that SNPs in the gene TRIM5 were inversely correlated with disease.,Conversely, SNPs around one retroviral locus, HERV-Fc1, showed a highly significant association with disease.,The latter association was limited to a narrow region that contains no other known genes.,We conclude that HERV-Fc1 and TRIM5 play a role in the etiology of multiple sclerosis.,If these results are confirmed, they point to new modes of treatment for multiple sclerosis.

B cells exert immunosuppressive effects and offer therapeutic potential for systemic lupus erythematosus (SLE), but the mechanism remains unclear.,Here we analyzed the B cell regulation of Th17/Th22 cell differentiation in lupus and found that α-IgM- and α-CD40-activated B cells could inhibit Th17 and promote Th22 cell differentiation from naive T cells under Th17 cell culture conditions.,B cell-induced Th22 cells demonstrated immunosuppressive effects and could decrease renal endothelial cell apoptosis in vitro.,Moreover, activated B cell infusion relieved lupus injuries via IL-22 production in vivo.,Mechanically, activated B cells affected Th17/Th22 cell differentiation by non-contact TNF-α secretion and mTOR activation.,Finally, activated B cells could affect Th17/Th22 cell differentiation in human peripheral blood T cells.,These data suggest that activated B cells might attenuate lupus autoimmunity by inhibiting Th17 but promoting Th22 cell differentiation, supporting B cell activation as a promising therapeutic for the treatment of lupus.

Although the aetiology of systemic lupus erythematosus (SLE) is unclear, dysregulated B cell responses have been implicated.,Here we show that an unusual CD11chiT-bet+ B cell subset, with a unique expression profile including chemokine receptors consistent with migration to target tissues, is expanded in SLE patients, present in nephrotic kidney, enriched for autoreactive specificities and correlates with defined clinical manifestations.,IL-21 can potently induce CD11chiT-bet+ B cells and promote the differentiation of these cells into Ig-secreting autoreactive plasma cells.,While murine studies have identified a role for T-bet-expressing B cells in autoimmunity, this study describes and exemplifies the importance of CD11chiT-bet+ B cells in human SLE.,Systemic lupus erythematosus (SLE) is associated with altered B cell responses but the underlying aetiology is still unclear.,Here the authors show that a CD11chiT-bet+ B cell subset with a unique phenotype and transcriptome is increased in patients with SLE, can be expanded by IL-21, and may contribute to autoimmune responses in SLE.

Smoking has been connected to citrullination of antigens and formation of anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA).,Since smoking can modify proteins by carbamylation (formation of homocitrulline), this study was conducted to investigate these effects on vimentin in animal models and RA.,The efficiency of enzymatic carbamylation of vimentin was characterised.,B-cell response was investigated after immunisation of rabbits with different vimentin isoforms.,Effects of tobacco smoke exposure on carbamylation of vimentin and formation of autoantibodies were analysed in mice.,The antibody responses against isoforms of vimentin were characterised with respect to disease duration and smoking status of patients with RA.,Enzymatic carbamylation of vimentin was efficiently achieved.,Subsequent citrullination of vimentin was not disturbed by homocitrullination.,Sera from rabbits immunised with carbamylated vimentin (carbVim), in addition to carbVim also recognised human IgG-Fc showing rheumatoid factor-like reactivity.,Smoke-exposed mice contained detectable amounts of carbVim and developed a broad immune response against carbamylated antigens.,Although the prevalence of anti-carbamylated antibodies in smokers and non-smokers was similar, the titres of carbamylated antibodies were significantly increased in sera of smoking compared with non-smoking RA.,CarbVim antibodies were observed independently of ACPAs in early phases of disease and double-positive patients for anti-mutated citrullinated vimentin (MCV) and anti-carbVim antibodies showed an extended epitope recognition pattern towards MCV.,Carbamylation of vimentin is inducible by cigarette smoke exposure.,The polyclonal immune response against modified antigens in patients with RA is not exclusively citrulline-specific and carbamylation of antigens could be involved in the pathogenesis of disease.,ISRCTN36745608; EudraCT Number: 2006-003146-41.

Rheumatoid arthritis (RA) is a prototypical autoimmune arthritis affecting nearly 1% of the world population and is a significant cause of worldwide disability.,Though prior studies have demonstrated the appearance of RA-related autoantibodies years before the onset of clinical RA, the pattern of immunologic events preceding the development of RA remains unclear.,To characterize the evolution of the autoantibody response in the preclinical phase of RA, we used a novel multiplex autoantigen array to evaluate development of the anti-citrullinated protein antibodies (ACPA) and to determine if epitope spread correlates with rise in serum cytokines and imminent onset of clinical RA.,To do so, we utilized a cohort of 81 patients with clinical RA for whom stored serum was available from 1-12 years prior to disease onset.,We evaluated the accumulation of ACPA subtypes over time and correlated this accumulation with elevations in serum cytokines.,We then used logistic regression to identify a profile of biomarkers which predicts the imminent onset of clinical RA (defined as within 2 years of testing).,We observed a time-dependent expansion of ACPA specificity with the number of ACPA subtypes.,At the earliest timepoints, we found autoantibodies targeting several innate immune ligands including citrullinated histones, fibrinogen, and biglycan, thus providing insights into the earliest autoantigen targets and potential mechanisms underlying the onset and development of autoimmunity in RA.,Additionally, expansion of the ACPA response strongly predicted elevations in many inflammatory cytokines including TNF-α, IL-6, IL-12p70, and IFN-γ.,Thus, we observe that the preclinical phase of RA is characterized by an accumulation of multiple autoantibody specificities reflecting the process of epitope spread.,Epitope expansion is closely correlated with the appearance of preclinical inflammation, and we identify a biomarker profile including autoantibodies and cytokines which predicts the imminent onset of clinical arthritis.

Rheumatoid arthritis is a chronic, systemic inflammatory disease that carries an increased risk of mortality due to cardiovascular disease.,The link between inflammation and atherosclerotic disease is clear; however, recent evidence suggests that inflammation may also play a role in the development of nonischemic heart disease in rheumatoid arthritis (RA) patients.,We consider here the link between inflammation and cardiovascular disease in the RA community with a focus on heart failure with preserved ejection fraction.,The effect of current anti-inflammatory therapeutics, used to treat RA patients, on cardiovascular disease are discussed as well as whether targeting resolution of inflammation might offer an alternative strategy for tempering inflammation and subsequent inflammation-driven comorbidities in RA.

T-cell large granular lymphocytic leukemia (T-LGLL) is a lymphoproliferative disorder characterized by a persistent increase in the number of large granular lymphocytes (LGLs), neutropenia, and splenomegaly.,Clinical manifestations of T-LGLL in the setting of rheumatoid arthritis (RA) are often identical to those in which one would suspect Felty's syndrome (FS).,These disorders are distinguished by the presence of T-cell clonality, which is present in T-LGLL but not in FS.,Mutations in the signal transducer and activator of transcription 3 (STAT3) and 5b (STAT5b) genes can be used as molecular markers of T-LGLL, but their prevalence in FS is unknown.,Eighty-one patients with RA and unexplained neutropenia or/and an increase in the number of LGLs above 2 × 109/L were stratified into RA-associated T-LGLL (N = 56) or FS (N = 25) groups based on the presence or absence of T-cell clonality.,STAT3 and STAT5b gene mutations were assessed in each group by means of allele-specific polymerase chain reaction assays.,Clinical, immunological, laboratory data and the results of immunophenotyping of blood and bone marrow lymphocytes were also evaluated.,Mutations of the STAT3 gene and an increase in the number of LGLs above 2 × 109/L were detected in RA-associated T-LGLL, but not in FS (39% vs 0% and 21% vs 0%, respectively).,Mutations in the STAT5b gene were not observed in either group.,Expression of CD57, CD16, and CD5−/dim on CD3+CD8+ T-lymphocytes was observed in both RA-associated T-LGLL and FS.,STAT3 gene mutations or LGL counts over 2 × 109/L in RA patients are indicative of T-LGLL.,The online version contains supplementary material available at 10.1007/s00296-020-04757-4.

In the past 15 years, B cells have been rediscovered to be not merely bystanders but rather active participants in autoimmune aetiology.,This has been fuelled in part by the clinical success of B cell depletion therapies (BCDTs).,Originally conceived as a method of eliminating cancerous B cells, BCDTs such as those targeting CD20, CD19 and BAFF are now used to treat autoimmune diseases, including systemic lupus erythematosus and multiple sclerosis.,The use of BCDTs in autoimmune disease has led to some surprises.,For example, although antibody-secreting plasma cells are thought to have a negative pathogenic role in autoimmune disease, BCDT, even when it controls the disease, has limited impact on these cells and on antibody levels.,In this Review, we update our understanding of B cell biology, review the results of clinical trials using BCDT in autoimmune indications, discuss hypotheses for the mechanism of action of BCDT and speculate on evolving strategies for targeting B cells beyond depletion.,Examining B cell depletion therapy (BCDT), an approved treatment for B cell malignancies, in autoimmune conditions has provided key insights into basic B cell biology.,In this Review, Gommerman and colleagues discuss BCDT in autoimmune conditions, highlighting diseases in which BCDT has been clinically effective and the potential and pitfalls for BCDT in autoimmune conditions in which it has not yet been efficacious.

The BAFF system plays a key role in the development of autoimmunity, especially in systemic lupus erythematosus (SLE).,This often leads to the assumption that BAFF is mostly a B cell factor with a specific role in autoimmunity.,Focus on BAFF and autoimmunity, driven by pharmaceutical successes with the recent approval of a novel targeted therapy Belimumab, has relegated other potential roles of BAFF to the background.,Far from being SLE-specific, the BAFF system has a much broader relevance in infection, cancer and allergy.,In this review, we provide the latest views on additional roles of the BAFF system in health and diseases, as well as an update on BAFF and autoimmunity, with particular focus on current clinical trials.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is associated with demyelination and neuronal loss.,Over recent years, the immunological and neuronal effects of tryptophan (Trp) metabolites have been largely investigated, leading to the hypothesis that these compounds and the related enzymes are possibly involved in the pathophysiology of MS.,Specifically, the kynurenine pathway of Trp metabolism is responsible for the synthesis of intermediate products with potential immunological and neuronal effects.,More recently, Trp metabolites, originating also from the host microbiome, have been identified in MS, and it has been shown that they are differently regulated in MS patients.,Here, we sought to discuss whether, in MS patients, a specific urinary signature of host/microbiome Trp metabolism can be potentially identified so as to select novel biomarkers and guide toward the identification of specific metabolic pathways as drug targets in MS.

The overlapping clinical features of relapsing remitting multiple sclerosis (RRMS), aquaporin-4 (AQP4)-antibody (Ab) neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein (MOG)-Ab disease mean that detection of disease specific serum antibodies is the gold standard in diagnostics.,However, antibody levels are not prognostic and may become undetectable after treatment or during remission.,Therefore, there is still a need to discover antibody-independent biomarkers.,We sought to discover whether plasma metabolic profiling could provide biomarkers of these three diseases and explore if the metabolic differences are independent of antibody titre.,Plasma samples from 108 patients (34 RRMS, 54 AQP4-Ab NMOSD, and 20 MOG-Ab disease) were analysed by nuclear magnetic resonance spectroscopy followed by lipoprotein profiling.,Orthogonal partial-least squares discriminatory analysis (OPLS-DA) was used to identify significant differences in the plasma metabolite concentrations and produce models (mathematical algorithms) capable of identifying these diseases.,In all instances, the models were highly discriminatory, with a distinct metabolite pattern identified for each disease.,In addition, OPLS-DA identified AQP4-Ab NMOSD patient samples with low/undetectable antibody levels with an accuracy of 92%.,The AQP4-Ab NMOSD metabolic profile was characterised by decreased levels of scyllo-inositol and small high density lipoprotein particles along with an increase in large low density lipoprotein particles relative to both RRMS and MOG-Ab disease.,RRMS plasma exhibited increased histidine and glucose, along with decreased lactate, alanine, and large high density lipoproteins while MOG-Ab disease plasma was defined by increases in formate and leucine coupled with decreased myo-inositol.,Despite overlap in clinical measures in these three diseases, the distinct plasma metabolic patterns support their distinct serological profiles and confirm that these conditions are indeed different at a molecular level.,The metabolites identified provide a molecular signature of each condition which is independent of antibody titre and EDSS, with potential use for disease monitoring and diagnosis.,The online version of this article (10.1186/s40478-017-0495-8) contains supplementary material, which is available to authorized users.

Myasthenia gravis (MG) may be refractory to traditional therapies.,Quality of life (QOL) and disease burden in patients with refractory and nonrefractory MG were compared using Myasthenia Gravis Foundation of America MG Patient Registry data.,Adults aged 18 years or older with MG diagnosed ≥2 years before enrollment were included.,Participants with refractory MG had received ≥2 previous and 1 current MG treatment and had MG Activities of Daily Living Scale total score ≥6 at enrollment; other participants had nonrefractory MG.,MG QOL 15-item scale (MG-QOL15) scores were compared.,In total, 56 participants with refractory and 717 participants with nonrefractory MG enrolled.,Participants with refractory MG had significantly higher mean (SD) MG-QOL15 total scores [31.4 (11.1) vs.,20.8 (15.0), P < 0.0001] and were more likely to have had exacerbations, emergency department visits, and recent hospitalizations.,Participants with refractory MG experience worse QOL and greater clinical burden than those with nonrefractory disease.

To develop formal consensus-based guidance for the management of myasthenia gravis (MG).,In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened.,The RAND/UCLA appropriateness methodology was used to develop consensus guidance statements.,Definitions were developed for goals of treatment, minimal manifestations, remission, ocular MG, impending crisis, crisis, and refractory MG.,An in-person panel meeting then determined 7 treatment topics to be addressed.,Initial guidance statements were developed from literature summaries.,Three rounds of anonymous e-mail votes were used to attain consensus on guidance statements modified on the basis of panel input.,Guidance statements were developed for symptomatic and immunosuppressive treatments, IV immunoglobulin and plasma exchange, management of impending and manifest myasthenic crisis, thymectomy, juvenile MG, MG associated with antibodies to muscle-specific tyrosine kinase, and MG in pregnancy.,This is an international formal consensus of MG experts intended to be a guide for clinicians caring for patients with MG worldwide.

Multiple sclerosis (MS) is a neuroinflammatory, demyelinating disease that represents one of the most frequent causes of irreversible disability in young adults.,Treatment options to halt disability are limited.,We discovered that T helper (Th)17 cells in contact with oligodendrocytes produce higher levels of glutamate and induce significantly greater oligodendrocyte damage than their Th2 counterpart.,Blockade of CD29, which is linked to glutamate release pathways and expressed in high levels on Th17 cells, preserved human oligodendrocyte processes from Th17-mediated injury.,Our data thus provide evidence for the direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for therapeutic opportunities to protect oligodendrocytes’ myelinating processes in MS.,T helper (Th)17 cells are considered to contribute to inflammatory mechanisms in diseases such as multiple sclerosis (MS).,However, the discussion persists regarding their true role in patients.,Here, we visualized central nervous system (CNS) inflammatory processes in models of MS live in vivo and in MS brains and discovered that CNS-infiltrating Th17 cells form prolonged stable contact with oligodendrocytes.,Strikingly, compared to Th2 cells, direct contact with Th17 worsened experimental demyelination, caused damage to human oligodendrocyte processes, and increased cell death.,Importantly, we found that in comparison to Th2 cells, both human and murine Th17 cells express higher levels of the integrin CD29, which is linked to glutamate release pathways.,Of note, contact of human Th17 cells with oligodendrocytes triggered release of glutamate, which induced cell stress and changes in biosynthesis of cholesterol and lipids, as revealed by single-cell RNA-sequencing analysis.,Finally, exposure to glutamate decreased myelination, whereas blockade of CD29 preserved oligodendrocyte processes from Th17-mediated injury.,Our data provide evidence for the direct and deleterious attack of Th17 cells on the myelin compartment and show the potential for therapeutic opportunities in MS.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by neuroinflammation, leading to demyelination and axonal degeneration.,Neuronal excitotoxity mediated by Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) results in neuronal damage in experimental autoimmune encephalitis (EAE), an animal model of MS.,Here, we define a critical role of excitatory neurons in the pathogenesis of CD4+ lymphocyte accumulation in EAE.,We silenced the activity of excitatory neurons in a mouse model of targeted EAE using inhibitory designer receptors exclusively activated by designer drugs (DREADD) under a CaMKIIα promoter.,Neuronal silencing mitigated clinical disease scores in EAE, reduced the expression of c-fos, Tnfα, Ccl2, and Ccr2 mRNAs in targeted EAE lesions, and prevented the migration of CD4+ lymphocytes towards neurons.,Ccl2 shRNA treatment of targeted EAE suppressed the migration of CD4+ lymphocytes and alleviated the motor deficits of EAE.,Our findings indicate that neuronal activation in EAE promotes the migration of CCR2+ CD4+ lymphocytes and that neuronal silencing with an inhibitory DREADD alleviates clinical and molecular markers of disease.,Neuronal CCL2 is thought to be involved in promoting lymphocytes migration.

To evaluate the immune-specific response after full severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination of patients with multiple sclerosis (MS) treated with different disease-modifying drugs by the detection of both serologic and T-cell responses.,Healthcare workers (HCWs) and patients with MS, having completed the 2-dose schedule of an mRNA-based vaccine against SARS-CoV-2 in the past 2-4 weeks, were enrolled from 2 parallel prospective studies conducted in Rome, Italy, at the National Institute for Infectious diseases Spallanzani-IRCSS and San Camillo Forlanini Hospital.,Serologic response was evaluated by quantifying the region-binding domain (RBD) and neutralizing antibodies.,Cell-mediated response was analyzed by a whole-blood test quantifying interferon (IFN)-γ response to spike peptides.,Cells responding to spike stimulation were identified by fluorescence-activated cell sorting analysis.,We prospectively enrolled 186 vaccinated individuals: 78 HCWs and 108 patients with MS.,Twenty-eight patients with MS were treated with IFN-β, 35 with fingolimod, 20 with cladribine, and 25 with ocrelizumab.,A lower anti-RBD antibody response rate was found in patients treated with ocrelizumab (40%, p < 0.0001) and fingolimod (85.7%, p = 0.0023) compared to HCWs and patients treated with cladribine or IFN-β.,Anti-RBD antibody median titer was lower in patients treated with ocrelizumab (p < 0.0001), fingolimod (p < 0.0001), and cladribine (p = 0.010) compared to HCWs and IFN-β-treated patients.,Serum neutralizing activity was present in all the HCWs tested and in only a minority of the fingolimod-treated patients (16.6%).,T-cell-specific response was detected in the majority of patients with MS (62%), albeit with significantly lower IFN-γ levels compared to HCWs.,The lowest frequency of T-cell response was found in fingolimod-treated patients (14.3%).,T-cell-specific response correlated with lymphocyte count and anti-RBD antibody titer (ρ = 0.554, p < 0.0001 and ρ = 0.255, p = 0.0078 respectively).,IFN-γ T-cell response was mediated by both CD4+ and CD8+ T cells.,mRNA vaccines induce both humoral and cell-mediated specific immune responses against spike peptides in all HCWs and in the majority of patients with MS.,These results carry relevant implications for managing vaccinations, suggesting promoting vaccination in all treated patients with MS.,This study provides Class III data that SARS-CoV-2 mRNA vaccination induces both humoral and cell-mediated specific immune responses against viral spike proteins in a majority of patients with MS.

Knowledge on immunity after SARS-CoV-2 infection in patients with multiple sclerosis (pwMS) and the impact of disease-modifying treatment (DMT) is limited.,To evaluate degree, duration and potential predictors of specific humoral immune response in pwMS with prior COVID-19.,Anti-SARS-CoV-2 antibody testing was performed in pwMS with PCR-confirmed diagnosis of symptomatic COVID-19 from a nation-wide registry.,Predictors of seropositivity were identified by multivariate regression models.,In 125 pwMS (mean age = 42.4 years (SD = 12.3 years), 70% female), anti-SARS-CoV-2 antibodies were detected in 76.0% after a median of 5.2 months from positive PCR.,Seropositivity rate was significantly lower in patients on IS-DMT (61.4%, p = 0.001) than without DMT or immunomodulatory DMT (80.6%; 86.0%, respectively).,In multivariate analysis, IS-DMT was associated with reduced probability of seropositivity (odds ratio (OR): 0.51; 95% confidence interval (95% CI): 0.17-0.82; p < 0.001).,Predefined subgroup analyses showed marked reduction of seropositivity in pwMS on rituximab/ocrelizumab (OR 0.15; 95% CI: 0.05-0.56; p < 0.001).,Rate of seropositivity did not change significantly over 6 months.,Humoral immunity is stable after SARS-CoV-2 infection in MS, but is reduced by immunosuppressive DMT, particularly anti-CD20 monoclonal antibodies.,This provides important evidence for advising pwMS as well as for planning and prioritizing vaccination.

Multiple sclerosis (MS) is an inflammatory-neurodegenerative disease of the central nervous system presenting with significant inter- and intraindividual heterogeneity.,However, the application of clinical and imaging biomarkers is currently not able to allow individual characterization and prediction.,Complementary, molecular biomarkers which are easily quantifiable come from the areas of immunology and neurobiology due to the causal pathomechanisms and can excellently complement other disease characteristics.,Only a few molecular biomarkers have so far been routinely used in clinical practice as their validation and transfer take a long time.,This review describes the characteristics that an ideal MS biomarker should have and the challenges of establishing new biomarkers.,In addition, clinically relevant and promising biomarkers from the blood and cerebrospinal fluid are presented which are useful for MS diagnosis and prognosis as well as for the assessment of therapy response and side effects.

Background: Oligoclonal IgG bands (OCB) in the cerebrospinal fluid (CSF) represent a typical marker for inflammation in multiple sclerosis (MS) patients and have a predictive and diagnostic value in patients with a first suspected demyelinating event.,The detection in tears remains controversial but some reports suggested a replacement of CSF analysis by OCB detection in tears.,We aimed to investigate the value of OCB detection in tears systematically in patients with MS.,Methods: Tears of 59 patients with suspected or diagnosed MS were collected with Schirmer filter paper strips.,Tear IgG was purified by affinity chromatography with protein G.,After isoelectric focusing in polyacrylamide gels OCB detection was performed with direct silver staining.,Paired triplets of CSF, serum, and tears were analyzed.,For comparison purposes we additionally used other tear collection methods (flush procedure and plastic capillary tubes) or detection techniques (Immunoblotting).,Clinical and paraclinical parameters are provided.,Results: IgG collection in tears was most reliable by using Schirmer strips.,Thirteen patients had to be excluded due to insufficient sample material.,Tear specific proteins that interfered with OCB detection were successfully eliminated by IgG purification.,The concordance of OCB in tears and CSF of all investigated MS patients was 39% with a high rate of only marginal pattern in tears.,Five patients demonstrated restricted bands in tears, neither detectable in CSF nor serum.,Occurrence of OCB in tears was significantly associated with pathological visual evoked potentials (P = 0.0094) and a history of optic neuritis (P = 0.0258).,Conclusion: Due to the limited concordance, high rate of samples with insufficient material, and the unknown origin of tear IgG we cannot recommend that tear OCB detection may replace CSF OCB detection in MS patients.,The detection of unique OCB in tears might offer new insights in ophthalmological diseases.

Rheumatoid arthritis (RA) is a complex and not fully understood autoimmune disease associated with multijoint damage.,The main effector cells, the synovial fibroblasts, are apoptosis resistant and hyperplastic which indicate that autophagy level is high in synovial tissue.,Real-time PCR, immunocytochemistry, and western blotting were used in this paper to study the autophagy status of the synovial tissues obtained from RA and OA patients at the time of joint replacement surgery.,We further evaluated the correlation between autophagy levels with RA activity-associated serum markers with SPSS.,The results showed that the expression levels (both in mRNA and in protein level) of autophagy-related proteins (belcin1, Atg5, and LC3) in the synovial tissue of patients with active rheumatoid arthritis (n = 20) were significantly higher than those in OA patients (n = 16).,We further showed that the LC3-II/β-actin relative gray value was strongly correlated with the serum levels of several RA activity-related markers: CRP, ESR, CCP, and RF.,Our results indicate that evaluating the autophagy level of synovial biopsies might be a useful way to diagnose RA and to estimate the disease activity.,Reducing the expression level of autophagy-related genes might become a new therapeutic target for active rheumatoid arthritis.

The objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA).,This was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE).,Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented.,Overall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks.,During the double-blind, placebo-controlled periods, the incidence of adverse events and serious adverse events was comparable between the OCR+MTX and placebo +MTX groups.,Infusion-related reactions were more common with OCR+MTX and decreased in frequency with subsequent infusions.,Serious infusion-related reactions were rare (0.1%).,Serious infections occurred more frequently with OCR500+MTX.,In the meta-analysis, a statistically significant difference from placebo +MTX in incidence of SIEs per 100 patient-years of 2.4 (95% CI, 0.3-4.5) was observed with OCR500+MTX, but not with OCR200+MTX (0.6; 95% CI, −1.3 to 2.4).,Patients recruited in Asia exhibited a higher risk of serious infections (hazard ratio, 1.78; 95% CI, 1.03-3.06).,The incidence of human anti-human antibodies was <5%.,Long-term follow-up indicated no differences in malignancy rates between the treatment groups.,There was no apparent difference in time to B-cell repletion between the OCR dose groups.,In placebo-controlled clinical trials of RA, OCR500+MTX was associated with a higher risk of serious infections compared with placebo +MTX.,The safety profile of OCR 200+MTX was comparable with placebo+MTX.,STAGE Clinical Trials.gov NCT00406419,SCRIPT Clinical Trials.gov NCT00476996,FILM Clinical Trials.gov NCT00485589,FEATURE Clinical Trials.gov NCT00673920

Calprotectin may be a sensitive biomarker of rheumatoid arthritis (RA) disease activity.,In the current study, we investigated whether calprotectin is a better biomarker than CRP for predicting clinical activity and ultrasound parameters in patients with RA.,A total of 160 patients with RA underwent clinical (swollen joint count-SJC, tender joint count-TJC, Disease Activity Score-DAS28, Clinical Disease Activity Index-CDAI, and simplified Disease Activity Index-SDAI) and ultrasound (German US7) examination.,Clinical and laboratory measures were correlated with ultrasound findings using Spearman´s correlation coefficient.,Differences in serum calprotectin levels in patients with variable disease activity according to the DAS28-ESR and CDAI scores were assessed using ANOVA.,Multivariate regression analysis was used to determine the predictive values of calprotectin, CRP and SJC for CDAI and PD US synovitis scores.,Serum calprotectin was significantly associated with DAS28-ESR (r = 0.321, p<0.001), DAS28-CRP (r = 0.346, p<0.001), SDAI (r = 0.305, p<0.001), CDAI (r = 0.279, p<0.001) scores and CRP levels (r = 0.556, p<0.001).,Moreover, calprotectin was significantly correlated with GS (r = 0.379, p<0.001) and PD synovitis scores (r = 0.419, p<0.001).,The multivariate regression analysis showed that calprotectin is a better predictor of the CDAI score and PD US synovitis than CRP.,The results of this study support an additional role of calprotectin in assessing inflammatory activity in patients with RA.

Increasing evidence indicates that microRNAs (miRNAs) play a critical role in the pathogenesis of inflammatory diseases.,The aim of the study was to investigate the expression pattern and function of miRNAs in CD4+ T cells from patients with rheumatoid arthritis (RA).,The expression profile of miRNAs in CD4+ T cells from synovial fluid (SF) and peripheral blood of 33 RA patients was determined by microarray assay and validated by qRT-PCR analysis.,The correlation between altered expression of miRNAs and cytokine levels was determined by linear regression analysis.,The role of miR-146a overexpression in regulating T cell apoptosis was evaluated by flow cytometry.,A genome-wide gene expression analysis was further performed to identify miR-146a-regulated genes in T cells.,miRNA expression profile analysis revealed that miR-146a expression was significantly upregulated while miR-363 and miR-498 were downregulated in CD4+ T cells of RA patients.,The level of miR-146a expression was positively correlated with levels of tumor necrosis factor-alpha (TNF-α), and in vitro studies showed TNF-α upregulated miR-146a expression in T cells.,Moreover, miR-146a overexpression was found to suppress Jurkat T cell apoptosis.,Finally, transcriptome analysis of miR-146a overexpression in T cells identified Fas associated factor 1 (FAF1) as a miR-146a-regulated gene, which was critically involved in modulating T cell apoptosis.,We have detected increased miR-146a in CD4+ T cells of RA patients and its close correlation with TNF-α levels.,Our findings that miR-146a overexpression suppresses T cell apoptosis indicate a role of miR-146a in RA pathogenesis and provide potential novel therapeutic targets.

The aim of this cross-sectional study was to compare plasma C-peptide presence and levels in people without diabetes (CON) and with Type 1 diabetes and relate C-peptide status to clinical factors.,In a subset we evaluated 50 microRNAs (miRs) previously implicated in beta-cell death and associations with clinical status and C-peptide levels.,Diabetes age of onset was stratified as adult (≥ 18 y.o) or childhood (< 18 y.o.), and diabetes duration was stratified as ≤ 10 years, 10-20 years and > 20 years.,Plasma C-peptide was measured by ultrasensitive ELISA.,Plasma miRs were quantified using TaqMan probe-primer mix on an OpenArray platform.,C-peptide was detectable in 55.3% of (n = 349) people with diabetes, including 64.1% of adults and 34.0% of youth with diabetes, p < 0.0001 and in all (n = 253) participants without diabetes (CON).,C-peptide levels, when detectable, were lower in the individuals with diabetes than in the CON group [median lower quartile (LQ)-upper quartile (UQ)] 5.0 (2.6-28.7) versus 650.9 (401.2-732.4) pmol/L respectively, p < 0.0001 and lower in childhood versus adult-onset diabetes [median (LQ-UQ) 4.2 (2.6-12.2) pmol/L vs.,8.0 (2.3-80.5) pmol/L, p = 0.02, respectively].,In the childhood-onset group more people with longer diabetes duration (> 20 years) had detectable C-peptide (60%) than in those with shorter diabetes duration (39%, p for trend < 0.05).,Nine miRs significantly correlated with detectable C-peptide levels in people with diabetes and 16 miRs correlated with C-peptide levels in CON.,Our cross-sectional study results are supportive of (a) greater beta-cell function loss in younger onset Type 1 diabetes; (b) persistent insulin secretion in adult-onset diabetes and possibly regenerative secretion in childhood-onset long diabetes duration; and (c) relationships of C-peptide levels with circulating miRs.,Confirmatory clinical studies and related basic science studies are merited.

The studies on microbiome in the human digestive tract indicate that fungi could also be one of the external factors affecting development of diabetes.,The aim of this study was to evaluate the quantitative and qualitative mycobiome composition in the colon of the adults with type 1 (T1D), n = 26 and type 2 (T2D) diabetes, n = 24 compared to the control group, n = 26.,The gut mycobiome was characterized in the stool samples using the analysis of the whole internal transcribed spacer (ITS) region of the fungal rDNA gene cluster by next-generation sequencing (NGS) with increased sensitivity.,At the L2 (phylum) level, Basidiomycota fungi were predominant in all 3 study groups.,Group T1D presented significantly lower number of Ascomycota compared to the T2D group, and at the L6 (genus) level, the T1D group presented significantly lower number of Saccharomyces genus compared to control and T2D groups.,In the T1D group, a significant positive correlation between total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels and fungi of the genus Saccharomyces, and in the T2D group, a negative correlation between the total cholesterol level and Malassezia genus was found.,The obtained results seem to be a good foundation to extend the analysis of the relationship between individual genera and species of fungi and the parameters determining the metabolism of carbohydrates and lipids in the human body.

Despite recent improvements in the quality of life of patients with systemic lupus erythematosus (SLE), osteoporosis, and osteoporotic fractures are one of the major complications of SLE.,Furthermore, limited data are available on the incidence and predictor of osteoporotic fractures in Korean patients with SLE.,Herein, we aimed to assess the incidence and risk factors for osteoporotic fractures in Korean SLE patients compared to those without SLE.,SLE patients aged ≥ 40 years (n = 10,434; mean age, 51.3 ± 9.1 years; women, 89.7%) were selected from the Korean National Health Insurance Service database, spanning a period from 2008 to 2014.,Age- and sex-matched controls (n = 52,170) were randomly sampled in a 5:1 ratio from non-SLE individuals.,The primary outcome was the first occurrence of osteoporotic fracture.,The incidence of osteoporotic fractures was significantly higher in the SLE patients (19.085 per 1,000 person-years) than in matched controls (6.530 per 1,000 person-years).,According to the multivariable Cox proportional analysis, patients with SLE exhibited a higher osteoporotic fracture rate than the control group (hazards ratio, 2.964; 95% confidence interval, 2.754 to 3.188), even after adjustment for confounding variables.,In the subgroup analysis, male SLE patients or SLE patients aged 40 to 65 years were associated with a higher osteoporotic fracture rate than women SLE patients or SLE patients aged ≥ 65 years, respectively.,We found a 2.964-fold increased risk of osteoporotic fracture in SLE patients compared to age- and sex-matched non-SLE controls.,Male or middle-aged SLE patients had a relatively higher fracture risk among patients with SLE.

Observational studies have indicated a high but heterogeneous prevalence of low bone mineral density (BMD) and vertebral fractures (VF) in patients with systemic lupus erythematosus (SLE).,Therefore, the objectives of this systematic review and meta-regression were: 1) to compare BMD between SLE patients and healthy controls and 2) to evaluate the relationship between BMD and glucocorticoid therapy and VF in SLE patients.,Articles were identified from electronic databases (PubMed, Embase, VHL, SciELO and the Cochrane Library).,Prospective longitudinal and cross-sectional studies were considered for review.,We evaluated the quality of the evidence included using the Oxford Centre for evidence-based medicine (EBM) Levels of Evidence.,In total, 38 articles were identified and analyzed (3442 SLE cases and 6198 controls) in the analysis of BMD (9232 women and 408 men).,There were significant differences in mean BMD between SLE patients and controls.,BMD mean difference in cases/controls: -0.0566 95% CI (-0.071, -0.0439; p = < 0.0001).,When only SLE patients were analyzed, the BMD did not significantly differ between patients who had or had not received glucocorticoid (GCT) therapy.,694 SLE patients were included in the analysis of VF (189 with VF vs. 505 without VF).,Patients with VF had lower BMD than patients without VF (BMD mean difference without VF/with VF: 0.033 (95%CI: 0.006-0.060); p-value: 0.0156).,Patients with SLE had lower BMD than healthy controls.,Moreover, SLE patients with VF had lower BMD than patients without VF.,However, our data did not show that GCT therapy had an impact on BMD.

Sjögren’s syndrome is a chronic autoimmune disease characterized by ocular and oral dryness resulting from lacrimal and salivary gland dysfunction.,Besides, a variety of systemic manifestations may occur, involving virtually any organ system.,As a result, the disease is characterized by pleomorphic clinical manifestations whose characteristics and severity may vary greatly from one patient to another.,Sjögren’s syndrome can be defined as primary or secondary, depending on whether it occurs alone or in association with other systemic autoimmune diseases, respectively.,The pathogenesis of Sjögren’s syndrome is still elusive, nevertheless, different, not mutually exclusive, models involving genetic and environmental factors have been proposed to explain its development.,Anyhow, the emergence of aberrant autoreactive B-lymphocytes, conducting to autoantibody production and immune complex formation, seems to be crucial in the development of the disease.,The diagnosis of Sjögren’s syndrome is based on characteristic clinical signs and symptoms, as well as on specific tests including salivary gland histopathology and autoantibodies.,Recently, new classification criteria and disease activity scores have been developed primarily for research purposes and they can also be useful tools in everyday clinical practice.,Treatment of Sjögren’s syndrome ranges from local and symptomatic therapies aimed to control dryness to systemic medications, including disease-modifying agents and biological drugs.,The objective of this review paper is to summarize the recent literature on Sjögren’s syndrome, starting from its pathogenesis to current therapeutic options.

Immune-mediated inner ear disease can be primary, when the autoimmune response is against the inner ear, or secondary.,The latter is characterized by the involvement of the ear in the presence of systemic autoimmune conditions.,Sensorineural hearing loss is the most common audiovestibular symptom associated with systemic autoimmune diseases, although conductive hearing impairment may also be present.,Hearing loss may present in a sudden, slowly, rapidly progressive or fluctuating form, and is mostly bilateral and asymmetric.,Hearing loss shows a good response to corticosteroid therapy that may lead to near-complete hearing restoration.,Vestibular symptoms, tinnitus, and aural fullness can be found in patients with systemic autoimmune diseases; they often mimic primary inner ear disorders such as Menière's disease and mainly affect both ears simultaneously.,Awareness of inner ear involvement in systemic autoimmune diseases is essential for the good response shown to appropriate treatment.,However, it is often misdiagnosed due to variable clinical presentation, limited knowledge, sparse evidence, and lack of specific diagnostic tests.,The aim of this review is to analyse available evidence, often only reported in the form of case reports due to the rarity of some of these conditions, of the different clinical presentations of audiological and vestibular symptoms in systemic autoimmune diseases.

Toll-like receptors (TLRs) play critical roles in regulating the abnormal activation of the immune cells resulting in the pathogenesis of inflammation and autoimmune diseases.,Pyruvate kinase M2 (PKM2), which governs the last step of glycolysis, is involved in multiple cellular processes and pathological conditions.,However, little is known about the involvement of PKM2 in regulating TLR-mediated inflammation and autoimmunity.,Herein, we investigated the role of PKM2 in the activation of the TLR pathways and the pathogenesis of inflammation and autoimmune diseases.,The activation of TLR4, TLR7 and TLR9 pathways was found to induce the up-regulation of PKM2 expression in macrophages, dendritic cells (DCs) and B cells.,The over-expression of PKM2 promotes the activation of TLR4, TLR7 and TLR9 pathways while interference with the PKM2 expression or the addition of the PKM2 inhibitor (PKM-IN) markedly inhibited the activation of TLR4, TLR7 and TLR9 pathways.,Mechanistically, PKM2 augmented the activation of TLR4, TLR7 and TLR9 pathways by promoting the activation of the proline-rich tyrosine kinase 2 (Pyk2).,Intriguingly, the PKM2 inhibitor PKM2-IN significantly protected the mice from the endotoxic shock mediated by the TLR4-agonist LPS.,Additionally, it alleviated the progression in the TLR7-agonist imiquimod-mediated lupus mice and spontaneous lupus MRL/lpr mice.,Moreover, PKM2 expression was highly elevated in the monocytes, DCs and B cells from systemic lupus erythematous (SLE) patients compared with those from the healthy donors.,Besides, the PKM2 expression level was positively correlated with the degree of activation of these immune cells.,In summary, PKM2 contributed to TLR-mediated inflammation and autoimmunity and can be a valuable target to control inflammation and autoimmunity.

Dysregulated neutrophil activation contributes to the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).,Neutrophil-derived reactive oxygen species (ROS) and granule proteases are implicated in damage to and destruction of host tissues in both conditions (cartilage in RA, vascular tissue in SLE) and also in the pathogenic post-translational modification of DNA and proteins.,Neutrophil-derived cytokines and chemokines regulate both the innate and adaptive immune responses in RA and SLE, and neutrophil extracellular traps (NETs) expose nuclear neoepitopes (citrullinated proteins in RA, double-stranded DNA and nuclear proteins in SLE) to the immune system, initiating the production of auto-antibodies (ACPA in RA, anti-dsDNA and anti-acetylated/methylated histones in SLE).,Neutrophil apoptosis is dysregulated in both conditions: in RA, delayed apoptosis within synovial joints contributes to chronic inflammation, immune cell recruitment and prolonged release of proteolytic enzymes, whereas in SLE enhanced apoptosis leads to increased apoptotic burden associated with development of anti-nuclear auto-antibodies.,An unbalanced energy metabolism in SLE and RA neutrophils contributes to the pathology of both diseases; increased hypoxia and glycolysis in RA drives neutrophil activation and NET production, whereas decreased redox capacity increases ROS-mediated damage in SLE.,Neutrophil low-density granulocytes (LDGs), present in high numbers in the blood of both RA and SLE patients, have opposing phenotypes contributing to clinical manifestations of each disease.,In this review we will describe the complex and contrasting phenotype of neutrophils and LDGs in RA and SLE and discuss their discrete roles in the pathogenesis of each condition.,We will also review our current understanding of transcriptomic and metabolomic regulation of neutrophil phenotype in RA and SLE and discuss opportunities for therapeutic targeting of neutrophil activation in inflammatory auto-immune disease.

Autoimmune arthritis is characterized by impaired regulatory T (Treg) cell migration into inflamed joint tissue and by dysregulation of the balance between Treg cells and Th17 cells.,Interleukin-6 (IL-6) is known to contribute to this dysregulation, but the molecular mechanisms behind impaired Treg cell migration remain largely unknown.,In this study, we assessed dynamic changes in membrane-bound IL-6 receptor (IL6R) expression levels on Th17 cells by flow cytometry during the development of collagen-induced arthritis (CIA).,In a next step, bioinformatics analysis based on proteomics was performed to evaluate potential pathways affected by altered IL-6R signaling in autoimmune arthritis.,Our analysis shows that membrane-bound IL-6R is upregulated on Th17 cells and is inversely correlated with IL-6 serum levels in experimental autoimmune arthritis.,Moreover, IL-6R expression is significantly increased on Th17 cells from untreated patients with rheumatoid arthritis (RA).,Interestingly, CD4+ T cells from CIA mice and RA patients show reduced phosphorylation of vasodilator-stimulated phosphoprotein (VASP).,Bioinformatics analysis based on proteomics of CD4+ T cells with low or high phosphorylation levels of VASP revealed that integrin signaling and related pathways are significantly enriched in cells with low phosphorylation of VASP.,Specific inhibition of p-VASP reduces the migratory function of Treg cells but has no influence on effector CD4+ T cells.,Importantly, IL-6R blockade restores the phosphorylation level of VASP, thereby improving the migratory function of Treg cells from RA patients.,Thus, our results establish a link between IL6R signaling and phosphorylation of VASP, which controls Treg cell migration in autoimmune arthritis.,The online version contains supplementary material available at 10.1007/s00018-021-04076-2.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS).,In the murine experimental autoimmune encephalomyelitis (EAE) model of MS, T regulatory (Treg) cell therapy has proved to be beneficial, but generation of stable CNS-targeting Tregs needs further development.,Here, we propose gene engineering to achieve CNS-targeting Tregs from naïve CD4 cells and demonstrate their efficacy in the EAE model.,CD4+ T cells were modified utilizing a lentiviral vector system to express a chimeric antigen receptor (CAR) targeting myelin oligodendrocyte glycoprotein (MOG) in trans with the murine FoxP3 gene that drives Treg differentiation.,The cells were evaluated in vitro for suppressive capacity and in C57BL/6 mice to treat EAE.,Cells were administered by intranasal (i.n.) cell delivery.,The engineered Tregs demonstrated suppressive capacity in vitro and could efficiently access various regions in the brain via i.n cell delivery.,Clinical score 3 EAE mice were treated and the engineered Tregs suppressed ongoing encephalomyelitis as demonstrated by reduced disease symptoms as well as decreased IL-12 and IFNgamma mRNAs in brain tissue.,Immunohistochemical markers for myelination (MBP) and reactive astrogliosis (GFAP) confirmed recovery in mice treated with engineered Tregs compared to controls.,Symptom-free mice were rechallenged with a second EAE-inducing inoculum but remained healthy, demonstrating the sustained effect of engineered Tregs.,CNS-targeting Tregs delivered i.n. localized to the CNS and efficiently suppressed ongoing inflammation leading to diminished disease symptoms.

IgG subclass 4-related disease (IgG4-RD) is characterized by increased serum levels of IgG4 and infiltration of biliary, pancreatic, and other tissues by IgG4-positive plasma cells.,We assessed the prevalence of allergy and/or atopy, serum, and tissue IgE antibodies, and blood and tissue eosinophils in patients with IgG4-RD.,We investigated the association between serum IgE and diagnosis and relapse of this disease.,We performed a prospective study of 48 patients with IgG4-RD, 42 patients with an increased serum level of IgG4 with other inflammatory and autoimmune conditions (disease control subjects), and 51 healthy individuals (healthy control subjects) recruited from Oxford, United Kingdom from March 2010 through March 2014, and followed for a median of 41 months (range, 3-73 months).,Serum levels of immunoglobulin were measured at diagnosis, during steroid treatment, and at disease relapse for patients with IgG4-RD; levels at diagnosis were compared with baseline levels of control subjects.,Allergen-specific IgEs were measured using the IgE ImmunoCAP.,Levels and distribution of IgG4 and IgE antibodies in lymphoid, biliary, and pancreatic tissues from patients with IgG4-RD and disease control subjects were measured by immunohistochemistry.,We analyzed data using the Spearman rank correlation and receiver operating characteristic curves.,Serum levels of IgG4 increased to 1.4 g/L or more, and IgE increased to 125 kIU/L or more, in 81% and 54% of patients with IgG4-RD, respectively, compared with 6% and 16% of healthy control subjects (P < .0001).,Peripheral blood eosinophilia was detected in 38% of patients with IgG4-RD versus 9% of healthy control subjects (P = .004).,Of patients with IgG4-RD, 63% had a history of allergy and 40% had a history of atopy with an IgE-specific response; these values were 60% and 53% in patients with increased serum levels of IgE (P < .05).,Level of IgE at diagnosis >480 kIU/L distinguished patients with IgG4-RD from disease control subjects with 86% specificity, 36% sensitivity, and a likelihood ratio of 3.2.,Level of IgE at diagnosis >380 kIU/L identified patients with disease relapse with 88% specificity, 64% sensitivity, and a likelihood ratio of 5.4.,IgE-positive mast cells and eosinophilia were observed in lymphoid, biliary, and pancreatic tissue samples from 50% and 86% of patients with IgG4-RD, respectively.,In a prospective study, we associated IgG4-RD with allergy, atopy, eosinophilia, increased serum levels of IgE, and IgE-positive mast cells in lymphoid, biliary, and pancreatic tissue.,An IgE-mediated allergic response therefore seems to develop in most patients with IgG4-RD; levels of IgE might be used in diagnosis and predicting relapse.

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition, characterised by an elevated serum IgG4 concentration and abundant IgG4-positive plasma cells in the involved organs.,An important question is whether the elevated IgG4 response is causal or a reflection of immune-regulatory mechanisms of the disease.,To investigate if the IgG4 response in IgG4-RD represents a generalised polyclonal amplification by examining the response to common environmental antigens.,Serum from 24 patients with IgG4-RD (14 treatment-naive, 10 treatment-experienced), 9 patients with primary sclerosing cholangitis and an elevated serum IgG4 (PSC-high IgG4), and 18 healthy controls were tested against egg white and yolk, milk, banana, cat, peanut, rice and wheat antigens by radioimmunoassay.,We demonstrated an elevated polyclonal IgG4 response to multiple antigens in patients with IgG4-RD and in PSC-high IgG4, compared with healthy controls.,There was a strong correlation between serum IgG4 and antigen-specific responses.,Responses to antigens were higher in treatment-naive compared with treatment-experienced patients with IgG4-RD.,Serum electrophoresis and immunofixation demonstrated polyclonality.,This is the first study to show enhanced levels of polyclonal IgG4 to multiple antigens in IgG4-RD.,This supports that elevated IgG4 levels reflect an aberrant immunological regulation of the overall IgG4 response, but does not exclude that causality of disease could be antigen-driven.

Our understanding of immune recognition and response to infection and non-infectious forms of cell damage and death is rapidly increasing.,The major focus is on host immunity and microbiological invasion.,However, it is also clear that these same pathways are important in the initiation and maintenance of autoimmunity and the damage caused to targeted organs.,Understanding the involvement of cell death in autoimmune disease is likely to help define critical pathways in the immunopathogenesis of autoimmune disease and new therapeutic targets.,An important immune responder cell population in host defense and autoimmunity is the neutrophil.,One autoimmune disease where neutrophils play important roles is MPO-ANCA Microscopic Vasculitis.,This a severe disease that results from inflammation to small blood vessels in the kidney, the glomeruli (high blood flow and pressure filters).,One of the best studied ways in which neutrophils participate in this disease is by cell death through NETosis resulting in the discharge of proinflammatory enzymes and nuclear fragments.,In host defense against infection this process helps neutralize pathogens however in auto immunity NETosis results in injury and death to the surrounding healthy tissues.,The major autoimmune target in this disease is myeloperoxidase (MPO) which is found uniquely in the cytoplasm of neutrophils.,Although the kidney is the major organ targeted in this disease MPO is not expressed in the kidney.,Autoantibodies target surface MPO on activated circulating neutrophils resulting in their lodgment in glomerular capillaries where they NETose releasing extracellularly MPO and nuclear fragments initiating injury and planting the key autoantigen MPO.,It is the cell death of neutrophils that changes the kidney from innocent bystander to major autoimmune target.,Defining the immunopathogenesis of this autoimmune disease and recognizing critical injurious pathways will allow therapeutic intervention to block these pathways and attenuate autoimmune injury.,The insights (regarding mechanisms of injury and potential therapeutic targets) are likely to be highly relevant to many other autoimmune diseases.

Rheumatoid arthritis (RA) is a systemic immune mediated inflammatory disease of unknown origin, which is predominantly affecting the joints.,Antibodies against citrullinated peptides are a rather specific immunological hallmark of this heterogeneous entity.,Furthermore, certain sequences of the third hypervariable region of human leukocyte antigen (HLA)-DR class II major histocompatibility (MHC) molecules, the so called “shared epitope” sequences, appear to promote autoantibody positive types of RA.,However, MHC-II molecule and other genetic associations with RA could not be linked to immune responses against specific citrullinated peptides, nor do genetic factors fully explain the origin of RA.,Consequently, non-genetic factors must play an important role in the complex interaction of endogenous and exogenous disease factors.,Tobacco smoking was the first environmental factor that was associated with onset and severity of RA.,Notably, smoking is also an established risk factor for oral diseases.,Furthermore, smoking is associated with extra-articular RA manifestations such as interstitial lung disease in anatomical proximity to the airway mucosa, but also with subcutaneous rheumatoid nodules.,In the mouth, Porphyromonas gingivalis is a periodontal pathogen with unique citrullinating capacity of foreign microbial antigens as well as candidate RA autoantigens.,Although the original hypothesis that this single pathogen is causative for RA remained unproven, epidemiological as well as experimental evidence linking periodontitis (PD) with RA is rapidly accumulating.,Other periopathogens such as Aggregatibacter actinomycetemcomitans and Prevotella intermedia were also proposed to play a specific immunodominant role in context of RA.,However, demonstration of T cell reactivity against citrullinated, MHC-II presented autoantigens from RA synovium coinciding with immunity against Prevotella copri (Pc.), a gut microbe attracted attention to another mucosal site, the intestine.,Pc. was accumulated in the feces of clinically healthy subjects with citrulline directed immune responses and was correlated with RA onset.,In conclusion, we retrieved more than one line of evidence for mucosal sites and different microbial taxa to be potentially involved in the development of RA.,This review gives an overview of infectious agents and mucosal pathologies, and discusses the current evidence for causality between different exogenous or mucosal factors and systemic inflammation in RA.

Multiple sclerosis (MS) is an autoimmune disorder where both T cells and B cells are implicated in pathology.,However, it remains unclear how these two distinct populations cooperate to drive disease.,There is ample evidence from studies in both MS patients and mouse models that Th17, B cells, and follicular T helper (TFH) cells contribute to disease.,This review article describes the literature that identifies mechanisms by which Th17, TFH, and B cells cooperatively drive disease activity in MS and experimental autoimmune encephalomyelitis (EAE).,The curation of this literature has identified that central nervous system (CNS) infiltrating TFH cells act with TH17 cell to contribute to an inflammatory B cell response in neuroinflammation.,This demonstrates that TFH cells and their products are promising targets for therapies in MS.

Increasing evidence implicates B cells in the pathogenesis of multiple sclerosis.,Smets et al. report that the CD40 multiple sclerosis risk allele lowers CD40 expression, whereas the CD86 risk allele increases CD86 expression.,B cells may have an important antigen presentation and immunoregulatory role in multiple sclerosis.,The increasing evidence supporting a role for B cells in the pathogenesis of multiple sclerosis prompted us to investigate the influence of known susceptibility variants on the surface expression of co-stimulatory molecules in these cells.,Using flow cytometry we measured surface expression of CD40 and CD86 in B cells from 68 patients and 162 healthy controls that were genotyped for the multiple sclerosis associated single nucleotide polymorphisms (SNPs) rs4810485, which maps within the CD40 gene, and rs9282641, which maps within the CD86 gene.,We found that carrying the risk allele rs4810485*T lowered the cell-surface expression of CD40 in all tested B cell subtypes (in total B cells P ≤ 5.10 × 10−5 in patients and ≤4.09 × 10−6 in controls), while carrying the risk allele rs9282641*G increased the expression of CD86, with this effect primarily seen in the naïve B cell subset (P = 0.048 in patients and 5.38 × 10−5 in controls).,In concordance with these results, analysis of RNA expression demonstrated that the risk allele rs4810485*T resulted in lower total CD40 expression (P = 0.057) but with an increased proportion of alternative splice-forms leading to decoy receptors (P = 4.00 × 10−7).,Finally, we also observed that the risk allele rs4810485*T was associated with decreased levels of interleukin-10 (P = 0.020), which is considered to have an immunoregulatory function downstream of CD40.,Given the importance of these co-stimulatory molecules in determining the immune reaction that appears in response to antigen our data suggest that B cells might have an important antigen presentation and immunoregulatory role in the pathogenesis of multiple sclerosis.

There are reports that stress-related disorders are increasing during coronavirus disease 2019 (COVID-19) pandemic.,Patients with Multiple Sclerosis (MS) are at higher risk of developing psychiatric disorders, which result in worsening of their disability.,There are concerns about the mental health of MS patients during this pandemic.,We aimed to evaluate the prevalence of anxiety, depression, and levels of fear about Corona in MS patients during the COVID-19 pandemic.,This was a cross-sectional study on MS patients who were admitted to the MS clinics affiliated with Isfahan University of medical sciences from May to June 2020.,Anxiety and depression were evaluated according to the Hospital Anxiety and Depression Scale (HADS).,The Corona Fear Questionnaire developed by Ahorsu et al. was applied to evaluate the state of fear about COVID-19.,Chi-square tests were used to compare depression and anxiety between different groups, Kruskal-Wallis was used for fear scores, Spearman correlation coefficient was also reported for correlations.,410 MS patients with a mean age of 38.6 years (±10.35) were enrolled in the study.,Among those patients who answered the HADS questionnaire completely (n=399, n=388, for anxiety and depression subscales respectively) the prevalence of anxiety and depression were 31.2% (n=128) and 39.3% (n=161), respectively.,There was no significant relationship between anxiety and depression with any of the following variables: sex, marital status, history of drug abuse, smoking, duration of taking psychiatric medication, being tested for COVID-19, being quarantined.,Regarding fear about COVID-19, patients with depression or anxiety showed higher scores on the fear questionnaire (p-value=0.03, p-value=0.008 respectively).,The prevalence of anxiety and depression in MS patients was higher than previously reported.,Fear about COVID-19 was correlated with anxiety and depression.,Multicenter studies are required to develop specific recommendations for screening mental health problems in MS patients during COVID pandemic.

•This study evaluates the incidence of COVID-19 in patients with MS, the rate of hospitalization or death in these patients.,•The rate of hospitalization was 25% which is far more than general population.,•Rituximab was associated with increase rate of COVID-19 infection but not with hospitalization rate.,•There was no significant correlation between use of other drugs and rate of infection.,This study evaluates the incidence of COVID-19 in patients with MS, the rate of hospitalization or death in these patients.,The rate of hospitalization was 25% which is far more than general population.,Rituximab was associated with increase rate of COVID-19 infection but not with hospitalization rate.,There was no significant correlation between use of other drugs and rate of infection.,COVID-19 is increasingly expanding all over the world.,People who have an underlying disease or taking immunosuppressive drugs are generally more likely to be infected than the others.,Multiple sclerosis (MS) patients may also be at risk of the disease and its complications depending on the medication they are taking.,In this study, we evaluated a large population of patients with MS with different disease modifying drugs to show if any of them increases the risk.,In addition, this study evaluates the incidence of COVID-19 in patients with MS, the rate of hospitalization or death in these patients.,This study was performed at the MS Clinic of Sina Hospital.,All patients were contacted and their demographic characteristics were recorded.,They were then asked about their COVID-19 symptoms.,Patients with these symptoms were further evaluated.,The documents were reviewed by treating neurologist and MS nurses to be sure about diagnosis of COVID19.,The positive polymerase chain reaction (PCR) result or compatible lung computed tomography (CT) scan was acceptable for COVID-19 diagnosis.,4647 patients answered the phone contact.,Of these, 68 were infected with the COVID-19.,The rate of hospitalization was 25% which is far more than general population.,Two patients died from COVID-19.,Rituximab was associated with increase rate of COVID-19 infection but not with hospitalization rate.,There was no significant correlation between use of other drugs and rate of infection.,This study revealed that the incidence of COVID-19 in MS patients is not more than general population, but the risk of hospitalization in these patients is higher than estimated for the disease.,This highlights the importance of communicating to patients the severity of COVID-19 and the importance of risk reduction behaviors like social distancing and mask use.

Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging.,To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs).,We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population.,In EUR we observed 50 different A-C-B-DRB1-DQA-DQB multilocus haplotype sequences per hundred individuals; in the AA sample, these multilocus haplotypes were twice as common compared to Europeans.,We also observed a strong narrow class II signal in AA as opposed to the long-range LD observed in EUR that includes class I alleles.,We performed a Bayesian model choice of the classical HLA alleles and a frequentist analysis that combined both single nucleotide polymorphisms (SNPs) and classical HLA alleles.,Both analyses converged on a similar subset of risk HLA alleles: in EUR HLA- B*08:01 + B*18:01 + (DRB1*15:01 frequentist only) + DQA*01:02 + DQB*02:01 + DRB3*02 and in AA HLA-C*17:01 + B*08:01 + DRB1*15:03 + (DQA*01:02 frequentist only) + DQA*02:01 + DQA*05:01+ DQA*05:05 + DQB*03:19 + DQB*02:02.,We observed two additional independent SNP associations in both populations: EUR rs146903072 and rs501480; AA rs389883 and rs114118665.,The DR2 serotype was best explained by DRB1*15:03 + DQA*01:02 in AA and by DRB1*15:01 + DQA*01:02 in EUR.,The DR3 serotype was best explained by DQA*05:01 in AA and by DQB*02:01 in EUR.,Despite some differences in underlying HLA allele risk models in EUR and AA, SNP signals across the extended MHC showed remarkable similarity and significant concordance in direction of effect for risk-associated variants.

DNA sequence variation within human leukocyte antigen (HLA) genes mediate susceptibility to a wide range of human diseases.,The complex genetic structure of the major histocompatibility complex (MHC) makes it difficult, however, to collect genotyping data in large cohorts.,Long-range linkage disequilibrium between HLA loci and SNP markers across the major histocompatibility complex (MHC) region offers an alternative approach through imputation to interrogate HLA variation in existing GWAS data sets.,Here we describe a computational strategy, SNP2HLA, to impute classical alleles and amino acid polymorphisms at class I (HLA-A, -B, -C) and class II (-DPA1, -DPB1, -DQA1, -DQB1, and -DRB1) loci.,To characterize performance of SNP2HLA, we constructed two European ancestry reference panels, one based on data collected in HapMap-CEPH pedigrees (90 individuals) and another based on data collected by the Type 1 Diabetes Genetics Consortium (T1DGC, 5,225 individuals).,We imputed HLA alleles in an independent data set from the British 1958 Birth Cohort (N = 918) with gold standard four-digit HLA types and SNPs genotyped using the Affymetrix GeneChip 500 K and Illumina Immunochip microarrays.,We demonstrate that the sample size of the reference panel, rather than SNP density of the genotyping platform, is critical to achieve high imputation accuracy.,Using the larger T1DGC reference panel, the average accuracy at four-digit resolution is 94.7% using the low-density Affymetrix GeneChip 500 K, and 96.7% using the high-density Illumina Immunochip.,For amino acid polymorphisms within HLA genes, we achieve 98.6% and 99.3% accuracy using the Affymetrix GeneChip 500 K and Illumina Immunochip, respectively.,Finally, we demonstrate how imputation and association testing at amino acid resolution can facilitate fine-mapping of primary MHC association signals, giving a specific example from type 1 diabetes.

Conventional pharmacological therapies for the treatment of juvenile idiopathic arthritis (JIA) consist of non-biological, disease-modifying antirheumatic drugs, among which methotrexate (MTX) is the most commonly prescribed.,However, there is a lack of consensus-based clinical and therapeutic recommendations for the use of MTX in the management of patients with JIA.,Therefore, the Methotrexate Advice and RecommendAtions on Juvenile Idiopathic Arthritis (MARAJIA) Expert Meeting was convened to develop evidence-based recommendations for the use of MTX in the treatment of JIA.,The preliminary executive committee identified a total of 9 key clinical issues according to the population, intervention, comparator, outcome (PICO) approach, and performed an evidence-based, systematic, literature review.,During the subsequent Expert Meeting, the relevant evidence was assessed and graded, and 10 recommendations were made.,Recommendations relating to the efficacy, optimal dosing and route of administration and duration of treatment with MTX in JIA, and to the issue of folic acid supplementation to prevent MTX side effects, use of MTX in the treatment of chronic JIA-associated uveitis, combination treatment with biologic agents, and the use of vaccinations in patients with JIA were developed.,The selected topics were considered to represent clinically important issues facing clinicians caring for patients with JIA.,Evidence was insufficient to formulate recommendations for the use of biomarkers predictive of treatment response.,These consensus recommendations provide balanced and evidence-based recommendations designed to have broad value for physicians and healthcare clinicians involved in the clinical management of patients with JIA.

There is a worldwide variation in the prevalence and subtype distribution of juvenile idiopathic arthritis (JIA) which may be affected by ethnicity and genetic factors.,The purpose of this study is to determine the prevalence, subtype distribution and characteristic features of JIA among Omani children and to compare our results with other ethnic populations worldwide.,A population-based, multicenter study among pediatric rheumatology clinics in the Sultanate over a 10 year period between 2004-2013.,The diagnosis of JIA and identification of JIA subtypes was based on the ILAR 2004 revised criteria.,The hospital charts of these patients were retrospectively reviewed and information was collected.,All patients were screened for uveitis by an ophthalmologist using slit lamp examination during regular follow up visits.,The study included a total of 107 cases of JIA in Oman over the study period.,Among the 107 patients, 71 % (n = 77) were girls with a female:male ratio of 2.5:1.,The mean age of disease onset was 6.85 ± 3.86 years (range 1-13years) while the mean disease duration of 4.8 ± 2.9 years (range 1-11 years).,The incidence of JIA was estimated at 2/100,000 with a prevalence of JIA of 20/100,000.,The prevalence of JIA in girls was 28/100,000 while the prevalence in boys was 12/100,000.,According to disease distribution, the most frequent subtype was polyarticular JIA rheumatoid factor negative (39.2 %) followed by oligoarthritis (31.8 %), systemic (17.8 %), polyarticular JIA rheumatoid factor positive (7.5 %).,The unique feature of the Omani cohort is the lack of occurrence of uveitis.,This is the first epidemiological JIA study conducted in Oman that highlights unique geographical disease phenotype.,Compared to Western counties, there were higher frequency of polyarticular disease and lack of occurrence of uveitis.,Further studies are needed to evaluate the implications of genetic, ethnic and environmental differences of disease expression.

The incidence of diabetes mellitus is rapidly increasing throughout the world.,Although the exact cause of the disease is not fully clear, perhaps, genetics, ethnic origin, obesity, age, and lifestyle are considered as few of many contributory factors for the disease pathogenesis.,In recent years, the disease progression is particularly linked with functional and taxonomic alterations in the gastrointestinal tract microbiome.,A change in microbial diversity, referred as microbial dysbiosis, alters the gut fermentation profile and intestinal wall integrity and causes metabolic endotoxemia, low-grade inflammation, autoimmunity, and other affiliated metabolic disorders.,This article aims to summarize the role of the gut microbiome in the pathogenesis of diabetes.,Additionally, we summarize gut microbial dysbiosis in preclinical and clinical diabetes cases reported in literature in the recent years.

The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D).,During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GAD antibody, IA-2A, or micro insulin autoantibodies) and 84 of them progressed to T1D.,We genotyped 5,164 Caucasian children for 41 non-HLA single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with T1D in the genome-wide association scan meta-analysis conducted by the Type 1 Diabetes Genetics Consortium.,In TEDDY participants carrying high-risk HLA genotypes, eight SNPs achieved significant association to development of IA using time-to-event analysis (P < 0.05), whereof four were significant after adjustment for multiple testing (P < 0.0012): rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27-1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14-1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19-1.61]), and rs1004446 in INS (HR 0.77 [0.66-0.90]).,These SNPs were also significantly associated with T1D in particular: rs2476601 (HR 2.42 [95% CI 1.70-3.44]).,Although genes in the HLA region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease.

Although women with rheumatoid arthritis (RA) face a number of challenges in negotiating the journey to parenthood, no studies have explored the information needs of women with RA in relation to their childbearing years.,This study aimed to determine the need for (and preferred mode/s of delivery of) information regarding pregnancy, post-natal care and early parenting among women with RA.,Interviews and focus groups were conducted with 27 women with RA who were pregnant in the last 5 years, currently pregnant or planning pregnancy.,Verbatim transcripts were analysed using both inductive and deductive approaches.,Two validated instruments were used to quantify information needs and preferences: the Educational Needs Assessment Tool (ENAT, range 0-156, higher scores indicate higher educational needs) and the Autonomy Preference Index (API, range 0-100, higher scores indicate stronger preferences).,Lack of information about medication safety, access to physical/emotional support services and practical strategies for coping with daily challenges related to parenting were the most prominent of the six key themes identified.,Rheumatologists were the primary source for information regarding treatment decisions while arthritis consumer organisations were perceived as critical ‘resource hubs’.,There was strong preference for information delivered electronically, especially among rural participants.,Quantitative outcomes supported the qualitative findings; on average, participants reported high educational needs (mean ENAT score 97.2, SD 30.8) and API scores indicated that desire for information (mean 89.8, SD 5.6) was greater than the need for involvement in treatment decision-making (mean 68.4, SD 8.2).,Many women with RA struggle to find adequate information on pregnancy planning, pregnancy and early parenting in relation to their chronic condition, and there is a clear need to develop accessible information that is consumer-focused and evidence-based.,Although most participants trusted their rheumatologist as their primary information source, there was consistent demand for more information, particularly regarding the safety of RA medications during pregnancy and breastfeeding, and the importance of learning from other women’s personal experiences was strongly emphasised.,The online version of this article (doi:10.1186/s12891-015-0657-4) contains supplementary material, which is available to authorized users.

The eumusc.net project is a European Union (EU) commission and European League Against Rheumatism (EULAR)funded project that aims to facilitate equal standards for musculoskeletal health in all EU countries.,One work-package was to develop evidence-based and patient-centred standards of care (SOC), for rheumatoid arthritis (RA) understandable for patients and professionals across Europe.,A review of documents covering clinical practice ‘guidelines’ and SOC for RA was conducted.,The obtained documents were evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) criteria, and all recommended methods to treat RA were extracted.,Based on this information, a three-round Delphi exercise was performed including a consensus group meeting of 21 researchers and patient representatives.,16 patient-centred SOC were formulated including a lay version in the format of a checklist.,An example is SOC 3: ‘People with RA should receive a treatment plan developed individually between them and their clinician at each visit.’,The corresponding checklist question reads: ‘Have I received a treatment plan which includes an explanation of my management, expected goals and outcomes and important contact details?’,The SOC for RA will be available in all 23 official European languages and contribute to more unified treatment approaches in Europe.

There is strong evidence for an involvement of different classes of non-coding RNAs, including microRNAs and long non-coding RNAs, in the regulation of β-cell activities and in diabetes development.,Circular RNAs were recently discovered to constitute a substantial fraction of the mammalian transcriptome but the contribution of these non-coding RNAs in physiological and disease processes remains largely unknown.,The goal of this study was to identify the circular RNAs expressed in pancreatic islets and to elucidate their possible role in the control of β-cells functions.,We used a microarray approach to identify circular RNAs expressed in human islets and searched their orthologues in RNA sequencing data from mouse islets.,We then measured the level of four selected circular RNAs in the islets of different Type 1 and Type 2 diabetes models and analyzed the role of these circular transcripts in the regulation of insulin secretion, β-cell proliferation, and apoptosis.,We identified thousands of circular RNAs expressed in human pancreatic islets, 497 of which were conserved in mouse islets.,The level of two of these circular transcripts, circHIPK3 and ciRS-7/CDR1as, was found to be reduced in the islets of diabetic db/db mice.,Mimicking this decrease in the islets of wild type animals resulted in impaired insulin secretion, reduced β-cell proliferation, and survival. ciRS-7/CDR1as has been previously proposed to function by blocking miR-7.,Transcriptomic analysis revealed that circHIPK3 acts by sequestering a group of microRNAs, including miR-124-3p and miR-338-3p, and by regulating the expression of key β-cell genes, such as Slc2a2, Akt1, and Mtpn.,Our findings point to circular RNAs as novel regulators of β-cell activities and suggest an involvement of this novel class of non-coding RNAs in β-cell dysfunction under diabetic conditions.,•β-cells express thousands of abundant circRNAs.•ciRS-7 and circHIPK3 display altered expression in Type 2 diabetes models.•ciRS-7 controls β-cell proliferation and insulin secretion.•circHIPK3 silencing impairs β-cell proliferation, β-cell survival and insulin secretion.•circHIPK3 appears to control β-cell gene expression by sequestering a group of miRNAs.,β-cells express thousands of abundant circRNAs.,ciRS-7 and circHIPK3 display altered expression in Type 2 diabetes models.,ciRS-7 controls β-cell proliferation and insulin secretion.,circHIPK3 silencing impairs β-cell proliferation, β-cell survival and insulin secretion.,circHIPK3 appears to control β-cell gene expression by sequestering a group of miRNAs.

Long noncoding RNAs (lncRNAs) have recently received wide attention as key molecules that mediate a variety of physiological and pathological processes by regulating gene expression; however, knowledge of lncRNAs in rheumatoid arthritis (RA) is limited.,Thus, we investigated the lncRNA expression profile in fibroblast-like synoviocytes (FLSs) from patients with RA and explored the function of abundantly expressed lncRNAs.,LncRNA and mRNA microarrays were performed to identify differentially expressed lncRNAs in RA FLSs compared with normal FLSs.,Quantitative polymerase chain reaction (qPCR) was used to validate the results, and correlation analysis was used to analyze the relationship between these aberrantly expressed lncRNAs and clinical characteristics.,A receiver operating characteristic (ROC) curve was constructed to evaluate the diagnostic value of the lncRNAs identified.,According to the gene expression profiles, 135 lncRNAs were differentially expressed between RA and normal FLSs.,Furthermore, qPCR data showed that lncRNA ENST00000483588 was up-regulated and that three lncRNAs (ENST00000438399, uc004afb.1, and ENST00000452247) were down-regulated in RA FLSs.,The expression level of ENST00000483588 was positively correlated with the level of C-reactive protein and the Simplified Disease Activity Index score.,Moreover, the areas under the ROC curve were 0.85, 0.92, 0.97, and 0.92 for ENST00000483588, ENST00000438399, uc004afb.1, and ENST00000452247, respectively.,The results indicate that the dysregulation of ENST00000483588, ENST00000438399, uc004afb.1, and ENST00000452247 may be involved in the pathological processes of RA and that these lncRNAs may have potential value for the diagnosis and assessment of the disease activity of RA.,The online version of this article (doi:10.1186/s13075-016-1129-4) contains supplementary material, which is available to authorized users.

As treatment options in advanced systematic lupus erythematosus (SLE) are limited, there is an urgent need for new and effective therapeutic alternatives for selected cases with severe disease.,Bortezomib (BTZ) is a specific, reversible, inhibitor of the 20S subunit of the proteasome.,Herein, we report clinical experience regarding efficacy and safety from all patients receiving BTZ as therapy for SLE in Sweden during the years 2014−2020. 8 females and 4 males were included with a mean disease duration at BTZ initiation of 8.8 years (range 0.7-20 years).,Renal involvement was the main target for BTZ.,Reduction of global disease activity was recorded by decreasing SLEDAI-2K scores over time and remained significantly reduced at the 6-month (p=0.007) and the 12-month (p=0.008) follow-up visits.,From BTZ initiation, complement protein 3 (C3) levels increased significantly after the 2nd treatment cycle (p=0.05), the 6-month (p=0.03) and the 12-month (p=0.04) follow-up visits.,The urine albumin/creatinine ratio declined over time and reached significance at the 6-month (p=0.008) and the 12-month follow-up visits (p=0.004).,Seroconversion of anti-dsDNA (27%), anti-C1q (50%) and anti-Sm (67%) was observed. 6 of 12 patients experienced at least one side-effect during follow-up, whereof the most common adverse events were infections.,Safety parameters (C-reactive protein, blood cell counts) mainly remained stable over time.,To conclude, we report favorable therapeutic effects of BTZ used in combination with corticosteroids in a majority of patients with severe SLE manifestations irresponsive to conventional immunosuppressive agents.,Reduction of proteinuria was observed over time as well as seroconversion of some autoantibody specificities.,In most patients, tolerance was acceptable but mild adverse events was not uncommon.,Special attention should be paid to infections and hypogammaglobinemia.

To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double‐blind, placebo‐controlled study of adults with moderate‐to‐severe systemic lupus erythematosus (SLE).,Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks.,Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4‐gene expression assay.,The primary end point was the percentage of patients achieving an SLE Responder Index (SRI[4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24).,Other end points (including SRI[4], British Isles Lupus Assessment Group [BILAG]-based Composite Lupus Assessment [BICLA], modified SRI[6], and major clinical response) were assessed at week 52.,The primary end point was analyzed in the modified intent‐to‐treat (ITT) population and type I IFN-high subpopulation.,The study result was considered positive if the primary end point was met in either of the 2 study populations.,The Type I error rate was controlled at 0.10 (2‐sided), within each of the 2 study populations for the primary end point analysis.,The primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo‐treated patients versus 36.0% [P = 0.004] and 28.2% [P = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively.,At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P < 0.001] and 53.8% [P = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P < 0.001] and 41.2% [P = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P = 0.002] and 44.7% [P = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P = 0.012] and 17.3% [P = 0.025], respectively), and several other global and organ‐specific end points.,Herpes zoster was more frequent in the anifrolumab‐treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups.,Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively).,Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate‐to‐severe SLE.

Autoimmune disease has presented an insurmountable barrier to restoration of durable immune tolerance.,Previous studies indicate that chronic therapy with metabolic inhibitors can reduce autoimmune inflammation, but it remains unknown whether acute metabolic modulation enables permanent immune tolerance to be established.,In an animal model of lupus, we determined that targeting glucose metabolism with 2-deoxyglucose (2DG) and mitochondrial metabolism with metformin enables endogenous immune tolerance mechanisms to respond to tolerance induction.,A 2-week course of 2DG and metformin, when combined with tolerance-inducing therapy anti-CD45RB, prevented renal deposition of autoantibodies for 6 months after initial treatment and restored tolerance induction to allografts in lupus-prone mice.,The restoration of durable immune tolerance was linked to changes in T cell surface glycosylation patterns, illustrating a role for glycoregulation in immune tolerance.,These findings indicate that metabolic therapy may be applied as a powerful preconditioning to reinvigorate tolerance mechanisms in autoimmune and transplant settings that resist current immune therapies.

Toll-like receptors (TLRs) play critical roles in regulating the abnormal activation of the immune cells resulting in the pathogenesis of inflammation and autoimmune diseases.,Pyruvate kinase M2 (PKM2), which governs the last step of glycolysis, is involved in multiple cellular processes and pathological conditions.,However, little is known about the involvement of PKM2 in regulating TLR-mediated inflammation and autoimmunity.,Herein, we investigated the role of PKM2 in the activation of the TLR pathways and the pathogenesis of inflammation and autoimmune diseases.,The activation of TLR4, TLR7 and TLR9 pathways was found to induce the up-regulation of PKM2 expression in macrophages, dendritic cells (DCs) and B cells.,The over-expression of PKM2 promotes the activation of TLR4, TLR7 and TLR9 pathways while interference with the PKM2 expression or the addition of the PKM2 inhibitor (PKM-IN) markedly inhibited the activation of TLR4, TLR7 and TLR9 pathways.,Mechanistically, PKM2 augmented the activation of TLR4, TLR7 and TLR9 pathways by promoting the activation of the proline-rich tyrosine kinase 2 (Pyk2).,Intriguingly, the PKM2 inhibitor PKM2-IN significantly protected the mice from the endotoxic shock mediated by the TLR4-agonist LPS.,Additionally, it alleviated the progression in the TLR7-agonist imiquimod-mediated lupus mice and spontaneous lupus MRL/lpr mice.,Moreover, PKM2 expression was highly elevated in the monocytes, DCs and B cells from systemic lupus erythematous (SLE) patients compared with those from the healthy donors.,Besides, the PKM2 expression level was positively correlated with the degree of activation of these immune cells.,In summary, PKM2 contributed to TLR-mediated inflammation and autoimmunity and can be a valuable target to control inflammation and autoimmunity.

Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown.,Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data.,We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4+ T-cell subsets, regulatory T-cells, CD8+ T-cells, B-cells, and monocytes.,We find that ~90% of causal variants are noncoding, with ~60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation.,Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs.,Rather, most noncoding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

Analysis of the ImmunoChip single nucleotide polymorphism (SNP) array in 2816 individuals, comprising the most common subtypes (oligoarticular and RF negative polyarticular) of juvenile idiopathic arthritis (JIA) and 13056 controls strengthens the evidence for association to three known JIA-risk loci (HLA, PTPN22 and PTPN2) and has identified fourteen risk loci reaching genome-wide significance (p < 5 × 10-8) for the first time.,Eleven additional novel regions showed suggestive evidence for association with JIA (p < 1 × 10-6).,Dense-mapping of loci along with bioinformatic analysis has refined the association to one gene for eight regions, highlighting crucial pathways, including the IL-2 pathway, in JIA disease pathogenesis.,The entire ImmunoChip loci, HLA region and the top 27 loci (p < 1 × 10-6) explain an estimated 18%, 13% and 6% risk of JIA, respectively.,Analysis of the ImmunoChip dataset, the largest cohort of JIA cases investigated to date, provides new insight in understanding the genetic basis for this childhood autoimmune disease.

Whether patients with inflammatory rheumatic and musculoskeletal diseases (RMD) are at higher risk to develop severe courses of COVID-19 has not been fully elucidated.,Aim of this analysis was to describe patients with RMD according to their COVID-19 severity and to identify risk factors for hospitalisation.,Patients with RMD with PCR confirmed SARS-CoV-2 infection reported to the German COVID-19 registry from 30 March to 1 November 2020 were evaluated.,Multivariable logistic regression was used to estimate ORs for hospitalisation due to COVID-19.,Data from 468 patients with RMD with SARS-CoV-2 infection were reported.,Most frequent diagnosis was rheumatoid arthritis, RA (48%). 29% of the patients were hospitalised, 5.5% needed ventilation. 19 patients died.,Multivariable analysis showed that age >65 years (OR 2.24; 95% CI 1.12 to 4.47), but even more>75 years (OR 3.94; 95% CI 1.86 to 8.32), cardiovascular disease (CVD; OR 3.36; 95% CI 1.5 to 7.55), interstitial lung disease/chronic obstructive pulmonary disease (ILD/COPD) (OR 2.79; 95% CI 1.2 to 6.49), chronic kidney disease (OR 2.96; 95% CI 1.16 to 7.5), moderate/high RMD disease activity (OR 1.96; 95% CI 1.02 to 3.76) and treatment with glucocorticoids (GCs) in dosages >5 mg/day (OR 3.67; 95% CI 1.49 to 9.05) were associated with higher odds of hospitalisation.,Spondyloarthritis patients showed a smaller risk of hospitalisation compared with RA (OR 0.46; 95% CI 0.23 to 0.91).,Age was a major risk factor for hospitalisation as well as comorbidities such as CVD, ILD/COPD, chronic kidney disease and current or prior treatment with GCs.,Moderate to high RMD disease activity was also an independent risk factor for hospitalisation, underlining the importance of continuing adequate RMD treatment during the pandemic.

Patients with rheumatoid arthritis (RA), including those treated with biologics, are at increased risk of some vaccine-preventable infections.,We evaluated the antibody response to standard 23-valent pneumococcal polysaccharide vaccine (PPSV23) and the 2011-2012 trivalent seasonal influenza vaccine in adults with RA receiving subcutaneous (SC) abatacept and background disease-modifying anti-rheumatic drugs (DMARDs).,Two multicenter, open-label sub-studies enrolled patients from the ACQUIRE (pneumococcal and influenza) and ATTUNE (pneumococcal) studies at any point during their SC abatacept treatment cycle following completion of ≥3 months’ SC abatacept.,All patients received fixed-dose abatacept 125 mg/week with background DMARDs.,A pre-vaccination blood sample was taken, and after 28 ± 3 days a final post-vaccination sample was collected.,The primary endpoint was the proportion of patients achieving an immunologic response to the vaccine at Day 28 among patients without a protective antibody level to the vaccine antigens at baseline (pneumococcal: defined as ≥2-fold increase in post-vaccination titers to ≥3 of 5 antigens and protective antibody level of ≥1.6 μg/mL to ≥3 of 5 antigens; influenza: defined as ≥4-fold increase in post-vaccination titers to ≥2 of 3 antigens and protective antibody level of ≥1:40 to ≥2 of 3 antigens).,Safety and tolerability were evaluated throughout the sub-studies.,Pre- and post-vaccination titers were available for 113/125 and 186/191 enrolled patients receiving the PPSV23 and influenza vaccine, respectively.,Among vaccinated patients, 47/113 pneumococcal and 121/186 influenza patients were without protective antibody levels at baseline.,Among patients with available data, 73.9 % (34/46) and 61.3 % (73/119) met the primary endpoint and achieved an immunologic response to PPSV23 or influenza vaccine, respectively.,In patients with pre- and post-vaccination data available, 83.9 % in the pneumococcal study demonstrated protective antibody levels with PPSV23 (titer ≥1.6 μg/mL to ≥3 of 5 antigens), and 81.2 % in the influenza study achieved protective antibody levels (titer ≥1:40 to ≥2 of 3 antigens) at Day 28 post-vaccination.,Vaccines were well tolerated with SC abatacept with background DMARDs.,In these sub-studies, patients with RA receiving SC abatacept and background DMARDs were able to mount an appropriate immune response to pneumococcal and influenza vaccines.,NCT00559585 (registered 15 November 2007) and NCT00663702 (registered 18 April 2008).,The online version of this article (doi:10.1186/s12891-016-1082-z) contains supplementary material, which is available to authorized users.

Phase III clinical trials of the tumour necrosis factor inhibitors SB4, SB2, and SB5 (biosimilars to etanercept, infliximab, and adalimumab, respectively) have demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA).,Data from these trials were used to identify baseline characteristics associated with radiographic progression and to build a matrix risk model for its prediction.,Patients with radiographic progression and baseline demographic and disease characteristic data were pooled across the 3 phase III studies of each biosimilar and its reference product.,Baseline demographics and disease characteristics were evaluated for their relationship with radiographic progression (1-year mean change in mTSS > 0); 3 factors were selected based on strongest Pearson’s correlation coefficient with the change in modified Total Sharp Score.,Univariate logistic regression was performed to assess the association between each baseline factor and the rate of radiographic progression, with subsequent matrix model development performed using multivariate logistic regression.,A total of 1371 patients were included in the analysis, with a radiographic progression rate of 27.4%.,The 3 baseline predictors of radiographic progression, based on Pearson’s correlation coefficient, were 28 swollen joint count (SJC28), C-reactive protein (CRP), and physician global assessment (PhGA).,A matrix model showed that the predicted risk of radiographic progression was higher with the increased level of SJC28, CRP, and PhGA (P < 0.001).,In this pooled analysis of phase III clinical trial data of biosimilars for RA, identifiable baseline factors (SJC28, CRP, and PhGA) associated with radiographic progression were similar to those described in prior studies.,Even though radiographic progression was minimal, a small number of patients who have increased SJC28, CRP, and PhGA at baseline should be closely monitored and follow treat-to-target approach.,EudraCT 2012-005026-30.,Registered 30 April 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005026-30/results,EudraCT 2012-005733-37.,Registered 10 July 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005733-37/results,EudraCT 2013-005013-13.,Registered 01 April 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-005013-13/results

Interleukin (IL)-12 and IL-23 have been implicated in the pathogenesis of rheumatoid arthritis (RA).,The safety and efficacy of ustekinumab, a human monoclonal anti-IL-12/23 p40 antibody, and guselkumab, a human monoclonal anti-IL-23 antibody, were evaluated in adults with active RA despite methotrexate (MTX) therapy.,Patients were randomly assigned (1:1:1:1:1) to receive placebo at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 8 weeks (n=55), ustekinumab 90 mg at weeks 0, 4 and every 12 weeks (n=55), guselkumab 50 mg at weeks 0, 4 and every 8 weeks (n=55), or guselkumab 200 mg at weeks 0, 4 and every 8 weeks (n=54) through week 28; all patients continued a stable dose of MTX (10-25 mg/week).,The primary end point was the proportion of patients with at least a 20% improvement in the American College of Rheumatology criteria (ACR 20) at week 28.,Safety was monitored through week 48.,At week 28, there were no statistically significant differences in the proportions of patients achieving an ACR 20 response between the combined ustekinumab group (53.6%) or the combined guselkumab group (41.3%) compared with placebo (40.0%) (p=0.101 and p=0.877, respectively).,Through week 48, the proportions of patients with at least one adverse event (AE) were comparable among the treatment groups.,Infections were the most common type of AE.,Treatment with ustekinumab or guselkumab did not significantly reduce the signs and symptoms of RA.,No new safety findings were observed with either treatment.,NCT01645280.

The POInT study, an investigator initiated, randomised, placebo-controlled, double-blind, multicentre primary prevention trial is conducted to determine whether daily administration of oral insulin, from age 4.0 months to 7.0 months until age 36.0 months to children with elevated genetic risk for type 1 diabetes, reduces the incidence of beta-cell autoantibodies and diabetes.,Infants aged 4.0 to 7.0 months from Germany, Poland, Belgium, UK and Sweden are eligible if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies as determined by genetic risk score or family history and human leucocyte antigen genotype.,Infants are randomised 1:1 to daily oral insulin (7.5 mg for 2 months, 22.5 mg for 2 months, 67.5 mg until age 36.0 months) or placebo, and followed for a maximum of 7 years.,Treatment and follow-up is stopped if a child develops diabetes.,The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies or diabetes.,Other outcomes are: (1) Any persistent confirmed beta-cell autoantibody (glutamic acid decarboxylase (GADA), IA-2A, autoantibodies to insulin (IAA) and zinc transporter 8 or tetraspanin 7), or diabetes, (2) Persistent confirmed IAA, (3) Persistent confirmed GADA and (4) Abnormal glucose tolerance or diabetes.,The study is approved by the ethical committees of all participating clinical sites.,The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial.,NCT03364868.

Diabetes (DM) as well as obesity, due to their increasing incidence, were recognized as epidemic by the World Health Organization.,Obesity is involved not only in the aetiopathogenesis of the most common worldwide type of DM-type 2 diabetes-but also in the development of its complications.,There is also increasing scientific evidence regarding the role of obesity and overweight in type 1 diabetes.,Weight gain may be considered as a complication of insulin treatment but also reveals significant pathophysiological impact on various stages of the disease.,Another very important aspect related to DM as well as obesity is the microbiome, which is highly variable.,The function of the gut microflora, its interaction with the whole organism, and its role in the development of obesity and type 1 diabetes as well as type 2 diabetes are still not fully understood and subject of ongoing investigations.,This review presents a summary of recently published results concerning the relation of obesity/overweight and DM as well as their associations with the microbiome.

It is suspected that patients with multiple sclerosis (MS) are at greater risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection due to disability and immunotherapy.,The relationship between MS and coronavirus disease 2019 (COVID-19) is uncertain.,The aim of the study was to collect and analyze this relationship.,All MS patients of the Neurological Outpatient Clinic in Zabrze, Poland, were regularly questioned for the symptoms of COVID-19 and contact with an infected person.,Patients that presented with COVID-19 symptoms or confirmed contact with an infected person were referred for the COVID-19 test.,All patients with confirmed SARS-CoV-2 infection (n = 41) were included in the analysis.,Medical records of the study group were analyzed.,Patient condition was monitored in the outpatient clinic after recovery.,In 26 subjects, additional examinations, including brain magnetic resonance imaging (MRI), electroneurography (ENG), electroencephalography (EEG), color duplex Doppler (CDD), visual evoked potentials (VEPs), brainstem auditory evoked potentials (BAEPs) and psychological assessment were performed following recovery.,Only one patient required hospitalization during COVID-19 infection, whereas 87.80% of patients did not require treatment for COVID-19.,In all patients, C-reactive protein (CRP) levels were below 10 mg/L.,In 2.44% of patients, oxygen partial pressure was below 95%.,In most MS patients, the results of further examinations after COVID-19 infection were similar to those prior to infection.,Psychological assessment revealed that anxiety was found in 42.31% of patients.,A mild course of COVID-19 in MS patients seems common despite disease-modifying drug treatment and disability.,Self-isolation is recommended to reduce the number of infected patients.,COVID-19 infection did not worsen the course of MS in most subjects.,Patients with MS may require additional psychological support during the pandemic due to their susceptibility to anxiety.

The use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) could affect COVID-19 outcomes by modulating the immune response, which, in turn, might favor viral replication and/or confer protection from COVID-19 induced inflammatory response,We report on two MS patients treated with cladribine, with heterogeneous demographics and clinical features, who developed mild or no symptoms from COVID-19 and produced anti-SARS-CoV-2 antibodies, notwithstanding low lymphocyte levels.,Benign COVID-19 clinical course and anti-SARS-CoV-2 antibody production can occur in MS patients with lymphopenia, suggesting the possibility to respond to COVID-19 vaccination, once available, in this vulnerable population.

The aim of this multicentre, randomised, controlled crossover study was to determine the efficacy of adding continuous glucose monitoring (CGM) to insulin pump therapy (CSII) in type 1 diabetes.,Children and adults (n = 153) on CSII with HbA1c 7.5-9.5% (58.5-80.3 mmol/mol) were randomised to (CGM) a Sensor On or Sensor Off arm for 6 months.,After 4 months’ washout, participants crossed over to the other arm for 6 months.,Paediatric and adult participants were separately electronically randomised through the case report form according to a predefined randomisation sequence in eight secondary and tertiary centres.,The primary outcome was the difference in HbA1c levels between arms after 6 months.,Seventy-seven participants were randomised to the On/Off sequence and 76 to the Off/On sequence; all were included in the primary analysis.,The mean difference in HbA1c was -0.43% (-4.74 mmol/mol) in favour of the Sensor On arm (8.04% [64.34 mmol/mol] vs 8.47% [69.08 mmol/mol]; 95% CI −0.32%, −0.55% [−3.50, −6.01 mmol/mol]; p < 0.001).,Following cessation of glucose sensing, HbA1c reverted to baseline levels.,Less time was spent with sensor glucose <3.9 mmol/l during the Sensor On arm than in the Sensor Off arm (19 vs 31 min/day; p = 0.009).,The mean number of daily boluses increased in the Sensor On arm (6.8 ± 2.5 vs 5.8 ± 1.9, p < 0.0001), together with the frequency of use of the temporary basal rate (0.75 ± 1.11 vs 0.26 ± 0.47, p < 0.0001) and manual insulin suspend (0.91 ± 1.25 vs 0.70 ± 0.75, p < 0.018) functions.,Four vs two events of severe hypoglycaemia occurred in the Sensor On and Sensor Off arm, respectively (p = 0.40).,Continuous glucose monitoring was associated with decreased HbA1c levels and time spent in hypoglycaemia in individuals with type 1 diabetes using CSII.,More frequent self-adjustments of insulin therapy may have contributed to these effects.,ClinicalTrials.gov registration no.,NCT00598663.,The study was funded by Medtronic International Trading Sarl Switzerland.

To compare the effect of the prepubertal duration of diabetes on the occurrence of complications in two groups of patients after the same number of years of the disease.,This multicenter study enrolled 105 patients aged 16-40.3 years; 53 were prepubertal at diagnosis (aged 0-3) and 52 were pubertal (Tanner stage) and aged 9-14.9.,The mean duration of disease was 19.8 and 19.5 years for prepubertal and pubertal patients, respectively.,In all patients, retinal photographs were taken and centrally graded.,Urinary albumin excretion (UAE; 86 case subjects), blood pressure (BP; 89 case subjects), and lifetime HbA1c (72 case subjects) were also evaluated.,The prevalence of diabetic retinopathy (DR) was higher in pubertal than in prepubertal patients, both for any grade DR (71 vs.,40%, P = 0.002) and for mild or more severe DR (P = 0.005).,The prevalence of abnormal UAE was not different in the two groups.,Hypertension was found only in three patients, all pubertal at diagnosis.,In the small group with moderate-to-severe DR, lifetime HbA1c levels, as percentages above the upper normal reference value, were higher (P < 0.01) in prepubertal than in pubertal patients.,If diabetes is diagnosed in infants or toddlers and the prepubertal duration of diabetes is very long, the patients seem to be protected against DR.,This protection disappears if lifetime metabolic control is bad.,Instead, when onset is at puberty, the DR risk is higher and less dependent on metabolic control and may be influenced by age-related factors, such as BP.

We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D).,Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect.,Of 112 subjects (ages 6-36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years.,The primary outcome-baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years-showed higher C-peptide with abatacept versus placebo.,Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months.,C-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168-0.268) and 0.141 nmol/L (95% CI 0.071-0.215) for abatacept and placebo groups, respectively (P = 0.046).,The C-peptide decline from baseline remained parallel with an estimated 9.5 months’ delay with abatacept.,Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group.,The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years.,Costimulation modulation with abatacept slowed decline of β-cell function and improved HbA1c in recent-onset T1D.,The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis.

The progressive infiltration of pancreatic islets by lymphocytes is mandatory for development of autoimmune type 1 diabetes.,This inflammatory process is mediated by several mediators that are potential therapeutic targets to arrest development of type 1 diabetes.,In this study, we investigate the role of one of these mediators, interleukin-16 (IL-16), in the pathogenesis of type 1 diabetes in NOD mice.,At different stages of progression of type 1 diabetes, we characterized IL-16 in islets using GEArray technology and immunoblot analysis and also quantitated IL-16 activity in cell migration assays.,IL-16 expression was localized in islets by immunofluorescence and confocal imaging.,In vivo neutralization studies were performed to assess the role of IL-16 in the pathogenesis of type 1 diabetes.,The increased expression of IL-16 in islets correlated with the development of invasive insulitis.,IL-16 immunoreactivity was found in islet infiltrating T-cells, B-cells, NK-cells, and dendritic cells, and within an insulitic lesion, IL-16 was derived from infiltrating cells.,CD4+ and CD8+ T-cells as well as B220+ B-cells were identified as sources of secreted IL-16.,Blockade of IL-16 in vivo protected against type 1 diabetes by interfering with recruitment of CD4+ T-cells to the pancreas, and this protection required the activity of the chemokine CCL4.,IL-16 production by leukocytes in islets augments the severity of insulitis during the onset of type 1 diabetes.,IL-16 and CCL4 appear to function as counterregulatory proteins during disease development.,Neutralization of IL-16 may represent a novel therapy for the prevention of type 1 diabetes.

The Wnt signaling pathway plays a key role in several biological processes, such as cellular proliferation and tissue regeneration, and its dysregulation is involved in the pathogenesis of many autoimmune diseases.,Several evidences support its role especially in bone complications of rheumatic diseases.,In Rheumatoid Arthritis (RA), the Wnt signaling is implicated in systemic and localized bone loss, while available data of its role in Spondyloarthritis (SpA) are conflicting.,In the last few decades, the quality of life of rheumatic patients has been dramatically improved by biological therapy, targeting cytokines involved in the pathogenesis of these diseases like tumor necrosis factor (TNF)α, interleukin (IL)-1, IL-6, IL-17.,In this review, we reviewed the role of Wnt signaling in RA and SpA, focusing on the effect of biological therapy on this pathway and its possible clinical implications.

Rheumatoid arthritis (RA) is a systemic disease that affects the osteoarticular system, associated with bone fragility and increased risk of fractures.,Herein, we aimed to characterize the systemic impact of the rat collagen-induced arthritis (CIA) model and explore its combination with femoral bone defect (FD).,The impact of CIA on endogenous mesenchymal stem/stromal cells (MSC) was also investigated.,CIA induction led to enlarged, more proliferative, spleen and draining lymph nodes, with altered proportion of lymphoid populations.,Upon FD, CIA animals increased the systemic myeloid cell proportions, and their expression of co-stimulatory molecules CD40 and CD86.,Screening plasma cytokine/chemokine levels showed increased tumor necrosis factor-α (TNF-α), Interleukin (IL)-17, IL-4, IL-5, and IL-12 in CIA, and IL-2 and IL-6 increased in CIA and CIA+FD, while Fractalkine and Leptin were decreased in both groups.,CIA-derived MSC showed lower metabolic activity and proliferation, and significantly increased osteogenic and chondrogenic differentiation markers.,Exposure of control-MSC to TNF-α partially mimicked the CIA-MSC phenotype in vitro.,In conclusion, inflammatory conditions of CIA led to alterations in systemic immune cell proportions, circulating mediators, and in endogenous MSC.,CIA animals respond to FD, and the combined model can be used to study the mechanisms of bone repair in inflammatory conditions.

The devastating neurodegenerative disease multiple sclerosis (MS) could substantially benefit from an adeno-associated virus (AAV) immunotherapy designed to restore a robust and durable antigen-specific tolerance.,However, developing a sufficiently potent and lasting immune-regulatory therapy that can intervene in ongoing disease is a major challenge and has thus been elusive.,We addressed this problem by developing a highly effective and robust tolerance-inducing in vivo gene therapy.,Using a pre-clinical animal model, we designed a liver-targeting gene transfer vector that expresses full-length myelin oligodendrocyte glycoprotein (MOG) in hepatocytes.,We show that by harnessing the tolerogenic nature of the liver, this powerful gene immunotherapy restores immune tolerance by inducing functional MOG-specific regulatory T cells (Tregs) in vivo, independent of major histocompatibility complex (MHC) restrictions.,We demonstrate that mice treated prophylactically are protected from developing disease and neurological deficits.,More importantly, we demonstrate that when given to mice with preexisting disease, ranging from mild neurological deficits to severe paralysis, the gene immunotherapy abrogated CNS inflammation and significantly reversed clinical symptoms of disease.,This specialized approach for inducing antigen-specific immune tolerance has significant therapeutic potential for treating MS and other autoimmune disorders.,Multiple sclerosis is a neurodegenerative autoimmune disease with no known cure.,Hoffman and colleagues present an AAV-based immunotherapy that induces antigen-specific tolerance to a neuropeptide that not only prevents disease onset, but is robust enough to alleviate preexisting neuro-inflammation and reverse disease in a model of MS.

See Winger and Zamvil (doi: 10.1093/brain/aww121 ) for a scientific commentary on this article.,Current therapies have limited effect on the chronic CNS inflammation observed in progressive multiple sclerosis (MS).,Mayo et al. show that CD3-specific antibody ameliorates disease in a mouse model of progressive MS.,The effect is dependent on induction of regulatory T-cells, which attenuate astrocyte and microglia activation via secretion of interleukin-10.,See Winger and Zamvil (doi: 10.1093/brain/aww121 ) for a scientific commentary on this article.,Current therapies have limited effect on the chronic CNS inflammation observed in progressive multiple sclerosis (MS).,Mayo et al. show that CD3-specific antibody ameliorates disease in a mouse model of progressive MS.,The effect is dependent on induction of regulatory T-cells, which attenuate astrocyte and microglia activation via secretion of interleukin-10.,See Winger and Zamvil (doi: 10.1093/brain/aww121 ) for a scientific commentary on this article.,Current therapies have limited effect on the chronic CNS inflammation observed in progressive multiple sclerosis (MS).,Mayo et al. show that CD3-specific antibody ameliorates disease in a mouse model of progressive MS.,The effect is dependent on induction of regulatory T-cells, which attenuate astrocyte and microglia activation via secretion of interleukin-10.,See Winger and Zamvil (doi: 10.1093/brain/aww121 ) for a scientific commentary on this article.,The innate immune system plays a central role in the chronic central nervous system inflammation that drives neurological disability in progressive forms of multiple sclerosis, for which there are no effective treatments.,The mucosal immune system is a unique tolerogenic organ that provides a physiological approach for the induction of regulatory T cells.,Here we report that nasal administration of CD3-specific antibody ameliorates disease in a progressive animal model of multiple sclerosis.,This effect is IL-10-dependent and is mediated by the induction of regulatory T cells that share a similar transcriptional profile to Tr1 regulatory cells and that suppress the astrocyte inflammatory transcriptional program.,Treatment results in an attenuated inflammatory milieu in the central nervous system, decreased microglia activation, reduced recruitment of peripheral monocytes, stabilization of the blood-brain barrier and less neurodegeneration.,These findings suggest a new therapeutic approach for the treatment of progressive forms of multiple sclerosis and potentially other types of chronic central nervous system inflammation.

Neuromyelitis optica (NMO) is an autoimmune, demyelinating disorder of the central nervous system (CNS) with typical clinical manifestations of optic neuritis and acute transverse myelitis attacks.,Previously believed to be a variant of multiple sclerosis (MS), it is now considered an independent disorder which needs to be differentiated from MS.,The discovery of autoantibodies against aquaporin-4 (AQP4-IgGs) changed our understanding of NMO immunopathogenesis and revolutionized the diagnostic process.,AQP4-IgG is currently regarded as a specific biomarker of NMO and NMO spectrum disorders (NMOsd) and a key factor in its pathogenesis.,Nevertheless, AQP4-IgG seronegativity in 10%-25% of NMO patients suggests that there are several other factors involved in NMO immunopathogenesis, i.e., autoantibodies against aquaporin-1 (AQP1-Abs) and antibodies against myelin oligodendrocyte glycoprotein (MOG-IgGs).,This manuscript reviews current knowledge about NMO immunopathogenesis, pointing out the controversial issues and showing potential directions for future research.,Further efforts should be made to broaden our knowledge of NMO immunology which could have important implications for clinical practice, including the use of potential novel biomarkers to facilitate an early and accurate diagnosis, and modern treatment strategies improving long-term outcome of NMO patients.

In 2008 the Austrian Task Force for Neuromyelitis Optica (NMO) started a nation-wide network for information exchange and multi-centre collaboration.,Their aim was to detect all patients with NMO or NMO spectrum disorders (NMO-SD) in Austria and to analyse their disease courses and response to treatment.,(1) As of March 2008, 1957 serum samples (of 1557 patients) have been tested with an established cell based immunofluorescence aquaporin-4 antibody (AQP4-ab) assay with a high sensitivity and specificity (both >95%).,All tests were performed in a single reference laboratory (Clinical Dept. of Neurology of the Innsbruck Medical University).,(2) A nation-wide survey with several calls for participation (via email newsletters, articles in the official journal of the Austrian Society of Neurology, and workshops) was initiated in 2008.,All collected data will be presented in a way that allows that every individual patient can be traced back in order to ensure transparency and to avoid any data distortion in future meta-analyses.,The careful and detailed presentation allows the visualization and comparison of the different disease courses in real time span.,Failure and response to treatment are made visible at one glance.,Database closure was 31 December 2011.,All co-operators were offered co-authorship.,All 71 NMO- or NMO-SD patients with AQP4-ab positivity (age range 12.3 to 79.6 years) were analysed in detail.,Sex ratio (m:f = 1:7) and the proportion of patients without oligoclonal bands in cerebrospinal fluid (86.6%) were in line with previously published results.,All identified patients were Caucasians.,A nationwide collaboration amongst Austrian neurologists with good network communications made it possible to establish a database of 71 AQP4-ab positive patients with NMO/NMO-SD.,This database is presented in detail and provides the basis for further studies and international cooperation in order to investigate this rare disease.

Mavrilimumab, a human monoclonal antibody, targets granulocyte-macrophage colony‐stimulating factor receptor α.,We undertook to determine the long‐term safety and efficacy of mavrilimumab in rheumatoid arthritis patients in 2 phase IIb studies (1071 and 1107) and in 1 open‐label extension study (ClinicalTrials.gov identifier: NCT01712399).,In study 1071, patients with an inadequate response to disease‐modifying antirheumatic drugs (DMARDs) received mavrilimumab (30, 100, or 150 mg) or placebo every other week plus methotrexate.,In study 1107, patients with an inadequate response to anti-tumor necrosis factor agents and/or DMARDs received 100 mg mavrilimumab every other week or 50 mg golimumab every 4 weeks plus methotrexate.,Patients entering the open‐label extension study received 100 mg mavrilimumab every other week plus methotrexate.,Long‐term safety and efficacy of mavrilimumab were assessed.,A total of 442 patients received mavrilimumab (14 of 245 patients from study 1071, 9 of 70 patients from study 1107, and 52 of 397 patients from the open‐label extension study discontinued mavrilimumab treatment throughout the studies).,The cumulative safety exposure was 899 patient‐years; the median duration of mavrilimumab treatment was 2.5 years (range 0.1-3.3 years).,The most common treatment‐emergent adverse events (AEs) were nasopharyngitis (n = 69; 7.68 per 100 patient‐years) and bronchitis (n = 51; 5.68 per 100 patient‐years).,At weeks 74 and 104, 3.5% and 6.2% of patients, respectively, demonstrated reduction in forced expiratory volume in 1 second, while 2.9% and 3.4% of patients, respectively, demonstrated reduction in forced vital capacity (>20% reduction from baseline to <80% predicted).,Most pulmonary changes were transient and only infrequently associated with AEs.,Mavrilimumab at 100 mg every other week demonstrated sustained efficacy; at week 122, 65.0% of patients achieved a Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) of <3.2, and 40.6% of patients achieved a DAS28‐CRP of <2.6.,Long‐term treatment with mavrilimumab maintained response and was well‐tolerated with no increased incidence of treatment‐emergent AEs.,Safety data were comparable with those from both phase IIb qualifying studies.

The treatment of rheumatoid arthritis (RA) patients with anti-tumor necrosis factor alpha (TNFα) biological drugs has dramatically improved the prognosis of these patients.,However, a third of the treated patients do not respond to this therapy.,Thus, the search for biomarkers of clinical response to these agents is currently highly active.,Our aim is to analyze the number and distribution of circulating monocytes, and of their CD14+highCD16-, CD14+highCD16+ and CD14+lowCD16+ subsets in methotrexate (MTX) non-responder patients with RA, and to determine their value in predicting the clinical response to adalimumab plus MTX treatment.,This prospective work investigated the number of circulating monocytes, and of their CD14+highCD16-, CD14+highCD16+ and CD14+lowCD16+ subsets, in 35 MTX non-responder patients with RA before and after three and six months of anti-TNFα treatment using multiparametric flow cytometry.,The number of circulating monocytes in an age- and sex-matched healthy population was monitored as a control.,Non-responder patients with RA show an increased number of monocytes and of their CD14+highCD16-, CD14+highCD16+ and CD14+lowCD16+ subsets after three months of adalimumab plus MTX treatment that remained significantly increased at six months.,In contrast, significant normalization of the numbers of circulating monocytes was found in responders at three months of adalimumab plus MTX treatment that lasts up to six months.,CX3CR1 expression is increased in monocytes in non-responders.,At three months of anti-TNFα treatment the number of circulating monocytes and their subsets was associated with at least 80% sensitivity, 84% specificity and an 86% positive predictive value (PPV) in terms of discriminating between eventual early responders and non-responders.,The absolute number of circulating monocytes and of their CD14+highCD16-, CD14+highCD16+ and CD14+lowCD16+ subsets at three months of adalimumab plus MTX treatment, have a predictive value (with high specificity and sensitivity) in terms of the clinical response after six months of anti-TNFα treatment in patients with RA.

Previous studies have demonstrated that mesenchymal stem cell (MSC) transplantation reduces the severity of collagen-induced arthritis (CIA) in mice, which is a model for rheumatoid arthritis (RA) in humans.,However, the underlying molecular mechanisms remain ill-defined.,Here, we showed that MSC transplantation reduced the activities of NF-κB signaling and decreased microRNA-548e (miR-548e) levels in the joint tissue in CIA-mice, seemingly through activation of transforming growth factor β receptor signaling.,Bioinformatics analyses revealed that miR-548e inhibited protein translation of the NF-κB inhibitor, IκB, through binding to the 3′-UTR of the IκB mRNA.,MSCs co-transplanted with adeno-associated virus (AAV) carrying miR-548e abolished the therapeutic effects of MSCs on CIA.,On the other hand, transplantation of AAV carrying antisense of miR-548e (as-miR-548e) partially mimicked the effects of MSC transplantation on CIA.,Together, these data suggest that MSC transplantation may alleviate experimental RA partially through suppressing miR-548e-mediated IκB inhibition.

Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)-GM-CSF receptor α axis (GM-CSFRα) may provide a new therapeutic target for the treatment of rheumatoid arthritis (RA).,Therefore, we investigated the cellular expression of GM-CSFRα in RA synovial tissue and investigated the effects of anti-GM-CSFRα antibody treatment in vitro and in vivo in a preclinical model of RA.,We compared GM-CSFRα expression on macrophages positive for CD68 or CD163 on synovial biopsy samples from patients with RA or psoriatic arthritis (PsA) to disease controls.,In addition, we studied the effects of CAM-3003, an anti-GM-CSFR antibody in a collagen induced arthritis model of RA in DBA/1 mice.,The pharmacokinetic profile of CAM-3003 was studied in naïve CD1(ICR) mice (see online supplement) and used to interpret the results of the pharmacodynamic studies in BALB/c mice.,GM-CSFRα was expressed by CD68 positive and CD163 positive macrophages in the synovium, and there was a significant increase in GM-CSFRα positive cells in patients in patients with RA as well as patients with PsA compared with patients with osteoarthritis and healthy controls.,In the collagen induced arthritis model there was a dose dependent reduction of clinical arthritis scores and the number of F4/80 positive macrophages in the inflamed synovium after CAM-3003 treatment.,In BALB/c mice CAM-3003 inhibited recombinant GM-CSF mediated margination of peripheral blood monocytes and neutrophils.,The findings support the ongoing development of therapies aimed at interfering with GM-CSF or its receptor in various forms of arthritis, such as RA and PsA.

Machine learning (ML) applied to patient-reported (PROs) and clinical-assessed outcomes (CAOs) could favour a more predictive and personalized medicine.,Our aim was to confirm the important role of applying ML to PROs and CAOs of people with relapsing-remitting (RR) and secondary progressive (SP) form of multiple sclerosis (MS), to promptly identifying information useful to predict disease progression.,For our analysis, a dataset of 3398 evaluations from 810 persons with MS (PwMS) was adopted.,Three steps were provided: course classification; extraction of the most relevant predictors at the next time point; prediction if the patient will experience the transition from RR to SP at the next time point.,The Current Course Assignment (CCA) step correctly assigned the current MS course with an accuracy of about 86.0%.,The MS course at the next time point can be predicted using the predictors selected in CCA.,PROs/CAOs Evolution Prediction (PEP) followed by Future Course Assignment (FCA) was able to foresee the course at the next time point with an accuracy of 82.6%.,Our results suggest that PROs and CAOs could help the clinician decision-making in their practice.

Lipid signaling has been suggested to be a major pathophysiological mechanism of multiple sclerosis (MS).,With the increasing knowledge about lipid signaling, acquired data become increasingly complex making bioinformatics necessary in lipid research.,We used unsupervised machine-learning to analyze lipid marker serum concentrations, pursuing the hypothesis that for the most relevant markers the emerging data structures will coincide with the diagnosis of MS.,Machine learning was implemented as emergent self-organizing feature maps (ESOM) combined with the U*-matrix visualization technique.,The data space consisted of serum concentrations of three main classes of lipid markers comprising eicosanoids (d = 11 markers), ceramides (d = 10), and lyosophosphatidic acids (d = 6).,They were analyzed in cohorts of MS patients (n = 102) and healthy subjects (n = 301).,Clear data structures in the high-dimensional data space were observed in eicosanoid and ceramides serum concentrations whereas no clear structure could be found in lysophosphatidic acid concentrations.,With ceramide concentrations, the structures that had emerged from unsupervised machine-learning almost completely overlapped with the known grouping of MS patients versus healthy subjects.,This was only partly provided by eicosanoid serum concentrations.,Thus, unsupervised machine-learning identified distinct data structures of bioactive lipid serum concentrations.,These structures could be superimposed with the known grouping of MS patients versus healthy subjects, which was almost completely possible with ceramides.,Therefore, based on the present analysis, ceramides are first-line candidates for further exploration as drug-gable targets or biomarkers in MS.

Rheumatoid arthritis (RA) is characterised by chronic synovial joint inflammation.,Treatment has been revolutionised by tumour necrosis factor alpha inhibitors (TNFi) but each available drug shows a significant non-response rate.,We conducted a genome-wide association study of 1752 UK RA TNFi-treated patients to identify predictors of change in the Disease Activity Score 28 (DAS28) and subcomponents over 3-6 months.,The rs7195994 variant at the FTO gene locus was associated with infliximab response when looking at a change in the swollen joint count (SJC28) subcomponent (p = 9.74 × 10−9).,Capture Hi-C data show chromatin interactions in GM12878 cells between rs2540767, in high linkage disequilibrium with rs7195994 (R2 = 0.9) and IRX3, a neighbouring gene of FTO.,IRX3 encodes a transcription factor involved in adipocyte remodelling and is regarded as the obesity gene at the FTO locus.,Importantly, the rs7195994 association remained significantly associated following adjustment for BMI.,In addition, using capture Hi-C data we showed interactions between TNFi-response associated variants and 16 RA susceptibility variants.

Increased expression of IL-33 and its receptor ST2, encoded by the IL1RL1 gene, has been detected in the inflamed arteries of giant cell arteritis (GCA) patients.,The aim of the present study was to investigate for the first time the potential influence of the IL33 and IL1RL1 loci on GCA predisposition.,A total of 1,363 biopsy-proven GCA patients and 3,908 healthy controls from four European cohorts (Spain, Italy, Germany and Norway) were combined in a meta-analysis.,Six genetic variants: rs3939286, rs7025417 and rs7044343, within the IL33 gene, and rs2058660, rs2310173 and rs13015714, within the IL1RL1 gene, previously associated with immune-related diseases, were genotyped using predesigned TaqMan assays.,A consistent association between the rs7025417 polymorphism and GCA was evident in the overall meta-analysis, under both allele (PMH = 0.041, OR = 0.88, CI 95% 0.78-0.99) and recessive (PMH = 3.40E-03, OR = 0.53, CI 95% 0.35-0.80) models.,No statistically significant differences between allele or genotype frequencies for the other IL33 and IL1RL1 genetic variants were detected in this pooled analysis.,Our results clearly evidenced the implication of the IL33 rs7025417 polymorphism in the genetic network underlying GCA.

The COVID-19 pandemic presents two main concerns for patients with myasthenia gravis (MG); chronic immunosuppression may put them at greater risk, and some proposed treatments for COVID-19 could cause MG exacerbation.,We present three patients with generalized seropositive MG who developed COVID-19.,All patients had a favorable outcome, with only one patient experiencing exacerbation.,In this case, exacerbation began before COVID-19; she required ICU admission, non-invasive ventilatory support, and received hydroxychloroquine, lopinavir and ritonavir which were well tolerated.,One patient received IVIG in place of scheduled plasma exchange.,Outcome was favorable in all cases despite immunosuppressive therapy, use of experimental COVID-19 medication and switching of plasma exchange for IVIG.,•Three cases of myasthenia gravis with COVID-19 with favorable outcome.,•Immunosuppressive therapy was continued during COVID-19 infection.,•Switching maintenance plasmapheresis with IVIg was well tolerated.,Three cases of myasthenia gravis with COVID-19 with favorable outcome.,Immunosuppressive therapy was continued during COVID-19 infection.,Switching maintenance plasmapheresis with IVIg was well tolerated.

Background and objectives: Myasthenia gravis (MG) and Guillain-Barré Syndrome (GBS) are autoimmune neuromuscular disorders that may present as neuromuscular emergencies requiring mechanical ventilation and critical care.,Comparative outcomes of these disease processes, once severe enough to require mechanical ventilation, are not known.,In this study, we compared the patients requiring mechanical ventilation in terms of in-hospital complications, length of stay, disability, and mortality between these two disease entities at a national level.,Materials and Methods: Mechanically ventilated patients with primary diagnosis of MG (n = 6684) and GBS (n = 5834) were identified through retrospective analysis of Nationwide Inpatient Sample (NIS) database for the years 2006 to 2014.,Results: Even though mechanically ventilated MG patients were older (61.0 ± 19.1 versus 54.9 ± 20.1 years) and presented with more medical comorbidities, they had lower disease severity on admission, as well as lower in-hospital complications sepsis, pneumonia, and urinary tract infections as compared with GBS patients.,In the multivariate analysis, after adjusting for confounders including treatment, GBS patients had significantly higher disability (odds ratio (OR) 15.6, 95% confidence interval (CI) 10.9-22.2) and a longer length of stay (OR 3.48, 95% CI 2.22-5.48).,There was no significant difference in mortality between the groups (8.45% MG vs.,10.0% GBS, p = 0.16).,Conclusion: Mechanically ventilated GBS patients have higher disease severity at admission along with more in-hospital complications, length of stay, and disability compared with MG patients.,Potential explanations for these findings include delay in the diagnosis, poor response to immunotherapy particularly in patients with axonal GBS variant, or longer recovery time after nerve damage.

During multiple sclerosis (MS), an inflammatory and neurodegenerative disease of the central nervous system (CNS), symptoms, and outcomes are determined by the location of inflammatory lesions.,While we and others have shown that T cell cytokines differentially regulate leukocyte entry into perivascular spaces and regional parenchymal localization in murine models of MS, the molecular mechanisms of this latter process are poorly understood.,Here, we demonstrate that astrocytes exhibit region‐specific responses to T cell cytokines that promote hindbrain versus spinal cord neuroinflammation.,Analysis of cytokine receptor expression in human astrocytes showed region‐specific responsiveness to Th1 and Th17 inflammatory cytokines.,Consistent with this, human and murine astrocytes treated with these cytokines exhibit differential expression of the T cell localizing molecules VCAM‐1 and CXCR7 that is both cytokine and CNS region‐specific.,Using in vivo models of spinal cord versus brain stem trafficking of myelin‐specific T cells and astrocyte‐specific deletion strategies, we confirmed that Th1 and Th17 cytokines differentially regulate astrocyte expression of VCAM‐1 and CXCR7 in these locations.,Finally, stereotaxic injection of individual cytokines into the hindbrain or spinal cord revealed region‐ and cytokine‐specific modulation of localizing cue expression by astrocytes.,These findings identify a role for inflammatory cytokines in mediating local astrocyte‐dependent mechanisms of immune cell trafficking within the CNS during neuroinflammation.,Regional astrocyte heterogeneity mediates autoimmune neuroinflammation.Th17‐associated cytokines regulate VCAM‐1 on brain stem astrocytes.IFNγ upregulates CXCR7 on spinal cord astrocytes to facilitate T cell entry.,Regional astrocyte heterogeneity mediates autoimmune neuroinflammation.,Th17‐associated cytokines regulate VCAM‐1 on brain stem astrocytes.,IFNγ upregulates CXCR7 on spinal cord astrocytes to facilitate T cell entry.

Th1 lymphocytes preferentially infiltrate into the spinal cord during EAE via a VLA-4-mediated mechanism while Th17 lymphocyte infiltration is dependent on LFA-1 expression.,The integrin α4β1 (VLA-4) is used by encephalitogenic T cells to enter the central nervous system (CNS).,However, both Th1 and Th17 cells are capable of inducing experimental autoimmune encephalomyelitis (EAE), and the molecular cues mediating the infiltration of Th1 versus Th17 cells into the CNS have not yet been defined.,We investigated how blocking of α4 integrins affected trafficking of Th1 and Th17 cells into the CNS during EAE.,Although antibody-mediated inhibition of α4 integrins prevented EAE when MOG35-55-specific Th1 cells were adoptively transferred, Th17 cells entered the brain, but not the spinal cord parenchyma, irrespective of α4 blockade.,Accordingly, T cell-conditional α4-deficient mice were not resistant to actively induced EAE but showed an ataxic syndrome with predominantly supraspinal infiltrates of IL-23R+CCR6+CD4+ T cells.,The entry of α4-deficient Th17 cells into the CNS was abolished by blockade of LFA-1 (αLβ2 integrin).,Thus, Th1 cells preferentially infiltrate the spinal cord via an α4 integrin-mediated mechanism, whereas the entry of Th17 cells into the brain parenchyma occurs in the absence of α4 integrins but is dependent on the expression of αLβ2.,These observations have implications for the understanding of lesion localization, immunosurveillance, and drug design in multiple sclerosis.

There is evidence for an impact of the gut microbiota on the immune system, which has consequences for inflammatory diseases.,Exclusive enteral nutrition (EEN) and the specific carbohydrate diet (SCD) have been demonstrated as effective anti-inflammatory treatments for children with Crohn’s disease.,We have previously shown an anti-inflammatory effect from these nutritional treatments in children with juvenile idiopathic arthritis (JIA).,The aim of this study was to investigate if improved clinical symptoms after EEN or SCD treatment in children with JIA could be linked to changes in faecal microbiota.,We included sixteen patients with JIA (age 7-17 years), six for treatment with EEN and ten with SCD.,EEN was given for 3-5 weeks and SCD for 4-5 weeks, with clinical and laboratory status assessed before and after treatment.,Faecal samples were analysed for microbiota diversity and composition using 16S rRNA gene sequencing.,Analyses of the faecal microbiota showed an effect on the overall composition with both interventions; the most striking result was a decreased relative abundance of the genus Faecalibacterium from EEN and of Bifidobacterium from SCD.,The α-diversity decreased significantly from SCD (P = 0.04), but not from EEN (P = 0.22).,Despite the study cohorts being small, both EEN and SCD were shown to impact the faecal microbiota.,Future larger studies with a focus on metagenomics or metabolomics could possibly reveal a link and clarify the clinical effects of those nutritional regimens.

The objective was to evaluate the 25(OH) vitamin D (25(OH)D) status of patients with juvenile idiopathic arthritis (JIA) and determine whether the 25(OH)D level is associated with disease activity and the course of JIA.,Patients ≤ 16 years of age with recently diagnosed JIA (< 12 months) were enrolled in the inception cohort of patients with newly diagnosed JIA (ICON), an ongoing prospective observational, controlled multicenter study started in 2010.,Clinical and laboratory parameters were ascertained quarterly during the first year and half-yearly thereafter.,Of the 954 enrolled patients, 360 patients with two blood samples taken during the first 2 years after inclusion and with follow up of 3 years were selected.,The serum 25(OH)D levels were determined and compared with those of subjects from the general population after matching for age, sex, migration status and the month of blood-drawing.,Nearly half of the patients had a deficient 25(OH)D level (< 20 ng/ml) in the first serum sample and a quarter had a deficient level in both samples.,Disease activity and the risk of developing JIA-associated uveitis were inversely correlated with the 25(OH)D level (β = − 0.20, 95% CI − 0.37; 0.03, hazard ratio 0.95, 95% CI 0.91; 0.99, respectively).,In this study, 25(OH)D deficiency was common and associated with higher disease activity and risk of developing JIA-associated uveitis.,Further studies are needed to substantiate these results and determine whether correcting 25(OH)D deficiency is beneficial in JIA.

To validate strategies to prevent exercise‐induced hypoglycaemia via insulin‐dose adjustment in adult patients with type 1 diabetes (T1D) on pump therapy.,A total of 20 patients randomly performed four 30‐min late post‐lunch (3 h after lunch) exercise sessions and a rest session: two moderate sessions [50% maximum oxygen consumption (VO2max)] with 50 or 80% basal rate (BR) reduction during exercise + 2 h and two intense sessions (75% VO2max) with 80% BR reduction or with their pump stopped.,Two additional early post‐lunch sessions (90 min after lunch) were analysed to compare hypoglycaemia incidence for BR reduction versus bolus reduction.,In all, 100 late post‐lunch sessions were analysed.,Regardless of exercise type and BR reduction, no more hypoglycaemic events occurred in the period until the next morning than occurred after the rest sessions.,In the afternoon, no more hypoglycaemic events occurred with 80% BR reduction/moderate exercise or with pump discontinuation/intense exercise than for the rest session, whereas more hypoglycaemic events occurred with 50% BR reduction/moderate exercise and 80% BR reduction/intense exercise.,After early post‐lunch exercise (n = 37), a trend towards fewer hypoglycaemic episodes was observed with bolus reduction versus BR reduction (p = 0.07).,Mean blood glucose fell by ∼3.3 mmol/l after 30 min of exercise, irrespective of dose reduction, remaining stable until the next morning with no rebound hyperglycaemia.,In adults with T1D, to limit the hypoglycaemic risk associated with 30 min of exercise 3 h after lunch, without carbohydrate supplements, the best options seem to be to reduce BR by 80% or to stop the pump for moderate or intense exercise, or for moderate exercise 90 min after lunch, to reduce the prandial bolus rather than the BR.

To examine the acute and 24-h glycemic responses to reductions in postexercise rapid-acting insulin dose in type 1 diabetic patients.,After preliminary testing, 11 male patients (24 ± 2 years, HbA1c 7.7 ± 0.3%; 61 ± 3.4 mmol/mol) attended the laboratory on three mornings.,Patients consumed a standardized breakfast (1 g carbohydrate ⋅ kg−1 BM; 380 ± 10 kcal) and self-administered a 25% rapid-acting insulin dose 60 min prior to performing 45 min of treadmill running at 72.5 ± 0.9% VO2peak.,At 60 min postexercise, patients ingested a meal (1 g carbohydrate ⋅ kg−1 BM; 660 ± 21 kcal) and administered a Full, 75%, or 50% rapid-acting insulin dose.,Blood glucose concentrations were measured for 3 h postmeal.,Interstitial glucose was recorded for 20 h after leaving the laboratory using a continuous glucose monitoring system.,All glycemic responses were similar across conditions up to 60 min postexercise.,After the postexercise meal, blood glucose was preserved under 50%, but declined under Full and 75%.,Thence at 3 h, blood glucose was highest under 50% (50% [10.4 ± 1.2] vs.,Full [6.2 ± 0.7] and 75% [7.6 ± 1.2 mmol ⋅ L−1], P = 0.029); throughout this period, all patients were protected against hypoglycemia under 50% (blood glucose ≤3.9; Full, n = 5; 75%, n = 2; 50%, n = 0).,Fifty percent continued to protect patients against hypoglycemia for a further 4 h under free-living conditions.,However, late-evening and nocturnal glycemia were similar; as a consequence, late-onset hypoglycemia was experienced under all conditions.,A 25% pre-exercise and 50% postexercise rapid-acting insulin dose preserves glycemia and protects patients against early-onset hypoglycemia (≤8 h).,However, this strategy does not protect against late-onset postexercise hypoglycemia.

New treatments for multiple sclerosis (MS) focused on B cells have created an atmosphere of excitement in the MS community.,B cells are now known to play a major role in disease, demonstrated by the highly impactful effect of a B cell-depleting antibody on controlling MS.,The idea that a virus may play a role in the development of MS has a long history and is supported mostly by studies demonstrating a link between B cell-tropic Epstein-Barr virus (EBV) and disease onset.,Efforts to develop antiviral strategies for treating MS are underway.,Although gaps remain in our understanding of the etiology of MS, the role, if any, of viruses in propagating pathogenic immune responses deserves attention.

The aim of this study was to investigate the protective effect of interleukin-6 (IL-6) receptor antagonist tocilizumab (TCZ) on rheumatoid arthritis (RA) and its related mechanism.,Thirty RA patients receiving long-term methotrexate therapy at moderate and severe active stages were selected and treated with TCZ 8 mg/kg/time iv gtt intravenously guttae every 4 weeks.,Peripheral blood was extracted before and 24 weeks after TCZ treatment.,Peripheral blood mononuclear cells (PBMC) were collected by density gradient centrifugation.,Flow cytometry was used to detect the ratio of CD4 naïve T cells and CD4 memory T cells, Th17 cells, and Treg cells in PBMC.,DAS28 score, CRP, RF, and CCP levels in patients were evaluated.,Compared with before treatment, IL-6 receptor antagonist TCZ significantly improved patients’ condition, including DAS28 score, CRP, RF, and CCP levels (P<0.01).,Furthermore, TCZ obviously upregulated CD4 naïve T cells proportion and decreased CD4 memory T cells ratio (P<0.01).,TCZ also markedly reduced the proportion of Th17 cells and increased the proportion of Treg cells (P<0.01).,TCZ can treat RA patients through regulating the ratio of CD4 naïve T cells, CD4 memory T cells, Th17 cells, and Treg cells in PBMC.

Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is characterized by the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind monocytes in addition to neutrophils.,While a pathological effect on neutrophils is acknowledged, the impact of ANCA on monocyte function is less well understood.,Using IgG from patients we investigated the effect of these autoantibodies on monocytes and found that anti-myeloperoxidase antibodies (MPO-ANCA) reduced both IL-10 and IL-6 secretion in response to LPS.,This reduction in IL-10 and IL-6 depended on Fc receptors and enzymatic myeloperoxidase and was accompanied by a significant reduction in TLR-driven signaling pathways.,Aligning with changes in TLR signals, oxidized phospholipids, which function as TLR4 antagonists, were increased in monocytes in the presence of MPO-ANCA.,We further observed that MPO-ANCA increased monocyte survival and differentiation to macrophages by stimulating CSF-1 production.,However, this was independent of myeloperoxidase enzymatic activity and TLR signaling.,Macrophages differentiated in the presence of MPO-ANCA secreted more TGF-β and further promoted the development of IL-10- and TGF-β-secreting CD4+ T cells.,Thus, MPO-ANCA may promote inflammation by reducing the secretion of antiinflammatory IL-10 from monocytes, and MPO-ANCA can alter the development of macrophages and T cells to potentially promote fibrosis.,Anti-myeloperoxidase antibodies from patients with anti-neutrophil cytoplasmic antibody (ANCA) vasculitis alter monocyte function in addition to previously described effects on neutrophils.

ANCA-Associated Systemic Vasculitis (AASV) is characterized by leukocytoclasis, accumulation of unscavenged apoptotic and necrotic neutrophils in perivascular tissues.,Dysregulation of neutrophil cell death may contribute directly to the pathogenesis of AASV.,Neutrophils from Healthy Blood Donors (HBD), patients with AASV most in complete remission, Polycythemia Vera (PV), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA) and renal transplant recipients (TP) were incubated in vitro, and the rate of spontaneous apoptosis was measured by FACS.,Plasma levels of cytokines and sFAS were measured with cytometric bead array and ELISA.,Expression of pro/anti-apoptotic factors, transcription factors C/EBP-α, C/EBP-β and PU.1 and inhibitors of survival/JAK2-pathway were measured by real-time-PCR.,AASV, PV and RA neutrophils had a significantly lower rate of apoptosis compared to HBD neutrophils (AASV 50±14% vs.,HBD 64±11%, p<0.0001).,In RA but not in AASV and PV, low apoptosis rate correlated with increased plasma levels of GM-CSF and high mRNA levels of anti-apoptotic factors Bcl-2A1 and Mcl-1.,AASV patients had normal levels of G-CSF, GM-CSF and IL-3.,Both C/EBP-α, C/EBP-β were significantly higher in neutrophils from AASV patients than HBD.,Levels of sFAS were significantly higher in AASV compared to HBD.,Neutrophil apoptosis rates in vitro are decreased in AASV, RA and PV but mechanisms seem to differ.,Increased mRNA levels of granulopoiesis-associated transcription factors and increased levels of sFAS in plasma were observed in AASV.,Additional studies are required to define the mechanisms behind the decreased apoptosis rates, and possible connections with accumulation of dying neutrophils in regions of vascular lesions in AASV patients.

•RFE-SVMs predict future outcome of CIS patients with conservative accuracy estimates between 64.9% and 88.1%.,•Recursive feature selection improves classification performance compared to using all information.,•Relevant features include regional WM lesion load and GM density, as well as the type of CIS onset.,•Cross-validation introduces positive bias on accuracy estimate.,RFE-SVMs predict future outcome of CIS patients with conservative accuracy estimates between 64.9% and 88.1%.,Recursive feature selection improves classification performance compared to using all information.,Relevant features include regional WM lesion load and GM density, as well as the type of CIS onset.,Cross-validation introduces positive bias on accuracy estimate.,Machine learning classification is an attractive approach to automatically differentiate patients from healthy subjects, and to predict future disease outcomes.,A clinically isolated syndrome (CIS) is often the first presentation of multiple sclerosis (MS), but it is difficult at onset to predict who will have a second relapse and hence convert to clinically definite MS.,In this study, we thus aimed to distinguish CIS converters from non-converters at onset of a CIS, using recursive feature elimination and weight averaging with support vector machines.,We also sought to assess the influence of cohort size and cross-validation methods on the accuracy estimate of the classification.,We retrospectively collected 400 patients with CIS from six European MAGNIMS MS centres.,Patients underwent brain MRI at onset of a CIS according to local standard-of-care protocols.,The diagnosis of clinically definite MS at one-year follow-up was the standard against which the accuracy of the model was tested.,For each patient, we derived MRI-based features, such as grey matter probability, white matter lesion load, cortical thickness, and volume of specific cortical and white matter regions.,Features with little contribution to the classification model were removed iteratively through an interleaved sample bootstrapping and feature averaging approach.,Classification of CIS outcome at one-year follow-up was performed with 2-fold, 5-fold, 10-fold and leave-one-out cross-validation for each centre cohort independently and in all patients together.,The estimated classification accuracy across centres ranged from 64.9% to 88.1% using 2-fold cross-validation and from 73% to 92.9% using leave-one-out cross-validation.,The classification accuracy estimate was higher in single-centre, smaller data sets than in combinations of data sets, being the lowest when all patients were merged together.,Regional MRI features such as WM lesions, grey matter probability in the thalamus and the precuneus or cortical thickness in the cuneus and inferior temporal gyrus predicted the occurrence of a second relapse in patients at onset of a CIS using support vector machines.,The increased accuracy estimate of the classification achieved with smaller and single-centre samples may indicate a model bias (overfitting) when data points were limited, but also more homogeneous.,We provide an overview of classifier performance from a range of cross-validation schemes to give insight into the variability across schemes.,The proposed recursive feature elimination approach with weight averaging can be used both in single- and multi-centre data sets in order to bridge the gap between group-level comparisons and making predictions for individual patients.

Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making.,Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking.,Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS.,While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression.,Strategies for future research to better define phenotypes are also outlined.

Metformin, a synthetic derivative of guanidine, is commonly used as an oral antidiabetic agent and is considered a multi-vector application agent in the treatment of other inflammatory diseases.,Recent studies have confirmed the beneficial effect of metformin on immune cells, with special emphasis on immunological mechanisms.,Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by various clinical courses.,Although the pathophysiology of MS remains unknown, it is most likely a combination of disturbances of the immune system and biochemical pathways with a disruption of blood-brain barrier (BBB), and it is strictly related to injury of intracerebral blood vessels.,Metformin has properties which are greatly desirable for MS therapy, including antioxidant, anti-inflammatory or antiplatelet functions.,The latest reports relating to the cardiovascular disease confirm an increased risk of ischemic events in MS patients, which are directly associated with a coagulation cascade and an elevated pro-thrombotic platelet function.,Hence, this review examines the potential favourable effects of metformin in the course of MS, its role in preventing inflammation and endothelial dysfunction, as well as its potential antiplatelet role.

▶ The classical MOG35-55-EAE is complemented by novel cortical and toxic MS models.,▶ Putative autoantigens of EAE/MS include myelin and axonal glycoproteins and lipids.,▶ MS risk genes involve DRB1*1501 and more than 10 novel candidate genes.,▶ Treg and Th17 cells deserve close attention in EAE/MS pathogenesis.,▶ Oral disease-modifiers and monoclonal antibodies show great promise for MS therapy.,Experimental autoimmune encephalomyelitis (EAE) is still the most widely accepted animal model of multiple sclerosis (MS).,Different types of EAE have been developed in order to investigate pathogenetic, clinical and therapeutic aspects of the heterogenic human disease.,Generally, investigations in EAE are more suitable for the analysis of immunogenetic elements (major histocompatibility complex restriction and candidate risk genes) and for the study of histopathological features (inflammation, demyelination and degeneration) of the disease than for screening of new treatments.,Recent studies in new EAE models, especially in transgenic ones, have in connection with new analytical techniques such as microarray assays provided a deeper insight into the pathogenic cellular and molecular mechanisms of EAE and potentially of MS.,For example, it was possible to better delineate the role of soluble pro-inflammatory (tumor necrosis factor-α, interferon-γ and interleukins 1, 12 and 23), anti-inflammatory (transforming growth factor-β and interleukins 4, 10, 27 and 35) and neurotrophic factors (ciliary neurotrophic factor and brain-derived neurotrophic factor).,Also, the regulatory and effector functions of distinct immune cell subpopulations such as CD4+ Th1, Th2, Th3 and Th17 cells, CD4+FoxP3+ Treg cells, CD8+ Tc1 and Tc2, B cells and γδ+ T cells have been disclosed in more detail.,The new insights may help to identify novel targets for the treatment of MS.,However, translation of the experimental results into the clinical practice requires prudence and great caution.

Insulin-dependent or type 1 diabetes is a prototypic autoimmune disease whose incidence steadily increased over the past decades in industrialized countries.,Recent evidence suggests the importance of the gut microbiota to explain this trend.,Here, non-obese diabetic (NOD) mice that spontaneously develop autoimmune type 1 diabetes were treated with different antibiotics to explore the influence of a targeted intestinal dysbiosis in the progression of the disease.,A mixture of wide spectrum antibiotics (i.e. streptomycin, colistin and ampicillin) or vancomycin alone were administered orally from the moment of conception, treating breeding pairs, and during the postnatal and adult life until the end of follow-up at 40 weeks.,Diabetes incidence significantly and similarly increased in male mice following treatment with these two antibiotic regimens.,In NOD females a slight yet not significant trend towards an increase in disease incidence was observed.,Changes in gut microbiota composition were assessed by sequencing the V3 region of bacterial 16S rRNA genes.,Administration of the antibiotic mixture resulted in near complete ablation of the gut microbiota.,Vancomycin treatment led to increased Escherichia, Lactobacillus and Sutterella genera and decreased members of the Clostridiales order and Lachnospiraceae, Prevotellaceae and Rikenellaceae families, as compared to control mice.,Massive elimination of IL-17-producing cells, both CD4+TCRαβ+ and TCRγδ+ T cells was observed in the lamina propria of the ileum and the colon of vancomycin-treated mice.,These results show that a directed even partial ablation of the gut microbiota, as induced by vancomycin, significantly increases type 1 diabetes incidence in male NOD mice thus prompting for caution in the use of antibiotics in pregnant women and newborns.

A recent study using a rat model found significant differences at the time of diabetes onset in the bacterial communities responsible for type 1 diabetes modulation.,We hypothesized that type 1 diabetes in humans could also be linked to a specific gut microbiota.,Our aim was to quantify and evaluate the difference in the composition of gut microbiota between children with type 1 diabetes and healthy children and to determine the possible relationship of the gut microbiota of children with type 1 diabetes with the glycemic level.,A case-control study was carried out with 16 children with type 1 diabetes and 16 healthy children.,The fecal bacteria composition was investigated by polymerase chain reaction-denaturing gradient gel electrophoresis and real-time quantitative polymerase chain reaction.,The mean similarity index was 47.39% for the healthy children and 37.56% for the children with diabetes, whereas the intergroup similarity index was 26.69%.,In the children with diabetes, the bacterial number of Actinobacteria and Firmicutes, and the Firmicutes to Bacteroidetes ratio were all significantly decreased, with the quantity of Bacteroidetes significantly increased with respect to healthy children.,At the genus level, we found a significant increase in the number of Clostridium, Bacteroides and Veillonella and a significant decrease in the number of Lactobacillus, Bifidobacterium, Blautia coccoides/Eubacterium rectale group and Prevotella in the children with diabetes.,We also found that the number of Bifidobacterium and Lactobacillus, and the Firmicutes to Bacteroidetes ratio correlated negatively and significantly with the plasma glucose level while the quantity of Clostridium correlated positively and significantly with the plasma glucose level in the diabetes group.,This is the first study showing that type 1 diabetes is associated with compositional changes in gut microbiota.,The significant differences in the number of Bifidobacterium, Lactobacillus and Clostridium and in the Firmicutes to Bacteroidetes ratio observed between the two groups could be related to the glycemic level in the group with diabetes.,Moreover, the quantity of bacteria essential to maintain gut integrity was significantly lower in the children with diabetes than the healthy children.,These findings could be useful for developing strategies to control the development of type 1 diabetes by modifying the gut microbiota.

The immune system is highly diverse, but characterization of its genetic architecture has lagged behind the vast progress made by genome-wide association studies (GWASs) of emergent diseases.,Our GWAS for 54 functionally relevant phenotypes of the adaptive immune system in 489 healthy individuals identifies eight genome-wide significant associations explaining 6%-20% of variance.,Coding and splicing variants in PTPRC and COMMD10 are involved in memory T cell differentiation.,Genetic variation controlling disease-relevant T helper cell subsets includes RICTOR and STON2 associated with Th2 and Th17, respectively, and the interferon-lambda locus controlling regulatory T cell proliferation.,Early and memory B cell differentiation stages are associated with variation in LARP1B and SP4.,Finally, the latrophilin family member ADGRL2 correlates with baseline pro-inflammatory interleukin-6 levels.,Suggestive associations reveal mechanisms of autoimmune disease associations, in particular related to pro-inflammatory cytokine production.,Pinpointing these key human immune regulators offers attractive therapeutic perspectives.,•GWAS provides understanding of genetic factors shaping adaptive immune system•Common and less common variants explain 10% of variance in cellular variables•Associations pinpoint key regulators of B and T cell differentiation•Associations offer therapeutic targets for controlling pro-inflammatory traits,GWAS provides understanding of genetic factors shaping adaptive immune system,Common and less common variants explain 10% of variance in cellular variables,Associations pinpoint key regulators of B and T cell differentiation,Associations offer therapeutic targets for controlling pro-inflammatory traits,Lagou et al. identify genetic factors explaining interindividual variation in composition of the adaptive immune system.,Factors pinpoint key human immune regulators controlling B and T cell differentiation and levels of disease-relevant T helper and regulatory cells.,These findings shed light on mechanisms of autoimmune disease and offer therapeutic perspectives.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by uncontrolled joint inflammation and destruction of bone and cartilage.,We previously reported that C-X-C motif chemokine 10 (CXCL10; also called IP-10) has important roles in joint inflammation and bone destruction in arthritis.,However, the specific mechanisms by which CXCL10 regulates the recruitment of inflammatory cells and the production of osteoclastogenic cytokines in RA progression are not fully understood.,Bone marrow-derived macrophages and CD4+ T cells were isolated from wild-type (WT), Cxcl10 -/-, and Cxcr3 -/- mice.,CXCL10-induced migration was performed using a Boyden chamber, and CXCL10-stimulated production of osteoclastogenic cytokines was measured by quantitative real-time PCR and ELISA.,Collagen antibody-induced arthritis (CAIA) was induced by administration of collagen type II antibodies and lipopolysaccharide to the mice.,Clinical scores were analyzed and hind paws were collected for high-resolution micro-CT, and histomorphometry.,Serum was used to assess bone turnover and levels of osteoclastogenic cytokines.,CXCL10 increased the migration of inflammatory cells through C-X-C chemokine receptor 3 (CXCR3)-mediated, but not toll-like receptor 4 (TLR4)-mediated, ERK activation.,Interestingly, both receptors CXCR3 and TLR4 were simultaneously required for CXCL10-stimulated production of osteoclastogenic cytokines in CD4+ T cells.,Furthermore, calcineurin-dependent NFATc1 activation was essential for CXCL10-induced RANKL expression.,In vivo, F4/80+ macrophages and CD4+ T cells robustly infiltrated into synovium of WT mice with CAIA but were significantly reduced in both Cxcl10 -/- and Cxcr3 -/- mice.,Serum concentrations of osteoclastogenic cytokines and bone destruction were also reduced in the knockout mice, leading to attenuated progression of arthritis.,These findings highlight the importance of CXCL10 signaling in the pathogenesis of RA and provide previously unidentified details of the mechanisms by which CXCL10 promotes the development of arthritis.,The online version of this article (doi:10.1186/s13075-017-1353-6) contains supplementary material, which is available to authorized users.

IgA nephropathy (IgAN) is a common cause of chronic kidney disease and end-stage renal failure, especially in young people.,Due to a wide range of clinical outcomes and difficulty in predicting response to immunosuppression, we need to understand why and identify which patients with IgAN will develop progressive renal impairment.,A deletion polymorphism affecting the genes encoding the complement factor H-related protein (FHR)-1 and FHR-3 is robustly associated with protection against IgAN.,Some FHR proteins, including FHR-1 and FHR-5, antagonize the ability of complement factor H (fH), the major negative regulator of the complement alternative pathway, to inhibit complement activation on surfaces, a process termed fH deregulation.,From a large cohort of patients, we demonstrated that plasma FHR-1 and the FHR-1/fH ratio were elevated in IgAN and associated with progressive disease.,Plasma FHR-1 negatively correlated with eGFR but remained elevated in patients with IgAN with normal eGFR.,Serum FHR5 was slightly elevated in IgAN but did not correlate with eGFR.,Neither FHR5 levels nor the FHR-5/fH ratio was associated with progressive disease.,However, higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score).,Thus, FHR-1 and FHR-5 have a role in IgAN disease progression.

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry.,We identified six novel genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA.,We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci.,The cumulative burden of risk alleles is strongly associated with age at disease onset.,Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens.,The geo-spatial distribution of risk alleles is highly suggestive of multi-locus adaptation and the genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.

To expand the knowledge about the immunological consequences of cladribine (CLAD), a pulsed immune reconstitution therapy approved for active multiple sclerosis (MS), beyond the known short‐term effects on peripheral immune cell subsets.,In this study, we characterized depletion and restitution kinetics as well as cytokine profiles of peripheral immune cell subsets in 18 patients with MS following treatment with oral CLAD.,The methods involved blood collection prior to CLAD and every three months over a period of 24 months, and extensive characterization of various immune cells subsets by multiparametric flow cytometry.,We found a selectivity of CLAD towards central memory T cells and memory B cells and detected a hyper‐repopulation of maturing B cells.,Counts of classical (−65%) and various nonclassical TH17 cells (−84% to −87%) were markedly reduced 24 months after treatment start, and were comparable with depletion rates of class‐switched memory B‐cell phenotypes (−87% to −95%).,The nadir of TH cells was more pronounced in the second treatment year.,We observed a proportional surge of CD20 T‐cell subsets and an expansion of regulatory T, B and NK cells.,Natural killer T cells (NKT) were only depleted in year two and did not recover.,Peripheral immune cell profiling revealed more differentiated insights into the immunological effects of CLAD.,While some immune cell subsets expanded, we also observed additive depleting effects after the second treatment course.,Further studies are required to elucidate whether these changes are paramount for the consistent and prolonged disease‐modifying effect of CLAD.

Natalizumab is an effective monoclonal antibody therapy for the treatment of relapsing- remitting multiple sclerosis (RRMS) and interferes with immune cell migration into the central nervous system by blocking the α4 subunit of very-late activation antigen-4 (VLA-4).,Although well tolerated and very effective, some patients still suffer from relapses in spite of natalizumab therapy or from unwanted side effects like progressive multifocal leukoencephalopathy (PML).,In search of a routine-qualified biomarker on the effectiveness of natalizumab therapy we applied flow cytometry and analyzed natalizumab binding to α4 and α4 integrin surface levels on T-cells, B-cells, natural killer (NK) cells, and NKT cells from 26 RRMS patients under up to 72 weeks of therapy.,Four-weekly infusions of natalizumab resulted in a significant and sustained increase of lymphocyte-bound natalizumab (p<0.001) which was paralleled by a significant decrease in detectability of the α4 integrin subunit on all lymphocyte subsets (p<0.001).,We observed pronounced natalizumab accumulations on T and B cells at single measurements in all patients who reported clinical disease activity (n = 4).,The natalizumab binding capacity of in vitro saturated lymphocytes collected during therapy was strongly diminished compared to treatment-naive cells indicating a therapy-induced reduction of α4.,Summing up, this pilot study shows that flow cytometry is a useful method to monitor natalizumab binding to lymphocytes from RRMS patients under therapy.,Investigating natalizumab binding provides an opportunity to evaluate the molecular level of effectiveness of natalizumab therapy in individual patients.,In combination with natalizumab saturation experiments, it possibly even provides a means of studying the feasability of patient-tailored infusion intervals.,A routine-qualified biomarker on the basis of individual natalizumab saturation on lymphocyte subsets might be an effective tool to improve treatment safety.

Tofacitinib and baricitinib are the first orally available, small-molecule inhibitors of Janus kinase (JAK) enzymes to be approved for the treatment of RA.,Tofacitinib is a selective JAK1, 3 inhibitor with less activity against JAK2 and TYK2 and baricitinib is a selective, oral JAK1, 2 inhibitor with moderate activity against TYK2 and significantly less activity against JAK3.,Both drugs have undergone extensive phase III clinical trials in RA and demonstrated rapid improvements in disease activity, function and patient-reported outcomes as well as disease modification.,Tofacitinib 5 mg bd, was approved by the Federal Drug Administration in 2012 for the treatment of RA in patients who are intolerant or unresponsive to MTX.,An extended release formulation for the treatment of RA was approved by Federal Drug Administration in 2016.,In 2017 the European Medicines Agency approved tofacitinib 5 mg bd in combination with MTX and baricitinib 4 mg and 2 mg once daily for the treatment of moderate to severe active RA in adult patients who are intolerant or unresponsive to one or more conventional synthetic DMARDs.

In this study, we examined the effect of oxidative stress on cellular energy metabolism and pro-angiogenic/pro-inflammatory mechanisms of primary rheumatoid arthritis synovial fibroblast cells (RASFC) and human umbilical vein endothelial cells (HUVEC).,Primary RASFC and HUVEC were cultured with the oxidative stress inducer 4-hydroxy-2-nonenal (4-HNE), and extracellular acidification rate, oxygen consumption rate, mitochondrial function and pro-angiogenic/pro-inflammatory mechanisms were assessed using the Seahorse analyser, complex I-V activity assays, random mutation mitochondrial capture assays, enzyme-linked immunosorbent assays and functional assays, including angiogenic tube formation, migration and invasion.,Expression of angiogenic growth factors in synovial tissue (ST) was assessed by IHC in patients with rheumatoid arthritis (RA) undergoing arthroscopy before and after administration of tumour necrosis factor inhibitors (TNFi).,In RASFC and HUVEC, 4-HNE-induced oxidative stress reprogrammed energy metabolism by inhibiting mitochondrial basal, maximal and adenosine triphosphate-linked respiration and reserve capacity, coupled with the reduced enzymatic activity of oxidative phosphorylation complexes III and IV.,In contrast, 4-HNE elevated basal glycolysis, glycolytic capacity and glycolytic reserve, paralleled by an increase in mitochondrial DNA mutations and reactive oxygen species.,4-HNE activated pro-angiogenic responses of RASFC, which subsequently altered HUVEC invasion and migration, angiogenic tube formation and the release of pro-angiogenic mediators.,In vivo markers of angiogenesis (vascular endothelial growth factor, angiopoietin 2 [Ang2], tyrosine kinase receptor [Tie2]) were significantly associated with oxidative damage and oxygen metabolism in the inflamed synovium.,Significant reduction in ST vascularity and Ang2/Tie2 expression was demonstrated in patients with RA before and after administration of TNFi.,Oxidative stress promotes metabolism in favour of glycolysis, an effect that may contribute to acceleration of inflammatory mechanisms and subsequent dysfunctional angiogenesis in RA.,The online version of this article (10.1186/s13075-018-1592-1) contains supplementary material, which is available to authorized users.

Iron may contribute to the pathogenesis and progression of multiple sclerosis (MS) due to its accumulation in the human brain with age.,Our study focused on nonheme iron distribution and the expression of the iron-related proteins ferritin, hephaestin, and ceruloplasmin in relation to oxidative damage in the brain tissue of 33 MS and 30 control cases.,We performed (1) whole-genome microarrays including 4 MS and 3 control cases to analyze the expression of iron-related genes, (2) nonheme iron histochemistry, (3) immunohistochemistry for proteins of iron metabolism, and (4) quantitative analysis by digital densitometry and cell counting in regions representing different stages of lesion maturation.,We found an age-related increase of iron in the white matter of controls as well as in patients with short disease duration.,In chronic MS, however, there was a significant decrease of iron in the normal-appearing white matter (NAWM) corresponding with disease duration, when corrected for age.,This decrease of iron in oligodendrocytes and myelin was associated with an upregulation of iron-exporting ferroxidases.,In active MS lesions, iron was apparently released from dying oligodendrocytes, resulting in extracellular accumulation of iron and uptake into microglia and macrophages.,Iron-containing microglia showed signs of cell degeneration.,At lesion edges and within centers of lesions, iron accumulated in astrocytes and axons.,Iron decreases in the NAWM of MS patients with increasing disease duration.,Cellular degeneration in MS lesions leads to waves of iron liberation, which may propagate neurodegeneration together with inflammatory oxidative burst.

Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups.,In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci.,Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region.,Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis.

The gut microbiome plays an important role in immune function and has been implicated in several autoimmune disorders.,Here we use 16S rRNA sequencing to investigate the gut microbiome in subjects with multiple sclerosis (MS, n=60) and healthy controls (n=43).,Microbiome alterations in MS include increases in Methanobrevibacter and Akkermansia and decreases in Butyricimonas, and correlate with variations in the expression of genes involved in dendritic cell maturation, interferon signalling and NF-kB signalling pathways in circulating T cells and monocytes.,Patients on disease-modifying treatment show increased abundances of Prevotella and Sutterella, and decreased Sarcina, compared with untreated patients.,MS patients of a second cohort show elevated breath methane compared with controls, consistent with our observation of increased gut Methanobrevibacter in MS in the first cohort.,Further study is required to assess whether the observed alterations in the gut microbiome play a role in, or are a consequence of, MS pathogenesis.,The gut microbiome has been implicated in several autoimmune disorders.,Here, the authors study the gut microbiome of patients with multiple sclerosis, and find correlations between altered abundance of certain gut microorganisms and changes in expression of immune defence genes.

Development of acute experimental autoimmune encephalomyelitis (EAE) depends on Th17 cells expressing the nuclear factor NR4A2.,However, in mice lacking NR4A2 in T cells, a late-onset disease is still inducible, despite a great reduction in acute inflammation.,We here reveal that development of this late onset disease depends on cytotoxic T-cell-like CD4+ T cells expressing the T-box transcription factor Eomesodermin (Eomes).,T-cell-specific deletion of the Eomes gene remarkably ameliorates the late-onset EAE.,Strikingly, similar Eomes+ CD4+ T cells are increased in the peripheral blood and cerebrospinal fluid from patients in a progressive state of multiple sclerosis.,Collective data indicate an involvement of granzyme B and protease-activated receptor-1 in the neuroinflammation mediated by Eomes+ CD4+ T cells.,Eomesodermin is a master regulator of effector CD8+ T cells.,Here the authors show that it also plays a critical role in pathogenic CD4+ cells in a mouse model of multiple sclerosis, and its inactivation ameliorates the chronic stage of the disease.

Multiple sclerosis (MS) is an immune-mediated disorder in the central nervous system (CNS) characterized by inflammation and demyelination as well as axonal and neuronal degeneration.,So far effective therapies to reverse the disease are still lacking; most therapeutic drugs can only ameliorate the symptoms or reduce the frequency of relapse.,Dendritic cells (DCs) are professional antigen presenting cells (APCs) that are key players in both mediating immune responses and inducing immune tolerance.,Increasing evidence indicates that DCs contribute to the pathogenesis of MS and might provide an avenue for therapeutic intervention.,Here, we summarize the immunogenic and tolerogenic roles of DCs in MS and review medicinal drugs that may affect functions of DCs and have been applied in clinic for MS treatment.,We also describe potential therapeutic molecules that can target DCs by inducing anti-inflammatory cytokines and inhibiting proinflammatory cytokines in MS.

Microglia are resident antigen-presenting cells in the central nervous system (CNS) that either suppress or promote disease depending on their activation phenotype and the microenvironment.,Multiple sclerosis (MS) is a chronic inflammatory disease causing demyelination and nerve loss in the CNS, and experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is widely used to investigate pathogenic mechanisms and therapeutic effects.,We isolated and cultured microglia from adult mouse brains and exposed them to specific combinations of stimulatory molecules and cytokines, the combination of IL-4, IL-10, and TGF-β yielding the optimal regime for induction of an immunosuppressive phenotype (M2).,M2 microglia were characterized by decreased expression or production of CD86, PD-L1, nitric oxide, and IL-6, increased expression of PD-L2, and having a potent capacity to retain their phenotype on secondary proinflammatory stimulation.,M2 microglia induced regulatory T cells, suppressed T-cell proliferation, and downmodulated M1-associated receptor expression in M1 macrophages.,Myelin oligodendrocyte glycoprotein (MOG)-induced EAE was induced in DBA/1 mice and at different time points (0, 5, 12, or 15 days postimmunization) 3 × 105 M2 microglia were transferred intranasally.,A single transfer of M2 microglia attenuated the severity of established EAE, which was particularly obvious when the cells were injected at 15 days postimmunization.,M2 microglia-treated mice had reduced inflammatory responses and less demyelination in the CNS.,Our findings demonstrate that adult M2 microglia therapy represents a novel intervention that alleviated established EAE and that this therapeutic principle may have relevance for treatment of MS patients.

Physical activity plays an important role in the treatment of persons with rheumatoid arthritis (RA) and is the non-pharmacological intervention with the strongest evidence to reduce fatigue.,However, physical activity can be challenging for persons who are fatigued.,The aim of this study was to investigate factors of importance for reducing fatigue in persons with RA.,This is a qualitative interview study based on semistructured, indepth individual interviews.,Interviews were analysed using qualitative content analysis.,Participants were 12 people with RA recruited from a previous randomised controlled trial of a person-centred treatment model focusing on health-enhancing physical activity and daily balance to lessen fatigue in persons with RA.,Interviews were conducted in a hospital setting.,The analysis resulted in one theme: an intellectual and embodied understanding that sustainable physical activity is important to handle fatigue.,This included five categories describing barriers and facilitating factors for sustainable physical activity: mentally overcoming the fatigue in order to be active, making exercise easy, reaching for balance, receiving support to be physically active and dealing with RA disease to be physically active.,The participants in this study expressed that physical activity was important in handling fatigue, but also that this insight could only come from personal experience.,The use of a person-centred ethic in physiotherapy coaching for patients with fatigue appears to promote sustainable physical activity behaviours by facilitating patients’ resources to overcome barriers to physical activity.

While rheumatologists often focus on treatment targets, for many patients with rheumatoid arthritis (RA), control over pain and fatigue, as well as sustaining physical function and quality of life (QoL), is of primary importance.,This literature review aimed at examining patients’ and physicians’ treatment aspirations, and identifying the unmet needs for patients with RA receiving ongoing treatment.,Searches were performed using MEDLINE, Embase, PsycINFO, and Econlit literature databases for articles published from 2004 to 2014 in the English language.,Published literature was screened to identify articles reporting the unmet needs in RA.,We found that, despite the wide range of available treatments, RA continues to pose a substantial humanistic and economic burden on patients, and there are still unmet needs across key domains such as pain, physical function, mental function, and fatigue.,These findings suggest that there is a need for further treatment advances in RA that address these domains of contemporary unmet need.

Failure of remyelination of multiple sclerosis (MS) lesions contributes to neurodegeneration that correlates with chronic disability in patients.,Currently, there are no available treatments to reduce neurodegeneration, but one therapeutic approach to fill this unmet need is to promote remyelination.,As many demyelinated MS lesions contain plentiful oligodendrocyte precursor cells (OPCs), but no mature myelinating oligodendrocytes, research has previously concentrated on promoting OPC maturation.,However, some MS lesions contain few OPCs, and therefore, remyelination failure may also be secondary to OPC recruitment failure.,Here, in a series of MS samples, we determined how many lesions contained few OPCs, and correlated this to pathological subtype and expression of the chemotactic molecules Semaphorin (Sema) 3A and 3F. 37 % of MS lesions contained low numbers of OPCs, and these were mostly chronic active lesions, in which cells expressed Sema3A (chemorepellent).,To test the hypothesis that differential Sema3 expression in demyelinated lesions alters OPC recruitment and the efficiency of subsequent remyelination, we used a focal myelinotoxic mouse model of demyelination.,Adding recombinant (r)Sema3A (chemorepellent) to demyelinated lesions reduced OPC recruitment and remyelination, whereas the addition of rSema3F (chemoattractant), or use of transgenic mice with reduced Sema3A expression increased OPC recruitment and remyelination.,We conclude that some MS lesions fail to remyelinate secondary to reduced OPC recruitment, and that chemotactic molecules are involved in the mechanism, providing a new group of drug targets to improve remyelination, with a specific target in the Sema3A receptor neuropilin-1.,The online version of this article (doi:10.1007/s00401-013-1112-y) contains supplementary material, which is available to authorized users.

Angiogenesis is a common finding in chronic inflammatory diseases; however, its role in multiple sclerosis (MS) is unclear.,Central nervous system lesions from both MS and experimental autoimmune encephalomyelitis (EAE), the animal model of MS, contain T cells, macrophages and activated glia, which can produce pro-angiogenic factors.,Previous EAE studies have demonstrated an increase in blood vessels, but differences between the different phases of disease have not been reported.,Therefore we examined angiogenic promoting factors in MS and EAE lesions to determine if there were changes in blood vessel density at different stages of EAE.,In this series of experiments we used a combination of vascular casting, VEGF ELISA and immunohistochemistry to examine angiogenesis in experimental autoimmune encephalomyelitis (EAE).,Using immunohistochemistry we also examined chronic active MS lesions for angiogenic factors.,Vascular casting and histological examination of the spinal cord and brain of rats with EAE demonstrated that the density of patent blood vessels increased in the lumbar spinal cord during the relapse phase of the disease (p < 0.05).,We found an increased expression of VEGF by inflammatory cells and a decrease in the recently described angiogenesis inhibitor meteorin.,Examination of chronic active human MS tissues demonstrated glial expression of VEGF and glial and blood vessel expression of the pro-angiogenic receptor VEGFR2.,There was a decreased expression of VEGFR1 in the lesions compared to normal white matter.,These findings reveal that angiogenesis is intimately involved in the progression of EAE and may have a role in MS.

Recently cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) and thrombosis following the adenoviral vector vaccine against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were reported.,A mechanism similar to heparin-induced thrombocytopenia was proposed with antibodies to platelet factor 4 (PF4).,Vaccine related arterial thrombosis in the brain is rare but life-threatening and optimal treatment is not established.,We report clinical, laboratory, imaging findings and treatment in a 51-year-old female presenting with acute left middle cerebral artery (MCA) occlusion 7 days after the first dose of ChAdOx1 nCoV-19 vaccine.,Due to low platelet count and suspicion of VITT she was not eligible for intravenous thrombolysis (IVT) and proceeded to mechanical thrombectomy (MER) with successful recanalization four hours after onset of symptoms.,Treatment with intravenous immunoglobulin (IVIG) and heparin pentasaccharide fondaparinux was initiated.,Presence of anti-PF4 antibodies was confirmed.,The patient improved clinically with normalization of platelet count.,Clinicians should be alert of VITT in patients with acute ischemic stroke after ChAdOx1 nCov-19 vaccination and low platelet counts.,MER showed to be feasible and effective.,We propose considering MER in patients with VITT and large vessel occlusion despite thrombocytopenia.,High-dose IVIG should be started immediately.,Alternative anticoagulation to heparin should be started 24 hours after stroke onset unless significant hemorrhagic transformation occurred.,Platelet transfusion is contraindicated and should be considered only in severe hemorrhagic complications.,Restenosis or reocclusion of the revascularized artery is possible due to the hypercoagulable state in VITT and angiographic surveillance after the procedure is reasonable.

Massive vaccination against COVID-19 has become a global priority.,Simultaneously, concerns regarding the safety of vaccines are growing.,We describe two patients who developed sensory Guillain-Barre syndrome (GBS) shortly after the first dose of the ChAdOx1 vaccine.,We also summarize 12 published cases of GBS after ChAdOx1 vaccination, highlighting their unique clinical and paraclinical features.,We propose a possible association between the risk of GBS and the ChAdOx1 vaccine and recommend surveillance for GBS following vaccination.,Population-based studies are needed to determine causality and whether specific subpopulations are susceptible.,Unlabelled Image

Pemphigus Vulgaris is an autoimmune disease of the skin and mucous membranes, which is due to the production of pathogenic autoantibodies targeting desmoglein (DSG) 1 and 3, which are adhesion proteins of the keratinocytes.,Rituximab is an anti-CD20 mAb which induces a prolonged depletion of blood B cells.,We recently showed that rituximab was more effective than a standard oral corticosteroid (CS) treatment, allowing 90% of patients to achieve complete remission (CR).,Additionally, we showed that DSG-specific-B (DSG positive) cells were still detectable during the B cell recovery which follows the initial rituximab-induced B cell depletion, even in patients in CR.,In order to characterize DSG positive B cells in patients in CR after rituximab or CS treatment relative to those detectable at baseline in patients with an active pemphigus, we studied the expression profile of 31 genes of interest related to inflammatory cytokines, TNF receptors and activation markers.,Using quantitative Polymerase Chain Reaction performed on one cell with a microfluidic technique, we found that patients' autoreactive B cells collected at baseline had a significantly higher expression of genes encoding for IL-1β, IL-23p19, and IL-12p35 pro-inflammatory cytokines and the IRF5 transcription factor, than non-autoreactive B cells.,Surprisingly, the gene expression profile of DSG positive B cells collected after rituximab treatment in patients in CR was close to that of DSG positive B cells at baseline in patients with active pemphigus, except for the IL-1β and the CD27 memory marker genes, which were under-expressed after rituximab compared to baseline.,Conversely, we observed a decreased expression of genes encoding for IL-1β and IL-23p19 in patients treated with CS relative to baseline.,This study showed that: (i) DSG positive autoreactive B cells have a different gene expression profile than non-autoreactive B cells; (ii) rituximab and CS have different effects on the genes' expression in autoreactive DSG positive B cells from pemphigus patients.

Because of the morbidity and limited therapeutic options of autoimmune diseases, there is a high, and thus far, unmet medical need for development of novel treatments.,Pemphigoid diseases, such as epidermolysis bullosa acquisita (EBA), are prototypical autoimmune diseases that are caused by autoantibodies targeting structural proteins of the skin, leading to inflammation, mediated by myeloid cells.,To identify novel treatment targets, we performed cutaneous genome-wide mRNA expression profiling in 190 outbred mice after EBA induction.,Comparison of genome-wide mRNA expression profiles in diseased and healthy mice, and construction of a co-expression network identified Sykb (spleen tyrosine kinase, SYK) as a major hub gene.,Aligned, pharmacological SYK inhibition protected mice from experimental EBA.,Using lineage-specific SYK-deficient mice, we identified SYK expression on myeloid cells to be required to induce EBA.,Within the predicted co-expression network, interactions of Sykb with several partners (e.g., Tlr13, Jdp2, and Nfkbid) were validated by curated databases.,Additionally, novel gene interaction partners of SYK were experimentally validated.,Collectively, our results identify SYK expression in myeloid cells as a requirement to promote inflammation in autoantibody-driven pathologies.,This should encourage exploitation of SYK and SYK-regulated genes as potential therapeutic targets for EBA and potentially other autoantibody-mediated diseases.

A variety of mechanisms have been suggested as the means by which infections can initiate and/or exacerbate autoimmune diseases.,One mechanism is molecular mimicry, where a foreign antigen shares sequence or structural similarities with self-antigens.,Molecular mimicry has typically been characterized on an antibody or T cell level.,However, structural relatedness between pathogen and self does not account for T cell activation in a number of autoimmune diseases.,A proposed mechanism that could have been misinterpreted for molecular mimicry is the expression of dual T cell receptors (TCR) on a single T cell.,These T cells have dual reactivity to both foreign and self-antigens leaving the host vulnerable to foreign insults capable of triggering an autoimmune response.,In this review, we briefly discuss what is known about molecular mimicry followed by a discussion of the current understanding of dual TCRs.,Finally, we discuss three mechanisms, including molecular mimicry, dual TCRs, and chimeric TCRs, by which dual reactivity of the T cell may play a role in autoimmune diseases.

Several genetic and environmental factors have been linked to Systemic Lupus Erythematosus (SLE).,One environmental trigger that has a strong association with SLE is the Epstein Barr Virus (EBV).,Our laboratory previously demonstrated that BALB/c mice expressing the complete EBNA-1 protein can develop antibodies to double stranded DNA (dsDNA).,The present study was undertaken to understand why anti-dsDNA antibodies arise during the immune response to EBNA-1.,In this study, we demonstrated that mouse antibodies elicited in response to EBNA-1 cross-react with dsDNA.,First, we showed that adsorption of sera reactive with EBNA-1 and dsDNA, on dsDNA cellulose columns, diminished reactivity with EBNA-1.,Next, we generated mononclonal antibodies (MAbs) to EBNA-1 and showed, by several methods, that they also reacted with dsDNA.,Examination of two cross-reactive MAbs-3D4, generated in this laboratory, and 0211, a commercial MAb-revealed that 3D4 recognizes the carboxyl region of EBNA-1, while 0211 recognizes both the amino and carboxyl regions.,In addition, 0211 binds moderately well to the ribonucleoprotein, Sm, which has been reported by others to elicit a cross-reactive response with EBNA-1, while 3D4 binds only weakly to Sm.,This suggests that the epitope in the carboxyl region may be more important for cross-reactivity with dsDNA while the epitope in the amino region may be more important for cross-reactivity with Sm.,In conclusion, our results demonstrate that antibodies to the EBNA-1 protein cross-react with dsDNA.,This study is significant because it demonstrates a direct link between the viral antigen and the development of anti-dsDNA antibodies, which are the hallmark of SLE.,Furthermore, it illustrates the crucial need to identify the epitopes in EBNA-1 responsible for this cross-reactivity so that therapeutic strategies can be designed to mask these regions from the immune system following EBV exposure.

This 24‐week, phase IIb, double‐blind study was undertaken to evaluate the efficacy and safety of mavrilimumab (a monoclonal antibody to granulocyte-macrophage colony‐stimulating factor receptor α) and golimumab (a monoclonal antibody to tumor necrosis factor [anti‐TNF]) in patients with rheumatoid arthritis (RA) who have had an inadequate response to disease‐modifying antirheumatic drugs (DMARDs) (referred to as DMARD‐IR) and/or inadequate response to other anti‐TNF agents (referred to as anti‐TNF-IR).,Patients with active RA and a history of DMARD‐IR (≥1 failed regimen) or DMARD‐IR (≥1 failed regimen) and anti‐TNF-IR (1-2 failed regimens) were randomized 1:1 to receive either mavrilimumab 100 mg subcutaneously every other week or golimumab 50 mg subcutaneously every 4 weeks alternating with placebo every 4 weeks, administered concomitantly with methotrexate.,The primary end points were the American College of Rheumatology 20% improvement (ACR20), 50% improvement, and 70% improvement response rates at week 24, percentage of patients achieving a Disease Activity Score in 28 joints using C‐reactive protein level (DAS28‐CRP) of <2.6 at week 24, percentage of patients with a score improvement of >0.22 on the Health Assessment Questionnaire (HAQ) disability index (DI) at week 24, and safety/tolerability measures.,This study was not powered to formally compare the 2 treatments.,At week 24, differences in the ACR20, ACR50, and ACR70 response rates between the mavrilimumab treatment group (n = 70) and golimumab treatment group (n = 68) were as follows: in all patients, −3.5% (90% confidence interval [90% CI] −16.8, 9.8), −8.6% (90% CI −22.0, 4.8), and −9.8% (90% CI −21.1, 1.4), respectively; in the anti‐TNF-IR group, 11.1% (90% CI −7.8, 29.9), −8.7% (90% CI −28.1, 10.7), and −0.7% (90% CI −18.0, 16.7), respectively.,Differences in the percentage of patients achieving a DAS28‐CRP of <2.6 at week 24 between the mavrilimumab and golimumab groups were −11.6% (90% CI −23.2, 0.0) in all patients, and −4.0% (90% CI −20.9, 12.9) in the anti‐TNF-IR group.,The percentage of patients achieving a >0.22 improvement in the HAQ DI score at week 24 was similar between the treatment groups.,Treatment‐emergent adverse events were reported in 51.4% of mavrilimumab‐treated patients and 42.6% of golimumab‐treated patients.,No deaths were reported, and no specific safety signals were identified.,The findings of this study demonstrate the clinical efficacy of both treatments, mavrilimumab at a dosage of 100 mg every other week and golimumab at a dosage of 50 mg every 4 weeks, in patients with RA.,Both regimens were well‐tolerated in patients who had shown an inadequate response to DMARDs and/or other anti‐TNF agents.

Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly.,The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights.,To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion.,A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items.,These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world.,Levels of evidence, strengths of recommendations and levels of agreement were derived.,The update resulted in 4 overarching principles and 10 recommendations.,The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts.,The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease.,The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before.,The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease.,Regular follow-up (every 1-3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended.,Follow-up examinations ought to employ composite measures of disease activity that include joint counts.,Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient.,Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10).,The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

The achievement of glycaemic control remains challenging for patients with type 1 diabetes.,We assessed the effectiveness of day-and-night hybrid closed-loop insulin delivery compared with sensor-augmented pump therapy in people with suboptimally controlled type 1 diabetes aged 6 years and older.,In this open-label, multicentre, multinational, single-period, parallel randomised controlled trial, participants were recruited from diabetes outpatient clinics at four hospitals in the UK and two centres in the USA.,We randomly assigned participants with type 1 diabetes aged 6 years and older treated with insulin pump and with suboptimal glycaemic control (glycated haemoglobin [HbA1c] 7·5-10·0%) to receive either hybrid closed-loop therapy or sensor-augmented pump therapy over 12 weeks of free living.,Training on study insulin pump and continuous glucose monitoring took place over a 4-week run-in period.,Eligible subjects were randomly assigned using central randomisation software.,Allocation to the two study groups was unblinded, and randomisation was stratified within centre by low (<8·5%) or high (≥8·5%) HbA1c.,The primary endpoint was the proportion of time that glucose concentration was within the target range of 3·9-10·0 mmol/L at 12 weeks post randomisation.,Analyses of primary outcome and safety measures were done in all randomised patients.,The trial is registered with ClinicalTrials.gov, number NCT02523131, and is closed to accrual.,From May 12, 2016, to Nov 17, 2017, 114 individuals were screened, and 86 eligible patients were randomly assigned to receive hybrid closed-loop therapy (n=46) or sensor-augmented pump therapy (n=40; control group).,The proportion of time that glucose concentration was within the target range was significantly higher in the closed-loop group (65%, SD 8) compared with the control group (54%, SD 9; mean difference in change 10·8 percentage points, 95% CI 8·2 to 13·5; p<0·0001).,In the closed-loop group, HbA1c was reduced from a screening value of 8·3% (SD 0·6) to 8·0% (SD 0·6) after the 4-week run-in, and to 7·4% (SD 0·6) after the 12-week intervention period.,In the control group, the HbA1c values were 8·2% (SD 0·5) at screening, 7·8% (SD 0·6) after run-in, and 7·7% (SD 0·5) after intervention; reductions in HbA1c percentages were significantly greater in the closed-loop group compared with the control group (mean difference in change 0·36%, 95% CI 0·19 to 0·53; p<0·0001).,The time spent with glucose concentrations below 3·9 mmol/L (mean difference in change −0·83 percentage points, −1·40 to −0·16; p=0·0013) and above 10·0 mmol/L (mean difference in change −10·3 percentage points, −13·2 to −7·5; p<0·0001) was shorter in the closed-loop group than the control group.,The coefficient of variation of sensor-measured glucose was not different between interventions (mean difference in change −0·4%, 95% CI −1·4% to 0·7%; p=0·50).,Similarly, total daily insulin dose was not different (mean difference in change 0·031 U/kg per day, 95% CI −0·005 to 0·067; p=0·09) and bodyweight did not differ (mean difference in change 0·68 kg, 95% CI −0·34 to 1·69; p=0·19).,No severe hypoglycaemia occurred.,One diabetic ketoacidosis occurred in the closed-loop group due to infusion set failure.,Two participants in each study group had significant hyperglycaemia, and there were 13 other adverse events in the closed-loop group and three in the control group.,Hybrid closed-loop insulin delivery improves glucose control while reducing the risk of hypoglycaemia across a wide age range in patients with suboptimally controlled type 1 diabetes.,JDRF, NIHR, and Wellcome Trust.

To evaluate the efficacy and safety of artificial pancreas treatment in non-pregnant outpatients with type 1 diabetes.,Systematic review and meta-analysis of randomised controlled trials.,Medline, Embase, Cochrane Library, and grey literature up to 2 February 2018.,Randomised controlled trials in non-pregnant outpatients with type 1 diabetes that compared the use of any artificial pancreas system with any type of insulin based treatment.,Primary outcome was proportion (%) of time that sensor glucose level was within the near normoglycaemic range (3.9-10 mmol/L).,Secondary outcomes included proportion (%) of time that sensor glucose level was above 10 mmol/L or below 3.9 mmol/L, low blood glucose index overnight, mean sensor glucose level, total daily insulin needs, and glycated haemoglobin.,The Cochrane Collaboration risk of bias tool was used to assess study quality.,40 studies (1027 participants with data for 44 comparisons) were included in the meta-analysis. 35 comparisons assessed a single hormone artificial pancreas system, whereas nine comparisons assessed a dual hormone system.,Only nine studies were at low risk of bias.,Proportion of time in the near normoglycaemic range (3.9-10.0 mmol/L) was significantly higher with artificial pancreas use, both overnight (weighted mean difference 15.15%, 95% confidence interval 12.21% to 18.09%) and over a 24 hour period (9.62%, 7.54% to 11.7%).,Artificial pancreas systems had a favourable effect on the proportion of time with sensor glucose level above 10 mmol/L (−8.52%, −11.14% to −5.9%) or below 3.9 mmol/L (−1.49%, −1.86% to −1.11%) over 24 hours, compared with control treatment.,Robustness of findings for the primary outcome was verified in sensitivity analyses, by including only trials at low risk of bias (11.64%, 9.1% to 14.18%) or trials under unsupervised, normal living conditions (10.42%, 8.63% to 12.2%).,Results were consistent in a subgroup analysis both for single hormone and dual hormone artificial pancreas systems.,Artificial pancreas systems are an efficacious and safe approach for treating outpatients with type 1 diabetes.,The main limitations of current research evidence on artificial pancreas systems are related to inconsistency in outcome reporting, small sample size, and short follow-up duration of individual trials.

As a consequence of the coronavirus disease 2019 (COVID-19) pandemic, a large amount of consultations will be delivered through tele-medicine, especially for diseases causing chronic disability and requiring immunomodulatory treatments, such as multiple sclerosis (MS).,We have hereby reviewed available tools for tele-neurology examination in MS, including components of neurological examination that can be assessed through video, patient-reported outcome measures (PROMs), and digital technology.,Overall, we have suggested a battery for assessing MS disability and relapses on tele-medicine, which brings together conventional examination, PROMs (e.g., Patient Determined Disease Steps, MS Impact Scale), and cognitive tests (Symbol Digit Modalities Test) that can be delivered remotely and in multiple languages.,The use of common tools for neurological examination could improve tele-neurology practice for both general neurologists and MS specialists, and quality of care for people with MS.

The impetus for this consensus discussion was to recommend clinical trial designs that can deliver high-quality data for effective therapies for pediatric patients, in a reasonable timeframe, with a key focus on short- and long-term safety.,The International Pediatric Multiple Sclerosis Study Group convened a meeting of experts to review the advances in the understanding of pediatric-onset multiple sclerosis (MS) and the advent of clinical trials for this population.,In the last few years, convincing evidence has emerged that the biological processes involved in MS are largely shared across the age span.,As such, treatments proven efficacious for the care of adults with MS have a biological rationale for use in pediatric MS given the relapsing-remitting course at onset and high relapse frequency.,There are also ethical considerations on conducting clinical trials in this age group including the use of placebo owing to highly active disease.,It is imperative to reconsider study design and implementation based on what information is needed.,Are studies needed for efficacy or should safety be the primary goal?,Further, there have been major recruitment challenges in recently completed and ongoing pediatric MS trials.,Phase 3 trials for every newly approved therapy for adult MS in the pediatric MS population are simply not feasible.,A primary goal is to ensure high-quality evidence-based treatment for children and adolescents with MS, which will improve our understanding of the safety of these agents and remove regulatory or insurance-based limitations in access to treatment.

Posttranslational modification (PTM) of self-proteins has been shown to elicit clinically relevant immune responses in rheumatoid arthritis and celiac disease.,Accumulating evidence suggests that recognition of modified self-proteins may also be important in type 1 diabetes.,Our objective was to identify posttranslationally modified GAD65 peptides, which are recognized by subjects with type 1 diabetes, and to assess their disease relevance.,We show that citrullination and transglutamination of peptides can enhance their binding to DRB1*04:01, a diabetes-susceptible HLA allele.,These and corresponding modifications to amino acids at T-cell contact positions modulated the recognition of multiple GAD65 peptides by self-reactive T cells.,Using class II tetramers, we verified that memory T cells specific for these modified epitopes were detectable directly ex vivo in the peripheral blood of subjects with type 1 diabetes at significantly higher frequencies than healthy controls.,Furthermore, T cells that recognize these modified epitopes were either less responsive or nonresponsive to their unmodified counterparts.,Our findings suggest that PTM contributes to the progression of autoimmune diabetes by eliciting T-cell responses to new epitope specificities that are present primarily in the periphery, thereby circumventing tolerance mechanisms.

Studies in type 1 diabetes indicate potential disease heterogeneity, notably in the rate of β-cell loss, responsiveness to immunotherapies, and, in limited studies, islet pathology.,We sought evidence for different immunological phenotypes using two approaches.,First, we defined blood autoimmune response phenotypes by combinatorial, multiparameter analysis of autoantibodies and autoreactive T-cell responses in 33 children/adolescents with newly diagnosed diabetes.,Multidimensional cluster analysis showed two equal-sized patient agglomerations characterized by proinflammatory (interferon-γ-positive, multiautoantibody-positive) and partially regulated (interleukin-10-positive, pauci-autoantibody-positive) responses.,Multiautoantibody-positive nondiabetic siblings at high risk of disease progression showed similar clustering.,Additionally, pancreas samples obtained post mortem from a separate cohort of 21 children/adolescents with recently diagnosed type 1 diabetes were examined immunohistologically.,This revealed two distinct types of insulitic lesions distinguishable by the degree of cellular infiltrate and presence of B cells that we termed “hyper-immune CD20Hi” and “pauci-immune CD20Lo.”,Of note, subjects had only one infiltration phenotype and were partitioned by this into two equal-sized groups that differed significantly by age at diagnosis, with hyper-immune CD20Hi subjects being 5 years younger.,These data indicate potentially related islet and blood autoimmune response phenotypes that coincide with and precede disease.,We conclude that different immunopathological processes (endotypes) may underlie type 1 diabetes, carrying important implications for treatment and prevention strategies.

Some patients with severe COVID-19 develop prothrombotic autoantibodies that are similar to antiphospholipid antibodies found in autoimmune diseases.,Patients with severe COVID-19 are at high risk for occlusion of blood vessels of all sizes.,This prothrombotic phenotype is reminiscent of patients with lupus and antiphospholipid syndrome, who have long-lived circulating antiphospholipid autoantibodies.,In new work, Zuo et al. measured eight types of antiphospholipid antibodies in serum from patients hospitalized with COVID-19 and found at least one antibody in half of patients.,Antibody levels were associated with neutrophil and coagulation pathway activation.,Purified antibodies from some patients activated neutrophils in vitro and potentiated thrombosis when injected into mice.,Together, these findings suggest that autoantibodies are a potential therapeutic target in severe COVID-19.,Patients with COVID-19 are at high risk for thrombotic arterial and venous occlusions.,Lung histopathology often reveals fibrin-based blockages in the small blood vessels of patients who succumb to the disease.,Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies).,Case series have recently detected aPL antibodies in patients with COVID-19.,Here, we measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19.,These aPL antibodies included anticardiolipin IgG, IgM, and IgA; anti-β2 glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/prothrombin (aPS/PT) IgG and IgM.,We detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples.,Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer’s threshold and in 30% using a more stringent cutoff (≥40 ELISA-specific units).,Higher titers of aPL antibodies were associated with neutrophil hyperactivity, including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate.,Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from patients with COVID-19 promoted NET release from neutrophils isolated from healthy individuals.,Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models.,These findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic.

Beta-2-Glycoprotein I (β2GPI) plays a number of essential roles throughout the body. β2GPI, C-reactive protein and thrombomodulin are the only three proteins that possess the dual capability to up and down regulate the complement and coagulation systems depending upon external stimulus.,Clinically, β2GPI is the primary antigen in the autoimmune condition antiphospholipid syndrome (APS), which is typically characterised by pregnancy morbidity and vascular thrombosis.,This protein is also capable of adopting at least two distinct structural forms, but it has been argued that several other intermediate forms may exist.,Thus, β2GPI is a unique protein with a key role in haemostasis, homeostasis and immunity.,In this review, we examine the genetics, structure and function of β2GPI in the body and how these factors may influence its contribution to disease pathogenesis.,We also consider the clinical implications of β2GPI in the diagnosis of APS and as a potentially novel therapeutic target.

Dysregulated functions of B1 cells have been implicated in the disease progression of various autoimmune disorders, but it remains largely unclear whether B1 cells are involved in the pathogenesis of autoimmune arthritis.,In this study, we found that peritoneal B1a cells underwent proliferation and migrated to the inflamed joint tissue with upregulated RANKL expression during collagen-induced arthritis (CIA) development in mice.,Adoptive transfer of B1a cells exacerbated arthritic severity and joint damage while intraperitoneal depletion of B1 cells ameliorated both arthritic symptoms and joint pathology in CIA mice.,In culture, RANKL-expressing B1a cells significantly promoted the expansion of osteoclasts derived from bone marrow cells, which were in accord with the in vivo findings of increased osteoclastogenesis in CIA mice transferred with B1a cells.,Together, these results have demonstrated a pathogenic role of B1a cells in the development of autoimmune arthritis through RANKL-mediated osteoclastogenesis.

A key phenomenon in rheumatoid arthritis is the formation of lymphoid follicles in the inflamed synovial membrane.,C-X-C motif chemokine 13 (CXCL13) is central in this process as it attracts C-X-C chemokine receptor type 5 (CXCR5)-expressing B cells and T follicular helper cells to the follicle.,We here examine the role of CXCL13 and its association with disease in patients with treatment-naïve early rheumatoid arthritis.,Plasma samples from patients in the OPERA trial were examined for CXCL13 at treatment initiation and after 6 months of treatment with either methotrexate plus placebo (DMARD) (n = 37) or methotrexate plus adalimumab (DMARD + ADA) (n = 39).,Treatment outcome was evaluated after 1 and 2 years.,CXCL13 plasma levels in healthy volunteers (n = 38) were also examined.,Baseline CXCL13 plasma levels were increased in early rheumatoid arthritis patients in comparison with healthy volunteers.,Also, plasma CXCL13 correlated positively with disease activity parameters; swollen joint count 28 (rho = 0.34) and 40 (rho = 0.39), visual analog score (rho = 0.38) and simplified disease activity index (rho = 0.25) (all P <0.05).,CXCL13 levels decreased a significantly twofold more in the DMARD + ADA group than in the DMARD group.,Baseline CXCL13 plasma levels in the DMARD group correlated inversely with disease activity parameters; disease activity score in 28 joints, four variables, C-reactive protein based (DAS28CRP) (rho = 0.58, P <0.05) at 12 months.,High baseline CXCL13 was associated with remission (DAS28CRP less than 2.6) after 2 years.,In treatment-naïve early rheumatoid arthritis patients, plasma CXCL13 levels were associated with joint inflammation.,Furthermore, patients with high baseline plasma CXCL13 levels had an improved chance of remission after 2 years.,We propose that high CXCL13 concentrations indicate recent onset of inflammation that may respond better to early aggressive treatment.,Thus, high levels of CXCL13 could reflect the ‘the window of opportunity’ for optimal treatment effect.,Clinicaltrial.gov NCT00660647.,Registered 10 April 2008

Epigenetics defines the persistent modifications of gene expression in a manner that does not involve the corresponding alterations in DNA sequences.,It includes modifications of DNA nucleotides, nucleosomal remodeling, and post-translational modifications (PTMs).,It is becoming evident that PTMs which act singly or in combination to form “histone codes” orchestrate the chromatin structure and dynamic functions.,PTMs of histone tails have been demonstrated to influence numerous biological developments, as well as disease onset and progression.,Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating and neurodegenerative disease of the central nervous system, of which the precise pathophysiological mechanisms remain to be fully elucidated.,There is a wealth of emerging evidence that epigenetic modifications may confer risk for MS, which provides new insights into MS.,Histone PTMs, one of the key events that regulate gene activation, seem to play a prominent role in the epigenetic mechanism of MS.,In this review, we summarize recent studies in our understanding of the epigenetic language encompassing histone, with special emphasis on histone acetylation and histone lysine methylation, two of the best characterized histone modifications.,We also discuss how the current studies address histone acetylation and histone lysine methylation influencing pathophysiology of MS and how future studies could be designed to establish optimized therapeutic strategies for MS.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration.,The mechanisms of tissue injury are poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process.,Mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, and we recently provided evidence for oxidative damage of oligodendrocytes and dystrophic axons in early stages of active multiple sclerosis lesions.,In this study, we identified potential sources of reactive oxygen and nitrogen species through gene expression in carefully staged and dissected lesion areas and by immunohistochemical analysis of protein expression.,Genome-wide microarrays confirmed mitochondrial injury in active multiple sclerosis lesions, which may serve as an important source of reactive oxygen species.,In addition, we found differences in the gene expression levels of various nicotinamide adenine dinucleotide phosphate oxidase subunits between initial multiple sclerosis lesions and control white matter.,These results were confirmed at the protein level by means of immunohistochemistry, showing upregulation of the subunits gp91phox, p22phox, p47phox, nicotinamide adenine dinucleotide phosphate oxidase 1 and nicotinamide adenine dinucleotide phosphate oxidase organizer 1 in activated microglia in classical active as well as slowly expanding lesions.,The subunits gp91phox and p22phox were constitutively expressed in microglia and were upregulated in the initial lesion.,In contrast, p47phox, nicotinamide adenine dinucleotide phosphate oxidase 1 and nicotinamide adenine dinucleotide phosphate oxidase organizer 1 expression were more restricted to the zone of initial damage or to lesions from patients with acute or early relapsing/remitting multiple sclerosis.,Double labelling showed co-expression of the nicotinamide adenine dinucleotide phosphate oxidase subunits in activated microglia and infiltrated macrophages, suggesting the assembly of functional complexes.,Our data suggest that the inflammation-associated oxidative burst in activated microglia and macrophages plays an important role in demyelination and free radical-mediated tissue injury in the pathogenesis of multiple sclerosis.

The incidence of type 1 diabetes is increasing more rapidly than can be explained by genetic drift.,Viruses may play an important role in the disease, as they seem to activate the 2′-5′-linked oligoadenylate (2′-5′A) pathway of the innate antiviral immune system.,Our aim was to investigate this possibility.,Innate antiviral immune pathways were searched for type 1 diabetes-associated polymorphisms using genome-wide association study data.,SNPs within ±250kb flanking regions of the transcription start site of 64 genes were examined.,These pathways were also investigated for type 1 diabetes-associated RNA expression profiles using laser-dissected islets from two to five tissue sections per donor from the Diabetes Virus Detection (DiViD) study and the network of Pancreatic Organ Donors (nPOD).,We found 27 novel SNPs in genes nominally associated with type 1 diabetes.,Three of those SNPs were located upstream of the 2′-5′A pathway, namely SNP rs4767000 (p = 1.03 × 10−9, OR 1.123), rs1034687 (p = 2.16 × 10−7, OR 0.869) and rs739744 (p = 1.03 × 10−9, OR 1.123).,We also identified a large group of dysregulated islet genes in relation to type 1 diabetes, of which two were novel.,The most aberrant genes were a group of IFN-stimulated genes.,Of those, the following distinct pathways were targeted by the dysregulation (compared with the non-diabetic control group): OAS1 increased by 111% (p < 1.00 × 10−4, 95% CI −0.43, −0.15); MX1 increased by 142% (p < 1.00 × 10−4, 95% CI −0.52, −0.22); and ISG15 increased by 197% (p = 2.00 × 10−4, 95% CI −0.68, −0.18).,We identified a genetic predisposition in the 2′-5′A pathway that potentially contributes to dysregulation of the innate antiviral immune system in type 1 diabetes.,This study describes a potential role for the 2′-5′A pathway and other components of the innate antiviral immune system in beta cell autoimmunity.,The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-021-05469-5.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcriptional factor widely expressed in immune cells.,Its ligands range from xenobiotics and natural substances to metabolites, which renders it capable of sensing and responding to a variety of environmental cues.,Although AHR signaling has long been recognized to be implicated in the pathogenesis of autoimmune disorders, such as rheumatoid arthritis (RA), colitis, and systemic lupus erythematosus (SLE), its effect on the pathogenesis of type 1 diabetes (T1D) remains less understood.,In this review, we intend to summarize its potential implication in T1D pathogenesis and to sort out the related regulatory mechanisms in different types of immune cells.,Emerging evidence supports that β cell destruction caused by autoimmune responses can be rectified by AHR signaling.,Upon activation by its ligands, AHR not only modulates the development and functionality of immune cells, but also suppresses the expression of inflammatory cytokines, through which AHR attenuates autoimmune responses during the course of T1D development.,Since AHR-initiated biological effects vary between different types of ligands, additional studies would be necessary to characterize or de novo synthesize effective and safe ligands aimed to replenish our arsenal in fighting autoimmune responses and β mass loss in a T1D setting.

A 32-year-old woman with highly active MS was infected with SARS-CoV-2 while on treatment with rituximab.,She recovered and was symptom-free for 21 days before receiving rituximab and IVIg for comorbid hypogammaglobulinemia.,Three days after the infusion she redeveloped respiratory symptoms and required admission.,Three SARS-CoV-2 nasopharyngeal swabs and antibody testing was negative; however, bronchial alveolar lavage detected SARS-CoV-2.,Reactivation of SARS-CoV-2 after rituximab for MS has not been reported but is a known risk in other conditions.,The timing of anti-CD20 treatment after SARS-CoV-2 infection requires further investigation and individual consideration to reduce the risk of reactivation.

To report outcomes on patients with multiple sclerosis (MS) and related disorders with coronavirus disease 2019 (COVID-19) illness.,From March 16 to April 30, 2020, patients with MS or related disorders at NYU Langone MS Comprehensive Care Center were identified with laboratory-confirmed or suspected COVID-19.,The diagnosis was established using a standardized questionnaire or by review of in-patient hospital records.,We identified 76 patients (55 with relapsing MS, of which 9 had pediatric onset; 17 with progressive MS; and 4 with related disorders).,Thirty-seven underwent PCR testing and were confirmed positive.,Of the entire group, 64 (84%) patients were on disease-modifying therapy (DMT) including anti-CD20 therapies (n = 34, 44.7%) and sphingosine-1-phosphate receptor modulators (n = 10, 13.5%).,The most common COVID-19 symptoms were fever and cough, but 21.1% of patients had neurologic symptom recrudescence preceding or coinciding with the infection.,A total of 18 (23.7%) were hospitalized; 8 (10.5%) had COVID-19 critical illness or related death.,Features more common among those hospitalized or with critical illness or death were older age, presence of comorbidities, progressive disease, and a nonambulatory status.,No DMT class was associated with an increased risk of hospitalization or fatal outcome.,Most patients with MS with COVID-19 do not require hospitalization despite being on DMTs.,Factors associated with critical illness were similar to the general at-risk patient population.,DMT use did not emerge as a predictor of poor COVID-19 outcome in this preliminary sample.

Fu et al. analyze Bcl6fl/flFoxp3Cre/Cre mice and show that Tfr deficiency enhances immunity to influenza virus but promotes autoimmunity, which sheds new light on the understanding and treatment of autoimmune diseases.,T follicular regulatory (Tfr) cells are a new subset of regulatory T (T reg) cells localized in the germinal center to limit the humoral response.,Until now, the physiological function of Tfr cells has been largely unknown.,In this study, we developed a Bcl6fl/flFoxp3Cre mouse to analyze the function of Tfr cells in immune and autoimmune responses.,These mice exhibited enhanced immunity to influenza virus; moreover, Bcl6fl/flFoxp3Cre/Cre mice developed late-onset spontaneous autoimmune diseases, affecting the salivary glands with lymphocyte infiltration and antibody deposition.,In a mouse experimental Sjögren’s syndrome model, ablation of Bcl6 in T reg cells greatly enhanced disease development.,Conversely, Bcl6fl/flCd4Cre mice were protected in the model.,Thus, our study indicates that Tfr cells control autoimmune diseases and can be targeted in infectious and autoimmune disease.

Programmed death cell 1 (PD-1) is an inhibitor of T cell activation and is also functionally linked to glycolysis.,We hypothesized that PD-1 expression is defective in activated T cells from children with type 1 diabetes (T1D), resulting in abnormal T cell glucose metabolism.,In this pilot study, we enrolled children with new onset T1D within 2 weeks of diagnosis (T1D), unaffected siblings of T1D (SIBS), unaffected, unrelated children (CTRL), children with new onset, and untreated Crohn disease (CD).,We repeated the assays 4-6 months post-diagnosis in T1D (T1D follow up).,We analyzed anti-CD3/-CD28-stimulated peripheral blood mononuclear cells (PBMC) subsets for PD-1 expression by flow cytometry at baseline and after 24 h in culture.,We measured cytokines in the culture medium by multiplex ELISA and glycolytic capacity with a flux analyzer.,We enrolled 37 children.,T cells derived from subjects with T1D had decreased PD-1 expression compared to the other study groups.,However, in T1D follow-up T cells expressed PD-1 similarly to controls, but had no differences in PBMC cytokine production.,Nonetheless, T1D follow up PBMCs had enhanced glycolytic capacity compared to T1D.,Activated T cells from T1D fail to upregulate PD-1 upon T-cell receptor stimulation, which may contribute to the pathogenesis of T1D.,T1D follow up PBMC expression of PD-1 normalizes, together with a significant increase in glycolysis compared to T1D.,Thus, insulin therapy in T1D children is associated with normal PD1 expression and heightened glycolytic capacity in PBMC.

Type I interferon (IFN) plays a central role in pathogenesis of systemic lupus erythematosus (SLE); tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been associated with a pathogenic role in lupus nephritis (LN).,Thus we investigated whether TWEAK could induce the activation of type I IFN pathway in LN.,We examined this in patient-derived peripheral blood mononuclear cells (PBMCs) as well as MRL/lpr mice, a murine LN model.,Relative to the control cohorts, MRL/lpr mice showed severe histological changes, high index levels of renal damage, and elevated expression of type I IFN-inducible genes.,After shRNA suppression of TWEAK, we observed that renal damage was significantly attenuated and expression of type I IFN-inducible genes was reduced in MRL/lpr mice.,In parallel, siRNA of TWEAK also significantly reduced the expression of type I IFN-inducible genes in PBMCs relative to control transfections.,In PBMCs, TWEAK stimulation also led to expression of type I IFN-inducible genes.,Our results illustrate a novel regulatory role of TWEAK, in which its activity positively regulates type I IFN pathway in LN based on preclinical models.,Our findings suggest TWEAK could act as a critical target in preventing renal damage in patients with LN.

Patients with systemic lupus erythematosus (SLE) are at increased risk of atherosclerosis, even after accounting for traditional risk factors.,High levels of leptin and low levels of adiponectin are associated with both atherosclerosis and immunomodulatory functions in the general population.,To examine the association between these adipokines and subclinical atherosclerosis in SLE, and also with other known inflammatory biomarkers of atherosclerosis.,Carotid ultrasonography was performed in 250 women with SLE and 122 controls.,Plasma leptin and adiponectin levels were measured.,Lipoprotein a (Lp(a)), oxidised phospholipids on apoB100 (OxPL/apoB100), paraoxonase, apoA-1 and inflammatory high-density lipoprotein (HDL) function were also assessed.,Leptin levels were significantly higher in patients with SLE than in controls (23.7±28.0 vs 13.3±12.9 ng/ml, p<0.001).,Leptin was also higher in the 43 patients with SLE with plaque than without plaque (36.4±32.3 vs 20.9±26.4 ng/ml, p=0.002).,After multivariate analysis, the only significant factors associated with plaque in SLE were leptin levels in the highest quartile (≥29.5 ng/ml) (OR=2.8, p=0.03), proinflammatory HDL (piHDL) (OR=12.8, p<0.001), age (OR=1.1, p<0.001), tobacco use (OR=7.7, p=0.03) and hypertension (OR=3.0, p=0.01).,Adiponectin levels were not significantly associated with plaque in our cohort.,A significant correlation between leptin and piHDL function (p<0.001), Lp(a) (p=0.01) and OxPL/apoB100 (p=0.02) was also present.,High leptin levels greatly increase the risk of subclinical atherosclerosis in SLE, and are also associated with an increase in inflammatory biomarkers of atherosclerosis such as piHDL, Lp(a) and OxPL/apoB100.,High leptin levels may help to identify patients with SLE at risk of atherosclerosis.

To review currently available data on the transfer of monoclonal antibodies (mAbs) in the breastmilk of women receiving treatment for neurologic and non-neurologic diseases.,We systematically searched the medical literature for studies referring to 19 selected mAb therapies frequently used in neurologic conditions and “breastmilk,” “breast milk,” “breastfeeding,” or “lactation.”,From an initial list of 288 unique references, 29 distinct full-text studies met the eligibility criteria.,One additional study was added after the literature search based on expert knowledge of an additional article.,These 30 studies were reviewed.,These assessed the presence of our selected mAbs in human breastmilk in samples collected from a total of 155 individual women.,Drug concentrations were typically low in breastmilk and tended to peak within 48 hours, although maximum levels could occur up to 14 days from infusion.,Most studies did not evaluate the breastmilk to maternal serum drug concentration ratio, but in those evaluating this, the highest ratio was 1:20 for infliximab.,Relative infant dose, a metric comparing the infant with maternal drug dose (<10% is generally considered safe), was evaluated for certolizumab (<1%), rituximab (<1%), and natalizumab (maximum of 5.3%; cumulative effects of monthly dosing are anticipated).,Importantly, a total of 368 infants were followed for ≥6 months after exposure to breastmilk of mothers treated with mAbs; none experienced reported developmental delay or serious infections.,The current data are reassuring for low mAb drug transfer to breastmilk, but further studies are needed, including of longer-term effects on infant immunity and childhood development.

Reduced MS disease activity with alemtuzumab versus subcutaneous interferon beta-1a (SC IFNB-1a) in core phase 2/3 studies was accompanied by increased incidence of infections that were mainly nonserious and responsive to treatment.,Alemtuzumab efficacy was durable over 6 years.,To evaluate infections over 6 years in alemtuzumab-treated patients.,Three randomized trials (CAMMS223, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I, and CARE-MS II) compared two courses of alemtuzumab 12 mg with SC IFNB-1a 44 μg in patients with active relapsing-remitting MS.,An extension study (CAMMS03409) provided further evaluation and as-needed alemtuzumab retreatment.,Infections occurred more frequently with alemtuzumab 12 mg than SC IFNB-1a during Years 1 (58.7% vs 41.3%) and 2 (52.6% vs 37.7%), but declined for alemtuzumab-treated patients in Years 3 (46.6%), 4 (42.8%), 5 (40.9%), and 6 (38.1%).,Serious infections were uncommon (1.0%-1.9% per year).,Infections were predominantly (>95%) mild to moderate and included upper respiratory tract infections, urinary tract infections, and mucocutaneous herpetic infections.,Prophylactic acyclovir reduced herpetic infections.,Lymphocyte counts after alemtuzumab therapy did not predict infection risk.,Infections with alemtuzumab were mostly mild to moderate and decreased over time, consistent with preservation of components of protective immunity.

To characterize long-term repopulation of peripheral immune cells following alemtuzumab-induced lymphopenia in relapsing-remitting MS (RRMS), with a focus on regulatory cell types, and to explore associations with clinical outcome measures.,The project was designed as a multicenter add-on longitudinal mechanistic study for RRMS patients enrolled in CARE-MS II, CARE-MS II extension at the University of Southern California and Stanford University, and an investigator-initiated study conducted at the Universities of British Columbia and Chicago.,Methods involved collection of blood at baseline, prior to alemtuzumab administration, and at months 5, 11, 17, 23, 36, and 48 post-treatment.,T cell, B cell, and natural killer (NK) cell subsets, chemokine receptor expression in T cells, in vitro cytokine secretion patterns, and regulatory T cell (Treg) function were assessed.,Clinical outcomes, including expanded disability status score (EDSS), relapses, conventional magnetic resonance imaging (MRI) measures, and incidents of secondary autoimmunity were tracked.,Variable shifts in lymphocyte populations occurred over time in favor of CD4+ T cells, B cells, and NK cells with surface phenotypes characteristic of regulatory subsets, accompanied by reduced ratios of effector to regulatory cell types.,Evidence of increased Treg competence was observed after each treatment course.,CD4+ and CD8+ T cells that express CXCR3 and CCR5 and CD8+ T cells that express CDR3 and CCR4 were also enriched after treatment, indicating heightened trafficking potential in activated T cells.,Patterns of repopulation were not associated with measures of clinical efficacy or secondary autoimmunity, but exploratory analyses using a random generalized estimating equation (GEE) Poisson model provide preliminary evidence of associations between pro-inflammatory cell types and increased risk for gadolinium (Gd+) enhancing lesions, while regulatory subsets were associated with reduced risk.,In addition, the risk for T2 lesions correlated with increases in CD3+CD8+CXCR3+ cells.,Lymphocyte repopulation after alemtuzumab treatment favors regulatory subsets in the T cell, B cell, and NK cell compartments.,Clinical efficacy may reflect the sum of interactions among them, leading to control of potentially pathogenic effector cell types.,Several immune measures were identified as possible biomarkers of lesion activity.,Future studies are necessary to more precisely define regulatory and effector subsets and their contributions to clinical efficacy and risk for secondary autoimmunity in alemtuzumab-treated patients, and to reveal new insights into mechanisms of immunopathogenesis in MS.,Parent trials for this study are registered with ClinicalTrials.gov: CARE-MS II: NCT00548405, CARE-MS II extension: NCT00930553 and ISS: NCT01307332.

Alemtuzumab is approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS).,Alemtuzumab-related secondary autoimmune disorders (sAID) are common, with thyroid sAID being the most frequent, and fundamentally affect the risk-benefit ratio.,Therefore, biomarkers indicating the development of sAID are urgently needed to instruct clinical decisions.,We evaluated whether the anti-thyroid autoantibodies (ThyAb) anti-thyroglobulin (anti-TG) and anti-thyroid-peroxidase (anti-TPO) detected at baseline by standard testing are able to indicate increased risk for thyroid sAID following alemtuzumab treatment in a multicentre prospective cohort of 106 alemtuzumab-treated RRMS patients.,We here present an interim-analysis with a median follow-up of 36 months.,Baseline characteristics demonstrated no significant differences between patients with or without thyroid sAID. 29/106 (27·4%) patients developed thyroid sAID between 5 and 51 months following alemtuzumab treatment initiation. 14/29 patients (48·3%) were positive for ThyAb at baseline and developed thyroid sAID.,Hazard ratio for time to thyroid autoimmunity was 12.15 (95% CI 4.73-31.2) indicating a highly increased risk for ThyAb positive patients.,Baseline ThyAb were associated with shorter time to sAID, but not with a specific disease entity of thyroid sAID.,Hazard ratios for age, sex, previous treatment, disease duration, disability and smoking status demonstrated no significant association with thyroid autoimmunity.,Standard ThyAb-testing for anti-TPO and anti-TG antibodies at baseline was able to indicate increased risk for clinically manifest thyroid sAID and should therefore be used in clinical decisions concerning alemtuzumab treatment initiation.,German Ministry of Education, Science, Research and Technology and the German Research foundation.

Abatacept, an inhibitor of CD28 mediated T-cell activation, has been shown to be effective in controlling inflammation during rheumatoid arthritis (RA).,However, its effects on immune regulatory B and T cells (Bregs and Tregs) has not been fully explored.,Thirty-one RA patients treated with abatacept for ≥ 6 months along with 31 RA patients treated with other modalities as well as 30 healthy controls were recruited.,Of these 62 RA patient, 49 (79%) were females with a mean age of 54 ± 12 years and disease duration of 10 ± 6 years.,The blood levels of Tregs and Bregs and their production of immunosuppressive cytokines, were determined using FACS analysis and Luminex Multiplex assay.,Treatment with abatacept significantly enhanced the blood level of IL-35+ IL-10+ Bregs (P = 0.0007).,Their levels were higher in the blood of remitted patients (DAS28-CRP < 2.6) compared to the unremitted ones (P = 0.0173), 6 months following abatacept treatment initiation.,Moreover, abatacept treatment significantly enhanced the blood levels of LAG3+ conventional and unconventional Tregs of RA patients.,This increase in the blood levels of Bregs and Tregs was accompanied with an elevated serum level of IL-35 and IFN-β in abatacept-treated patients.,Therefore, Abatacept efficiency to achieve remittance in RA could be attributed, in part, to its ability to enhance immune regulatory cells, especially IL-35+ IL-10+ Bregs.

Using the Immunochip custom single nucleotide polymorphism (SNP) array, designed for dense genotyping of 186 genome wide association study (GWAS) confirmed loci we analysed 11,475 rheumatoid arthritis cases of European ancestry and 15,870 controls for 129,464 markers.,The data were combined in meta-analysis with GWAS data from additional independent cases (n=2,363) and controls (n=17,872).,We identified fourteen novel loci; nine were associated with rheumatoid arthritis overall and 5 specifically in anti-citrillunated peptide antibody positive disease, bringing the number of confirmed European ancestry rheumatoid arthritis loci to 46.,We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at six loci and association to low frequency variants (minor allele frequency <0.05) at 4 loci.,Bioinformatic analysis of the data generated strong hypotheses for the causal SNP at seven loci.,This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.

To report the understanding and decision-making of neuroimmunologists and their treatment of patients with multiple sclerosis (MS) during the early stages of the SARS-CoV-2 (COVID-19) outbreak.,A survey instrument was designed and distributed online to neurologists in April 2020.,There were 250 respondents (response rate 21.8%). 243 saw > = 10 MS patients in the prior 6 months (average 197 patients) and were analyzed further (92% USA, 8% Canada; average practice duration 16 years; 5% rural, 17% small city, 38% large city, 40% highly urbanized).,Patient volume dropped an average of 79% (53-11 per month). 23% were aware of patients self-discontinuing a DMT due to fear of COVID-19 with 43% estimated to be doing so against medical advice. 65% of respondents reported deferring > = 1 doses of a DMT (49%), changing the dosing interval (34%), changing to home infusions (20%), switching a DMT (9%), and discontinuing DMTs altogether (8%) as a result of COVID-19.,Changes in DMTs were most common with the high-efficacy therapies alemtuzumab, cladribine, ocrelizumab, rituximab, and natalizumab. 35% made no changes to DMT prescribing. 98% expressed worry about their patients contracting COVID-19 and 78% expressed the same degree of worry about themselves. > 50% believed high-efficacy DMTs prolong viral shedding of SARS-CoV-2 and that B-cell therapies might prevent protective vaccine effects.,Accelerated pace of telemedicine and practice model changes were identified as major shifts in practice.,Reported prescribing changes and practice disruptions due to COVID-19 may be temporary but could have a lasting influence on MS care.,The online version of this article (10.1007/s00415-020-10045-9) contains supplementary material, which is available to authorized users.

Interferon-beta (IFNβ) regulates the expression of a complex set of pro- as well as anti-inflammatory genes.,In cohorts of MS patients unstratified for therapeutic response to IFNβ, normal vaccine-specific immune responses have been observed.,Data capturing antigen-specific immune responses in cohorts of subjects defined by response to IFNβ-therapy are not available.,To assess antigen-specific immune responses in a cohort of MS patients responding clinically and radiologically to IFNβ.,In 26 MS patients, clinical and MRI disease activity were assessed before and under treatment with IFNβ.,Humoral and cellular immune response to influenza vaccine was prospectively characterized in these individuals, and 33 healthy controls by influenza-specific Enzyme-Linked Immunosorbent Assay (ELISA) and Enzyme Linked Immuno Spot Technique (ELISPOT).,Related to pre-treatment disease activity, IFNβ reduced clinical and radiological MS disease-activity.,Following influenza vaccination, frequencies of influenza-specific T cells and concentrations of anti-influenza A and B IgM and IgG increased comparably in MS-patients and in healthy controls.,By showing in a cohort of MS-patients responding to IFNβ vaccine-specific immune responses comparable to controls, this study indicates that antigen-specific immune responses can be preserved under successful IFNβ-therapy.

The purpose of this analysis is to evaluate the cost-effectiveness of belimumab, a new biological treatment specifically developed for the treatment of Systemic Lupus Erythematosus (SLE), in the Italian setting.,SLE is a chronic non-organ specific autoimmune disease characterized by a disregulation of the immune system that involves many organs and systems.,A cost-effectiveness micro-simulation model with a lifetime horizon originally developed for the UK was adapted to the Italian setting.,The analysis compared Standard of Care (SoC) alone vs belimumab plus SoC from a National Healthcare Service (NHS) and societal perspective.,Health-economic consequences of treatments and organ damage progression were calculated.,When available, Italian data were used, otherwise UK costs were converted using Purchasing Power Parities (PPPs).,Utility values were based on the EQ-5D™ assessments in the belimumab clinical trials (BLISS 52 and 76).,Results were discounted with 3% for costs and effects.,A maximum belimumab treatment duration of 6 years was assumed and wastage costs were considered.,Cost per life year gained (Incremental Cost-Effectiveness Ratio, ICER) and cost per Quality Adjusted Life Year (QALY) (Incremental Cost-Utility Ratio, ICUR) were €22,990 and €32,859, respectively.,These values reduced to €20,119 and €28,754, respectively, when indirect costs were included.,It may be concluded that in the Italian setting and according to the guidelines of the Italian Association of Health Economics (IAHE), belimumab was shown to be cost-effective, in terms of both ICER and ICUR, (€25-40,000/QALY).

BLyS and APRIL are closely related members of the TNF ligand superfamily.,These cytokines individually may contribute importantly to the development and maintenance of systemic lupus erythematosus (SLE).,Dillon and colleagues demonstrate that in contrast to most members of the TNF ligand superfamily, which form only homotrimers, BLyS and APRIL can complex as heterotrimers.,These complexes have in vitro biological activity, and circulating levels of BLyS/APRIL heterotrimers are frequently elevated in SLE, but not rheumatoid arthritis, patients.,Although the mechanism and regulation of heterotrimer formation, the interconversion (if any) between homotrimers and heterotrimers, and, indeed, the normal physiologic role for such heterotrimers remain unknown, their preferential overexpression in SLE, but not in rheumatoid arthritis, raises the possibility that such heterotrimers may be playing a contributory role in SLE.

Autoimmune hepatitis (AIH) is a severe and chronic liver disease, and its incidence has increased worldwide in recent years.,Research into the pathogenesis of AIH remains limited largely owing to the lack of suitable mouse models.,The concanavalin A (ConA) mouse model is a typical and well-established model used to investigate T cell-dependent liver injury.,However, ConA-induced hepatitis is acute and usually disappears after 48 h; thus, it does not mimic the pathogenesis of AIH in the human body.,Several studies have explored various AIH mouse models, but as yet there is no widely accepted and valid mouse model for AIH.,Immunosuppression is the standard clinical therapy for AIH, but patient side effects and recurrence limit its use.,Regulatory T cells (Tregs) play critical roles in the maintenance of immune homeostasis and in the prevention of autoimmune diseases, which may provide a potential therapeutic target for AIH therapy.,However, the role of Tregs in AIH has not yet been clarified, partly because of difficulties in diagnosing AIH and in collecting patient samples.,In this review, we discuss the studies related to Treg in various AIH mouse models and patients with AIH and provide some novel insights for this research area.

Follicular helper T (TFH) cell provides germinal centre (GC) B cell with critical signals for autoantibody production in the immunopathogenesis and progression of autoimmune hepatitis (AIH).,However, the immunoregulatory functions of follicular regulatory T (TFR) cell in AIH are still unclear.,The numbers of circulating TFR/TFH cells were measured in AIH patients.,Moreover, we established experimental autoimmune hepatitis (EAH) model to examine the function of TFR cells on B‐cell differentiation and autoantibody production in vivo and vitro.,AIH patients had significantly increased numbers of TFH cells and decreased numbers of TFR cells as well as imbalanced TFR/TFH‐type cytokines (IL‐10, TGF‐β1 and IL‐21) compared with healthy controls (HCs).,In addition, TFR cell numbers negatively correlated with TFH cell numbers.,Also, serum hypergammaglobulinaemia (IgG and IgM) concentration negatively correlated the levels of serum IL‐21, but positively correlated with the levels of serum IL‐10 in AIH patients.,Furthermore, in comparison with control group, significantly higher frequencies of spleen TFR cells but lower frequencies of spleen TFH cells were detected in the EAH group.,Further analysis found that TFR cells simultaneously express the phenotypic characteristics of Treg and TFH cells, but exercise as negative regulators of autoantibody production in vitro culture.,Our findings demonstrated that dysregulated between TFR and TFH cells might cause excessive production of autoantibodies and destruction of the immune homeostasis, leading to the immunopathological process in AIH.

B lymphocytes are the source of humoral immunity and are thus a critical component of the adaptive immune system.,However, B cells can also be pathogenic and the origin of disease.,Deregulated B-cell function has been implicated in several autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis.,B cells contribute to pathological immune responses through the secretion of cytokines, costimulation of T cells, antigen presentation, and the production of autoantibodies.,DNA-and RNA-containing immune complexes can also induce the production of type I interferons, which further promotes the inflammatory response.,B-cell depletion with the CD20 antibody rituximab has provided clinical proof of concept that targeting B cells and the humoral response can result in significant benefit to patients.,Consequently, the interest in B-cell targeted therapies has greatly increased in recent years and a number of new biologics exploiting various mechanisms are now in clinical development.,This review provides an overview on current developments in the area of B-cell targeted therapies by describing molecules and subpopulations that currently offer themselves as therapeutic targets, the different strategies to target B cells currently under investigation as well as an update on the status of novel therapeutics in clinical development.,Emerging data from clinical trials are providing critical insight regarding the role of B cells and autoantibodies in various autoimmune conditions and will guide the development of more efficacious therapeutics and better patient selection.

B cells are believed to be central to the disease process in systemic lupus erythematosus (SLE), making them a target for new therapeutic intervention.,In recent years there have been many publications regarding the experience in SLE of B-cell depletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells, reporting promising results in uncontrolled open studies and in routine clinical use.,However, the two large randomised controlled trials in extra-renal lupus (EXPLORER study) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints.,Based on the clinical experience with rituximab this failure was somewhat unexpected and raised a number of questions and concerns, not only into the true level of benefit of B-cell depletion in a broad population but also how to test the true level of effectiveness of an investigational agent as we seek to improve the design of therapeutic trials in SLE.,A better understanding of what went wrong in these trials is essential to elucidate the underlying reasons for the disparate observations noted in open studies and controlled trials.,In this review, we focus on various factors that may affect the ability to accurately and confidently establish the level of treatment effect of the investigational agent, in this case rituximab, in the two studies and explore hurdles faced in the randomised controlled trials investigating the efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE.,Further, based on the lessons learned from the clinical trials, we make suggestions that could be implemented in future clinical trial design to overcome the hurdles faced.

Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies.,The assessment of antibody assays needs to reflect their clinical utility.,We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD).,Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1).,Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD).,On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays.,The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples.,The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres.,Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way.,The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS with severe involvement of the optic nerve and spinal cord.,Highly specific serum IgG autoantibodies (NMO-IgG) that react with aquaporin-4 (AQP4), the most abundant CNS water channel protein, are found in patients with NMO.,However, in vivo evidence combining the results of AQP4 antibody serum levels and brain pathology is lacking.,We report a patient with NMO whose AQP4 antibody levels decreased simultaneously with clinical deterioration caused by the development of a tumor-like brain lesion.,In the seminecrotic biopsied brain lesion, there was activated complement complex, whereas only very scattered immunoreactivity to AQP4 protein was detectable.,The decrease in serum AQP4 antibody levels and the loss of AQP4 in the tumor-like lesion could represent a “serum antibody-consuming effect” during lesion formation.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and subsequent proliferation of synovial tissues, which eventually leads to cartilage and bone destruction without effective treatments.,Anti-citrullinated cyclic peptide/protein antibody (ACPA) and rheumatoid factor (RF) are two main characteristic autoantibodies found in RA patients and are associated with unfavorable disease outcomes.,Although etiologies and causes of the disease have not been fully clarified yet, it is likely that interactive contributions of genetic and environmental factors play a main role in RA pathology.,Previous works have demonstrated several genetic and environmental factors as risks of RA development and/or autoantibody productions.,Among these, cigarette smoking and HLA-DRB1 are the well-established environmental and genetic risks, respectively.,In this narrative review, we provide a recent update on genetic contributions to RA and the environmental risks of RA with a special focus on cigarette smoking and its impacts on RA pathology.,We also describe gene-environmental interaction in RA pathogenesis with an emphasis on cigarette smoking and HLA-DRB1.

Autoantibodies such as anti-citrullinated protein antibodies (ACPA) are major risk factors for articular bone destruction from the earliest phases of rheumatoid arthritis (RA).,The aim of the current study was to determine whether RA-associated autoantibodies also impact on systemic bone loss in patients with early disease.,Systemic bone mineral density (BMD) was measured in the lumbar spine and the hip in 155 consecutive treatment-naïve patients with early RA (median symptom duration 13 weeks).,Demographic and disease-specific parameters, including clinical disease activity, ultrasonographic (US) examination of the hands and wrists, radiographic scoring of joint damage, ACPA and rheumatoid factor (RF) levels were recorded from all patients.,Reduced BMD was defined as Z score ≤ -1 SD and analysed in relation to disease-related characteristics and autoantibody subgroups.,Reduced BMD was found in 25.5 % of the patients in the spine and 19.4 % in the hip.,Symptom duration, clinical and US disease activity, functional disability and radiographic damage did not significantly impact on spine and hip BMD loss in regression analyses adjusted for possible confounders (age, gender, menopausal status, current smoking, body mass index).,In contrast, ACPA positivity (at any level) negatively affected the spine Z-score (adjusted OR (95 % CI) 2.76 (1.19 to 6.42)); the hip Z score was affected by high titres only (adjusted OR (95 % CI) 2.96 (1.15 to 7.66)).,The association of ACPA with reduced BMD in the spine was confirmed even at low levels of RF (adjusted OR (95 % CI) 2.65 (1.01 to 7.24)), but was further increased by concomitant high RF (adjusted OR (95 % CI) 3.38 (1.11 to 10.34)).,In contrast, Z scores in the hip were significantly reduced only in association with high ACPA and RF (adjusted OR (95 % CI) 4.96 (1.48 to 16.64)).,Systemic BMD in patients with early RA is reduced in relation with ACPA positivity and high RF levels.,This finding supports the notion that RA-associated autoimmunity may have a direct causative role in bone remodeling.

Continuous glucose monitoring (CGM) enables users to view real-time interstitial glucose readings and provides information on the direction and rate of change of blood glucose levels.,Users can also access historical data to inform treatment decisions.,While the clinical and psychological benefits of CGM are well established, little is known about how individuals use CGM to inform diabetes self-management.,We explored participants’ experiences of using CGM in order to provide recommendations for supporting individuals to make optimal use of this technology.,In-depth interviews (n = 24) with adults, adolescents and parents who had used CGM for ≥4 weeks; data were analysed thematically.,Participants found CGM an empowering tool because they could access blood glucose data effortlessly, and trend arrows enabled them to see whether blood glucose was rising or dropping and at what speed.,This predicative information aided short-term lifestyle planning and enabled individuals to take action to prevent hypoglycaemia and hyperglycaemia.,Having easy access to blood glucose data on a continuous basis also allowed participants to develop a better understanding of how insulin, activity and food impacted on blood glucose.,This understanding was described as motivating individuals to make dietary changes and break cycles of over-treating hypoglycaemia and hyperglycaemia.,Participants also described how historical CGM data provided a more nuanced picture of blood glucose control than was possible with blood glucose self-monitoring and, hence, better information to inform changes to background insulin doses and mealtime ratios.,However, while participants expressed confidence making immediate adjustments to insulin and lifestyle to address impending hypoglycaemia and hypoglycaemia, most described needing and expecting health professionals to interpret historical CGM data and determine changes to background insulin doses and mealtime ratios.,While alarms could reinforce a sense of hypoglycaemic safety, some individuals expressed ambivalent views, especially those who perceived alarms as signalling personal failure to achieve optimal glycaemic control.,CGM can be an empowering and motivational tool which enables participants to fine-tune and optimize their blood glucose control.,However, individuals may benefit from psycho-social education, training and/or technological support to make optimal use of CGM data and use alarms appropriately.

Gait speed is a powerful clinical marker for mobility impairment in patients suffering from neurological disorders.,However, assessment of gait speed in coordination with delivery of comprehensive care is usually constrained to clinical environments and is often limited due to mounting demands on the availability of trained clinical staff.,These limitations in assessment design could give rise to poor ecological validity and limited ability to tailor interventions to individual patients.,Recent advances in wearable sensor technologies have fostered the development of new methods for monitoring parameters that characterize mobility impairment, such as gait speed, outside the clinic, and therefore address many of the limitations associated with clinical assessments.,However, these methods are often validated using normal gait patterns; and extending their utility to subjects with gait impairments continues to be a challenge.,In this paper, we present a machine learning method for estimating gait speed using a configurable array of skin-mounted, conformal accelerometers.,We establish the accuracy of this technique on treadmill walking data from subjects with normal gait patterns and subjects with multiple sclerosis-induced gait impairments.,For subjects with normal gait, the best performing model systematically overestimates speed by only 0.01 m/s, detects changes in speed to within less than 1%, and achieves a root-mean-square-error of 0.12 m/s.,Extending these models trained on normal gait to subjects with gait impairments yields only minor changes in model performance.,For example, for subjects with gait impairments, the best performing model systematically overestimates speed by 0.01 m/s, quantifies changes in speed to within 1%, and achieves a root-mean-square-error of 0.14 m/s.,Additional analyses demonstrate that there is no correlation between gait speed estimation error and impairment severity, and that the estimated speeds maintain the clinical significance of ground truth speed in this population.,These results support the use of wearable accelerometer arrays for estimating walking speed in normal subjects and their extension to MS patient cohorts with gait impairment.

In most cases, multiple sclerosis (MS) begins with a relapsing-remitting course followed by insidious disability worsening that is independent from clinically apparent relapses and is termed secondary progressive MS (SMPS).,Major differences exist between relapsing-remitting MS (RRMS) and SPMS, especially regarding therapeutic response to treatment.,This review provides an overview of the pathology, differentiation, and challenges in the diagnosis and treatment of SPMS.,We emphasize the criticality of conversion from a relapsing-remitting to a secondary progressive disease course not only because such conversion is evidence of disability progression, but also because, until recently, treatments that effectively reduced disability progression in relapsing MS were not proven to be effective in SPMS.,Clear clinical, imaging, immunologic, or pathologic criteria marking the transition from RRMS to SPMS have not yet been established.,Early identification of SPMS will require tools that, together with the use of appropriate treatments, may result in better long-term outcomes for the population of patients with SPMS.

We have previously demonstrated that induction of pathogenic eomesodermin-positive CD4+ T cells (Eomes+ T helper [Th] cells) is associated with transition from an acute stage to a later stage of experimental autoimmune encephalomyelitis (EAE).,In the late phase of EAE, B cells and non-B cell antigen-presenting cells (APCs) recruited to the central nervous system strikingly up-regulate prolactin (PRL).,The PRL-producing APCs have the potential to promote generation of Eomes+ Th cells from naïve T cells in an MHC class II-restricted manner, and therapies inhibitory for PRL production suppress the induction of Eomes+ Th cells and ameliorate clinical signs of EAE.,Our study highlights the unexpected role of extrapituitary PRL in the development of persistent neuroinflammation.,Induction of eomesodermin-positive CD4+ T cells (Eomes+ T helper [Th] cells) has recently been correlated with the transition from an acute stage to a later stage of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis.,Moreover, these cells’ pathogenic role has been experimentally proven in EAE.,While exploring how the pathogenic Eomes+ Th cells are generated during the course of EAE, we unexpectedly found that B cells and MHC class II+ myeloid cells isolated from the late EAE lesions strikingly up-regulated the expression of prolactin (PRL).,We demonstrate that such PRL-producing cells have a unique potential to induce Eomes+ Th cells from naïve T cells ex vivo, and that anti-MHC class II antibody could block this process.,Furthermore, PRL levels in the cerebrospinal fluid were significantly increased in the late phase of EAE, and blocking the production of PRL by bromocriptine or Zbtb20-specific siRNA significantly reduced the numbers of Eomes+ Th cells in the central nervous system (CNS) and ameliorated clinical signs in the later phase of EAE.,The PRL dependency of Eomes+ Th cells was confirmed in a series of in vitro and ex vivo experiments.,Collectively, these results indicate that extrapituitary PRL plays a crucial role in the CNS inflammation mediated by pathogenic Eomes+ Th cells.,Cellular interactions involving PRL-producing immune cells could be considered as a therapeutic target for the prevention of chronic neuroinflammation.

This study sought to investigate the genome-wide transcriptional effects of a combination of disease modifying anti-rheumatic drugs (tDMARD; methotrexate, sulfasalazine and hydroxychloroquine) in synovial tissues obtained from early rheumatoid arthritis (RA) patients.,While combination DMARD strategies have been investigated for clinical efficacy, very little data exists on the potential molecular mechanism of action.,We hypothesized that tDMARD would impact multiple biological pathways, but the specific pathways were unknown.,Paired synovial biopsy samples from early RA patients before and after 6 months of tDMARD therapy were collected by arthroscopy (n = 19).,These biopsies as well as those from subjects with normal synovium (n = 28) were profiled by total RNA sequencing.,Large differences in gene expression between RA and control biopsies (over 5000 genes) were identified.,Despite clinical efficacy, the expression of a restricted set of less than 300 genes was reversed after 6 months of treatment.,Many genes remained elevated, even in patients who achieved low disease activity.,Interestingly, tDMARD downregulated genes included those involved in T cell activation and signaling and plasmablast/plasma cell differentiation and function.,We have identified transcriptomic signatures that characterize synovial tissue from RA patients with early disease.,Analysis after 6 months of tDMARD treatment highlight consistent alterations in expression of genes related to T cell activation and plasmablast/plasma cell differentiation.,These results provide novel insight into the biology of early RA and the mechanism of tDMARD action and may help identify novel drug targets to improve rates of treatment-induced disease remission.

Fibroblast-like synoviocytes (FLSs) are a major cell population of the pannus that invades adjacent cartilage and bone in rheumatoid arthritis (RA).,The study was undertaken to determine the effect of interleukin-17 (IL-17) on the survival and/or proliferation of FLSs from RA patients and to investigate whether signal tranducer and activator of transcription 3 (STAT3) is implicated in this process.,Bcl-2 and Bax expression in FLSs was determined using the real-time PCR and western blot analysis.,The expression of Bcl-2 and phosphoSTAT3 in synovial tissues was investigated by confocal microscope.,Apoptosis of FLSs was detected by Annexin V/propidium iodide staining and/or phase contrast microscopy.,The proliferation of FLSs was determined by CCK-8 ELISA assay.,The pro-apoptotic Bax is decreased and anti-apoptotic Bcl-2 is increased in FLSs from RA patients compared with those from patients with osteoarthritis (OA).,IL-17 upregulated the expression of Bcl-2 in FLSs from RA patients, but not in FLSs from OA patients.,STAT3 was found to mediate IL-17-induced Bcl-2 upregulation in FLSs from RA patients.,Additionally, IL-17 promoted the survival and proliferation of FLSs from RA patients.,Most importantly, treatment with STAT3 inhibitor reversed the protective effect of IL-17 on FLSs apoptosis induced by sodium nitroprusside (SNP).,Our data demonstrate that STAT3 is critical in IL-17-induced survival of FLS from RA patients.,Therefore, therapeutic strategies that target the IL-17/STAT3 pathway might be strong candidates for RA treatment modalities.

EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas.,The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology.,Infectious mononucleosis increases the risk of developing MS, and immune reactivity toward EBV is higher in persons with MS, indicating inadequate control of the virus.,Previous studies have suggested that persistent EBV infection in the CNS stimulates an immunopathological response, causing bystander neural cell damage.,To verify this, we need to identify the immune culprits responsible for the detrimental antiviral response in the CNS.,In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus-infected cells.,This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology.,Epstein-Barr virus (EBV) is a ubiquitous herpesvirus strongly associated with multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS).,However, the mechanisms linking EBV infection to MS pathology are uncertain.,Neuropathological and immunological studies suggest that a persistent EBV infection in the CNS can stimulate a CD8 T-cell response aimed at clearing the virus but inadvertently causing CNS injury.,Inasmuch as in situ demonstration of EBV-specific CD8 T cells and their effector function is missing, we searched for EBV-specific CD8 T cells in MS brain tissue using the pentamer technique.,Postmortem brain samples from 12 donors with progressive MS and known HLA class I genotype were analyzed.,Brain sections were stained with HLA-matched pentamers coupled with immunogenic peptides from EBV-encoded proteins, control virus (cytomegalovirus and influenza A virus) proteins, and myelin basic protein.,CD8 T cells recognizing proteins expressed in the latent and lytic phases of the EBV life cycle were visualized in white matter lesions and/or meninges of 11/12 MS donors.,The fraction (median value) of CD8 T cells recognizing individual EBV epitopes ranged from 0.5 to 2.5% of CNS-infiltrating CD8 T cells.,Cytomegalovirus-specific CD8 T cells were detected at a lower frequency (≤0.3%) in brain sections from 4/12 MS donors.,CNS-infiltrating EBV-specific CD8 T cells were CD107a positive, suggesting a cytotoxic phenotype, and stuck to EBV-infected cells.,Together with local EBV dysregulation, selective enrichment of EBV-specific CD8 T cells in the MS brain supports the notion that skewed immune responses toward EBV contribute to inflammation causing CNS injury.,IMPORTANCE EBV establishes a lifelong and asymptomatic infection in most individuals and more rarely causes infectious mononucleosis and malignancies, like lymphomas.,The virus is also strongly associated with MS, a chronic neuroinflammatory disease with unknown etiology.,Infectious mononucleosis increases the risk of developing MS, and immune reactivity toward EBV is higher in persons with MS, indicating inadequate control of the virus.,Previous studies have suggested that persistent EBV infection in the CNS stimulates an immunopathological response, causing bystander neural cell damage.,To verify this, we need to identify the immune culprits responsible for the detrimental antiviral response in the CNS.,In this study, we analyzed postmortem brains donated by persons with MS and show that CD8 cytotoxic T cells recognizing EBV enter the brain and interact locally with the virus-infected cells.,This antiviral CD8 T cell-mediated immune response likely contributes to MS pathology.

Multiple sclerosis (MS) is a chronic neuroinflammatory condition of the central nervous system (CNS).,It is a major cause of neurological disability in young adults, particularly women.,What triggers the destruction of myelin sheaths covering nerve fibres is unknown.,Both genetic and infectious agents have been implicated.,Of the infectious agents, Epstein-Barr virus (EBV), a common herpesvirus, has the strongest epidemiological and serological evidence.,However, the presence of EBV in the CNS and demonstration of the underlying mechanism(s) linking EBV to the pathogenesis of MS remain to be elucidated.,We aimed at understanding the contribution of EBV infection in the pathology of MS.,We examined 1055 specimens (440 DNA samples and 615 brain tissues) from 101 MS and 21 non-MS cases for the presence of EBV using PCR and EBER-in situ hybridization (EBER-ISH).,EBV was detected by PCR and/or EBER-ISH in 91/101 (90%) of MS cases compared to only 5/21 (24%) of non-MS cases with other neuropathologies.,None of the samples were PCR positive for other common herpesviruses (HSV-1, CMV, HHV-6).,By quantitative PCR, EBV viral load in MS brain was mainly low to moderate in most cases.,However, in 18/101 (18%) of MS cases, widespread but scattered presence of EBV infected cells was noted in the affected tissues by EBER-ISH.,Immunohistochemical analysis of EBV gene expression in the 18 heavily infected cases, revealed that the EBV latent protein EBNA1, and to a lesser extent the early lytic protein BZLF1 were expressed.,Furthermore, using double-staining we show for the first time that astrocytes and microglia, in addition to B-cells can also be infected.,To the best of our knowledge, this is the most comprehensive study demonstrating that EBV is present and transcriptionally active in the brain of most cases of MS and supports a role for the virus in MS pathogenesis.,Further studies are required to address the mechanism of EBV involvement in MS pathology.

Fatigue is one of the most common symptoms in multiple sclerosis (MS), with a major impact on patients’ quality of life.,Currently, treatment proceeds by trial and error with limited success, probably due to the presence of multiple different underlying mechanisms.,Recent neuroscientific advances offer the potential to develop tools for differentiating these mechanisms in individual patients and ultimately provide a principled basis for treatment selection.,However, development of these tools for differential diagnosis will require guidance by pathophysiological and cognitive theories that propose mechanisms which can be assessed in individual patients.,This article provides an overview of contemporary pathophysiological theories of fatigue in MS and discusses how the mechanisms they propose may become measurable with emerging technologies and thus lay a foundation for future personalised treatments.

Multiple Sclerosis (MS) require medications controlling severity of the pathology and depression, affecting more than half of the patients.,In this study, the effect of antidepressant drug fluvoxamine, a selective serotonin reuptake inhibitor, was investigated in vitro and in vivo.,Nanomolar concentrations of fluvoxamine significantly increased cell viability and proliferation of neural stem cells (NSCs) through increasing mRNA expression of Notch1, Hes1 and Ki-67, and protein levels of NICD.,Also, physiological concentrations of fluvoxamine were optimal for NSC differentiation toward oligodendrocytes, astrocytes and neurons.,In addition, fluvoxamine attenuated experimental autoimmune encephalomyelitis (EAE) severity, a rat MS model, by significantly decreasing its clinical scores.,Moreover, fluvoxamine treated EAE rats showed a decrease in IFN-γ serum levels and an increase in IL-4, pro- and anti-inflammatory cytokines respectively, compared to untreated EAE rats.,Furthermore, immune cell infiltration and demyelination plaque significantly decreased in spinal cords of fluvoxamine-treated rats, which was accompanied by an increase in protein expression of MBP and GFAP positive cells and a decrease in lactate serum levels, a new biomarker of MS progression.,In summary, besides its antidepressant activity, fluvoxamine stimulates proliferation and differentiation of NSCs particularly toward oligodendrocytes, a producer of CNS myelin.

The glycoprotein YKL-40 is a new marker of early inflammation and endothelial dysfunction.,Adiponectin is a collagen-like protein with anti-atherogenic and anti-inflammatory effects.,Increased concentrations of both markers have been reported in patients with type 1 diabetes (T1D).,To assess the possible role of YKL-40 and adiponectin as a marker of subclinical cardiovascular disease in asymptomatic patients with type 1 diabetes with no history of ischemic or macrovascular heart disease and its relationship with other classic inflammatory biomarkers.,Concentrations of YKL-40, adiponectin, IL-6, IL-1β, TNF- α, hsCRP and homocysteine were determined in 150 T1D patients (58 % men, age: 38.6 ± 8.1 years, 20.4 ± 8.1 years of evolution, BMI: 25.1 ± 3.6 kg/m2; HbA1c 8.1 ± 2.3 %, 48 % smokers; 26 % retinopathy, microalbuminuria 9 %) and 50 controls age, sex and smoke condition matched.,Subclinical atherosclerosis was assessed by a carotid ultrasonography and a computed tomography for evaluation of calcium artery calcification score (CACS).,82 % of T1D patients and 92 % of controls had a calcium score of 0.,T1D patients showed a significantly higher mean common carotid artery intima media thickness (CIMT) compared to controls (0.55 ± 0.14 vs 0.48 ± 0.14 mm, p = 0.01).,Concentrations of YKL-40 and adiponectin were significantly higher in T1D [42.6 (10.4-195.0) vs ±28.7 (11.0-51.2) ng/ml, p = 0.001 and 15.8 ± 9.1 vs.,12.4 ± 5.3 mg/ml, p = 0.008], with no differences when compared to other inflammatory parameters.,In T1D patients no association was found between YKL-40 and adiponectin and screening test for subclinical arterial disease (neither CACS nor CIMT).,A positive correlation was found between levels of YKL-40 and age and duration of disease (r = 0.28, p = 0.003; r = 0.35, p = 0.001).,There were no differences in the YKL-40 in relation to the presence or absence of retinopathy or nephropathy.,Levels of adiponectin were higher in patients with nephropathy (21.84 ± 8.15 vs.,14.88 ± 8.27 mg/ml, p = 0.008).,Type 1 diabetes patients from a Mediterranean area with a longer disease evolution, although a lower degree of subclinical disease, showed significatively higher concentrations of YKL-40 and adiponectin compared with the controls.,Therefore, we conclude that YKL-40 and adiponectin are early inflammatory markers in diabetic subjects even in the presence of a low atherosclerotic background.

Knowledge on mortality in autoimmune diabetes with adult onset is limited.,We compared mortality in adult-onset autoimmune diabetes and type 2 diabetes, taking into account metabolic risk factors, HbA1c, lifestyle, and socioeconomic factors.,Participants of the population-based HUNT2 Study (second survey of the Norwegian HelseUndersøkelsen i Nord-Trøndelag Study; n = 64,264) were followed up prospectively for mortality in the Cause of Death Registry (1995-2009).,Diabetes with onset ≥35 years was classified as autoimmune diabetes in adults if anti-GAD was positive (n = 208) and as type 2 diabetes if anti-GAD was negative (n = 2,425).,Hazard ratios (HRs) of mortality from all-causes, cardiovascular disease (CVD), and ischemic heart disease (IHD) were calculated using the Cox proportional hazards model.,Prevalence of the metabolic syndrome was lower in autoimmune diabetes than in type 2 diabetes (55 vs.,77%, P < 0.001).,Still, autoimmune diabetes was associated with an increased risks of mortality from all-causes (HR 1.55 [95% CI 1.25-1.92]), CVD (1.87 [1.40-2.48]), and IHD (2.39 [1.57-3.64]), equally high as in type 2 diabetes in analyses where individuals without diabetes were used as the reference group.,The increased risk was not explained by overweight, lifestyle, socioeconomic position, or presence of the metabolic syndrome.,Excess mortality was primarily observed in individuals with elevated HbA1c.,Mortality in autoimmune diabetes was as high as in type 2 diabetes, despite a more favorable baseline metabolic risk profile.,Excess risk was associated with poor glycemic control.,The results from this study, the largest so far on mortality in autoimmune diabetes in adults, underscore the importance of optimal treatment modalities to improve survival in adult-onset autoimmune diabetes.

Background: Vitamin D deficiency is a known risk factor for Systemic Lupus Erythematosus (SLE), yet clinical trials have not demonstrated efficacy and few studies have utilized lupus models to understand the mechanism underlying this relationship.,The Act1-/- mouse is a spontaneous model of lupus and Sjögren’s syndrome, characterized by increased Th17 cells and peripheral B cell expansion.,Vitamin D3 has anti-inflammatory properties, reduces Th17 cells and impairs B cell differentiation/activation.,Therefore, we assessed how varying amounts of vitamin D3 affected lupus-like disease in the Act1-/- mouse.,Methods: Act1-/- mice were fed either low/restricted (0 IU/kg), normal (2 IU/kg), or high/supplemented (10 IU/kg) vitamin D3 chow for 9 weeks, after which lupus-like features were analyzed.,Results: While we found no differences in Th17 cells between vitamin D3 groups, vitamin D3 restriction specifically promoted memory B cell development, accompanied by elevated levels of serum IgM, IgG1, IgG3, and anti-dsDNA IgG.,A similar significant negative association between serum vitamin D and memory B cells was confirmed in a cohort of SLE patients.,Conclusion: Low levels of vitamin D3 are associated with elevated levels of memory B cells in an animal model of lupus and well-controlled SLE patients.

Type 1 diabetes (T1D) is a chronic autoimmune disease leading to immune-mediated destruction of pancreatic beta cells, resulting in the need for insulin therapy.,The incidence of T1D is increasing worldwide, thus prompting researchers to investigate novel immunomodulatory strategies to halt autoimmunity and modify disease progression.,T1D is considered as a multifactorial disease, in which genetic predisposition and environmental factors interact to promote the triggering of autoimmune responses against beta cells.,Over the last decades, it has become clear that vitamin D exerts anti-inflammatory and immunomodulatory effects, apart from its well-established role in the regulation of calcium homeostasis and bone metabolism.,Importantly, the global incidence of vitamin D deficiency is also dramatically increasing and epidemiologic evidence suggests an involvement of vitamin D deficiency in T1D pathogenesis.,Polymorphisms in genes critical for vitamin D metabolism have also been shown to modulate the risk of T1D.,Moreover, several studies have investigated the role of vitamin D (in different doses and formulations) as a potential adjuvant immunomodulatory therapy in patients with new-onset and established T1D.,This review aims to present the current knowledge on the immunomodulatory effects of vitamin D and summarize the clinical interventional studies investigating its use for prevention or treatment of T1D.

Emerging data suggest that type 1 diabetes is a more aggressive disease in children than in adults, with important differences in pathophysiology and clinical course.,Therefore, the efficacy of disease-modifying therapies may be different in the two populations.,Understanding the developmental and regulatory pathways for type 1 diabetes-modifying therapies in children will enable industry, academia, funders, advocacy groups, and regulators to translate new science to clinical care.,This consensus report characterizes the fundamental differences in type 1 diabetes between children and adults and proposes a thoughtful approach to better understand the development and regulatory pathways for type 1 diabetes therapies.

Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of the potentially toxic immunosuppressive therapy required for their control.,Gene expression-based biomarkers facilitating individual tailoring of chemotherapy in cancer, but not autoimmunity, have been identified and translated into clinical practice1,2.,We show that transcriptional profiling of purified CD8 T cells, which avoids the confounding influences of unseparated cells3,4, identifies two distinct patient subgroups predicting long-term prognosis in two different autoimmune diseases, anti-neutrophil cytoplasmic antibody (ANCA) - associated vasculitis (AAV), a chronic, severe disease characterized by inflammation of medium and small blood vessels5, and systemic lupus erythematosus (SLE), characterized by autoantibodies, immune complex deposition and diverse clinical manifestations ranging from glomerulonephritis to neurological dysfunction6.,We show that genes defining the poor prognostic group are enriched for genes of the IL7R pathway, TCR signalling and those expressed by memory T cells.,Furthermore, the poor prognostic group is associated with an expanded CD8 T cell memory population.,These subgroups, which are also found in the normal population and can be identified by measuring expression of only three genes, raise the prospect of individualized therapy and suggest novel potential therapeutic targets in autoimmunity.

Despite important advances in the treatment of multiple sclerosis (MS) over recent years, the introduction of several disease-modifying therapies (DMTs), the burden of progressive disability and premature mortality associated with the condition remains substantial.,This burden, together with the high healthcare and societal costs associated with MS, creates a compelling case for early treatment optimization with highly efficacious therapies.,Often, patients receive several first-line therapies, while more recent and in part more effective treatments are still being introduced only after these have failed.,However, with the availability of highly efficacious therapies, a novel treatment strategy has emerged, where the aim is to achieve no evidence of disease activity (NEDA).,Achieving NEDA necessitates regular monitoring of relapses, disability and functionality.,However, there is only a poor correlation between conventional magnetic resonance imaging measures like T2 hyperintense lesion burden and the level of clinical disability.,Hence, MRI-based measures of brain atrophy have emerged in recent years potentially reflecting the magnitude of MS-related neuroaxonal damage.,Currently available DMTs differ markedly in their effects on brain atrophy: some, such as fingolimod, have been shown to significantly slow brain volume loss, compared to placebo, whereas others have shown either no, inconsistent, or delayed effects.,In addition to regular monitoring, treatment optimization also requires early intervention with efficacious therapies, because accumulating evidence shows that effective intervention during a limited period early in the course of MS is critical for maintaining neurological function and preventing subsequent disability.,Together, the advent of new MS therapies and evolving management strategies offer exciting new opportunities to optimize treatment outcomes.

Fingolimod (Gilenya®) is an oral medication for patients with highly active relapsing-remitting Multiple Sclerosis (RRMS).,Clinical trials and post-marketing experience on more than 114,000 patients have established a detailed safety profile.,Total patient exposure now exceeds 195,000 patient-years as stated in the last financial report (Dec 2014) of the Novartis Pharma AG, Basel, Switzerland.,However, less is known about the safety of long-term fingolimod use in daily practice.,Here, we describe the study design of PANGAEA (Post-Authorization Non-interventional German sAfety of GilEnyA in RRMS patients), a prospective, multicenter, non-interventional, long-term study to collect safety, efficacy, and pharmacoeconomic data on RRMS patients treated with fingolimod (0.5 mg/daily) under real-world conditions in Germany.,PANGAEA is striving to assess a real-world safety and efficacy profile of fingolimod, based on data from 4,000 RRMS patients, obtained during a 60-month observational phase.,A pharmacoeconomic sub-study of 800 RRMS patients further collects patient-reported outcome measures of disability, quality of life, compliance, treatment satisfaction, and usage of resources during a 24-month observational phase.,Descriptive statistical analyses of the safety set as well as of stratified subgroups such as patients with concomitant diabetes mellitus and pretreated patients (e.g., natalizumab) will be conducted.,PANGAEA seeks to confirm the current safety profile of fingolimod obtained in phase I-III clinical trials.,The study design presented here will additionally provide guidance on the therapeutic use of fingolimod in clinical practice and possibly assists physicians in making evidence-based decisions.

Patients with rheumatoid arthritis (RA) have an increased risk of certain solid cancers, in particular lung cancer, compared to the general population.,Treatment with tumour necrosis factor (TNF) inhibitors (TNFi) may further enhance this risk.,To compare the risk of solid cancer in patients with RA treated with TNFi to that in patients treated with non-biologic (synthetic) disease modifying antirheumatic drugs (sDMARDs).,Patients with a physician diagnosis of RA enrolled in the British Society for Rheumatology Biologics Register, a national prospective cohort study established in 2001 to monitor the long-term safety of TNFi, were followed via record linkage with the national cancer registries until first solid cancer, death, for 5 years, or until 2011.,Rates of solid cancers in 11 767 patients without prior cancer who received TNFi were compared to those in 3249 patients without prior cancer treated with sDMARDs.,427 solid cancers were reported in 52 549 patient-years follow-up for the TNFi group (81 (95% CI 74 to 89) per 10 000 patient-years) and 136 cancers were reported in 11 672 patient-years in the sDMARD cohort (117 (95% CI 98 to 138) per 10 000 patient-years).,After adjusting for differences in baseline characteristics there was no difference in risk of solid cancer for TNFi compared to sDMARD treated patients: HR 0.83 (95% CI 0.64 to 1.07).,There was no difference in the relative risk of cancer for any of the individual TNFi drugs.,The addition of TNFi to sDMARD does not alter the risk of cancer in RA patients selected for TNFi in the UK.

To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission.,ACT-RAY was a double-blind 3-year trial.,Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy).,Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2.,Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year.,If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued.,Of the 556 randomised patients, 76% completed year 2.,Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission.,Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction.,Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment.,Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients.,In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%).,Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped.,Biologic-free remission was maintained for about 3 months, but most patients eventually flared.,TCZ restart led to rapid improvement.,NCT00810199.

Lupus nephritis (LN) frequently progresses to end-stage renal disease.,Finding a biomarker for LN and a predictor for the development of chronic kidney disease (CKD) is important for patients with systemic lupus erythematosus (SLE).,Ninety patients with SLE were divided into biopsy-proven LN (n = 54) and no kidney involvement (non-LN) (n = 36) groups and followed up for 54 months.,Of 36 patients with LN, 3 (5.6%) had class II disease, 3 (5.6%) had class III, 35 (64.8%) had class IV, 10 (18.5%) had class V, and 3 (5.6%) had class VI (advanced sclerosis).,Compared to the non-LN group, patients in the LN group had higher autoimmunity evidenced by a higher proportion of low C3 and C4 levels, positive anti-double-stranded DNA antibody levels, and lower estimated glomerular filtration rates (eGFR).,Urinary neutrophil gelatinase-associated lipocalin (uNGAL) levels were significantly higher in the LN group (LN vs non-LN, 670 vs 33 ng/mL, respectively).,The patients with LN had a higher urinary polyomavirus BK (BKV) load (3.6 vs 3.0 log copies/mL) and a lower urinary BKV miRNA (miR-B1) 5p level (0.29 vs 0.55 log copies/mL, p = 0.025), while there was no significant difference in the level of miR-B1-3p.,Urinary miR-B1-5p level but not urinary BKV load was negatively correlated with uNGAL level (r = -0.22, p = 0.004).,At the cutoff value of 80 ng/mL, the receiver operating characteristic curve analysis showed that uNGAL level as a predictor of the presence of LN had a high sensitivity (98%) and specificity (100%) (area under the curve [AUC], 0.997; p < 0.001).,During the 54-month follow-up period, 14 (7%) patients with LN and none of the non-LN patients developed CKD.,Multivariate Cox regression analysis revealed that baseline uNGAL level was the only predictive factor for CKD development, while baseline serum creatinine level and eGFR were not.,An elevated urinary BKV viral load with a decreased level of miR-B1 implies the presence of LN.,In addition, an increased uNGAL level is a good biomarker not only in predicting the presence of LN but also for prediction of CKD development in patients with SLE.

Neuropsychiatric manifestation in systemic lupus erythematosus (NPSLE) is one of the most serious complications of the disease.,Previous studies revealed the strong association between serum anti-Sm and organic brain syndrome, consisting mainly of acute confusional state (ACS) of diffuse psychiatric/neuropsychological syndromes (diffuse NPSLE).,However, the precise mechanism by which anti-Sm causes diffuse NPSLE remains unclear.,Of note, recent studies demonstrated that anti-U1 RNP antibodies (anti-RNP) in cerebrospinal fluid (CSF) are associated with NPSLE.,The present study was designed to explore the association of anti-Sm antibodies in CSF with NPSLE.,Paired serum and CSF specimens were obtained from 72 patients with NPSLE (49 with diffuse NPSLE, 23 with neurological syndromes or peripheral neuropathy (focal NPSLE) and from 22 control patients with non-SLE neurological diseases.,Sera were also obtained from 41 patients with active SLE without neuropsychiatric manifestations (non-NPSLE).,Anti-Sm and anti-RNP were measured by enzyme-linked immunosorbent assay (ELISA).,Blood-brain barrier (BBB) function and intrathecal anti-Sm production were evaluated by Q albumin and CSF anti-Sm index, respectively.,Binding of anti-Sm to neuroblastoma cell lines SK-N-MC and Neuro2a was examined by flow cytometry and by cell ELISA.,Anti-Sm and anti-RNP in CSF and sera were elevated in NPSLE compared with non-SLE control.,CSF anti-Sm, but not CSF anti-RNP, was significantly elevated in ACS compared with non-ACS diffuse NPSLE or with focal NPSLE.,By contrast, there were no significant differences in serum anti-Sm or anti-RNP among subsets of NPSLE and non-NPSLE.,Whereas there were no significant differences in CSF anti-Sm index, Q albumin was elevated in ACS compared with non-ACS or with focal NPSLE.,Notably, CSF anti-Sm was correlated with Q albumin (r = 0.2373, P = 0.0447) or with serum anti-Sm (r = 0.7185, P <0.0001) in 72 patients with NPSLE.,Finally, monoclonal anti-Sm and purified human anti-Sm bound to the surface of SK-N-MC and Neuro2a.,These results demonstrate that the elevation of CSF anti-Sm through transudation from systemic circulation due to damaged BBB plays a critical role in the pathogenesis of ACS.,More importantly, the data indicate that anti-Sm is yet another autoantibody with presumed neural toxicity, but might not be the last.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by circulating autoantibodies and the formation of immune complexes.,In these responses, the selecting self-antigens likely derive from the remains of dead and dying cells, as well as from disturbances in clearance.,During cell death/activation, microparticles (MPs) can be released to the circulation.,Previous MP studies in SLE have been limited in size and differ regarding numbers and phenotypes.,Therefore, to characterize MPs more completely, we investigated 280 SLE patients and 280 individually matched controls.,MPs were measured with flow cytometry and phenotyped according to phosphatidylserine expression (PS+/PS−), cellular origin and inflammatory markers.,MPs, regardless of phenotype, are 2-10 times more abundant in SLE blood compared to controls.,PS− MPs predominated in SLE, but not in controls (66% vs.,42%).,Selectively in SLE, PS− MPs were more numerous in females and smokers.,MP numbers decreased with declining renal function, but no clear association with disease activity was observed.,The striking abundance of MPs, especially PS− MPs, suggests a generalized disturbance in SLE.,MPs may be regarded as “liquid biopsies” to assess the production and clearance of dead, dying and activated cells, i.e. pivotal events for SLE pathogenesis.

Signals controlling the generation of regulatory B (Breg) cells remain ill-defined.,Here we report an “auto”-regulatory feedback mechanism between plasmacytoid dendritic cells (pDCs) and Breg cells.,In healthy individuals, pDCs drive the differentiation of CD19+CD24hiCD38hi (immature) B cells into IL-10-producing CD24+CD38hi Breg cells and plasmablasts, via the release of IFN-α and CD40 engagement.,CD24+CD38hi Breg cells conversely restrained IFN-α production by pDCs via IL-10 release.,In systemic lupus erythematosus (SLE), this cross-talk was compromised; pDCs promoted plasmablast differentiation but failed to induce Breg cells.,This defect was recapitulated in healthy B cells upon exposure to a high concentration of IFN-α.,Defective pDC-mediated expansion of CD24+CD38hi Breg cell numbers in SLE was associated with altered STAT1 and STAT3 activation.,Both altered pDC-CD24+CD38hi Breg cell interactions and STAT1-STAT3 activation were normalized in SLE patients responding to rituximab.,We propose that alteration in pDC-CD24+CD38hi Breg cell interaction contributes to the pathogenesis of SLE.,•pDCs induce the differentiation of Breg cells in an IFN-α-dependent manner•Breg cells limit pDC-derived IFN-α in an IL-10-dependent mechanism•pDCs are hyperactivated in SLE and fail to induce Breg cells•Patients responding to rituximab display a normalized pDC-Breg cell interaction,pDCs induce the differentiation of Breg cells in an IFN-α-dependent manner,Breg cells limit pDC-derived IFN-α in an IL-10-dependent mechanism,pDCs are hyperactivated in SLE and fail to induce Breg cells,Patients responding to rituximab display a normalized pDC-Breg cell interaction,The signals required for Breg cell differentiation in humans are currently unknown.,Mauri and colleagues show that plasmacytoid dendritic cells, via the provision of IFN-α, govern the differentiation of immature B cells into regulatory B cells that restrain inflammation.

Namilumab (AMG203), an immunoglobulin G1 monoclonal antibody that binds with high affinity to granulocyte-macrophage colony-stimulating factor (GM-CSF), was evaluated in a phase II randomized, double-blind, placebo-controlled study to investigate the efficacy and safety in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX-IR) or anti-tumour necrosis factor therapy (TNF-IR).,Subcutaneous namilumab (20, 80, or 150 mg) or placebo was administered at baseline and weeks 2, 6, and 10 in patients on stable background methotrexate therapy who were with MTX-IR or TNF-IR.,Primary endpoint was mean change from baseline in the 28-joint Disease Activity Score, C-reactive protein version (DAS28-CRP) at week 12 comparing each of the three doses of namilumab to placebo.,Safety and tolerability were assessed by adverse events (AEs) and pulmonary parameters.,Results were analysed using the per-protocol population.,One hundred eight patients from Europe and Japan (48.4 ± 12.02 years old; 77.8% female; mean DAS28-CRP 5.60-5.79; rheumatoid factor/anti-citrullinated protein antibodies + 75%) were randomized to placebo or namilumab 20, 80, or 150 mg (n = 27, 28, 25, and 28, respectively).,Ninety-two were MTX-IR; 16 were TNF-IR.,At week 12, a statistically significant difference in DAS28-CRP (p = 0.005) was seen for namilumab 150 mg versus placebo and separation was seen as early as week 2 for namilumab 150 mg (p < 0.05), with higher ACR50 and response rates versus placebo at week 12.,A dose-response effect was observed across the DAS28-CRP endpoint with separation versus placebo evident from week 2.,The most common treatment-emergent AEs were nasopharyngitis (18.5%, 17.9%, 4.0%, 14.3%), dyspnoea (0.0%, 3.6%, 8.0%, 10.7%), bronchitis (7.4%, 3.6%, 4.0%, 3.6%), and headache (3.7%, 3.6%, 12.0%, 0.0%) for placebo and 20, 80, or 150 mg of namilumab, respectively.,No serious infections were observed.,One serious AE (myocardial infarction) was observed with 150 mg of namilumab.,There was no apparent dose relationship for AEs.,A biomarker-based disease activity score showed a dose-dependent decrease at week 12.,This phase II study demonstrates the benefit of inhibiting macrophage activity targeting the GM-CSF for RA.,The study met its primary endpoint with a clear dose-response effect.,An acceptable tolerability profile was demonstrated over the 12-week study.,ClinicalTrials.gov, NEXUS; NCT02379091, submitted November 28, 2014,The online version of this article (10.1186/s13075-019-1879-x) contains supplementary material, which is available to authorized users.

Mavrilimumab, a human monoclonal antibody, targets granulocyte-macrophage colony‐stimulating factor receptor α.,We undertook to determine the long‐term safety and efficacy of mavrilimumab in rheumatoid arthritis patients in 2 phase IIb studies (1071 and 1107) and in 1 open‐label extension study (ClinicalTrials.gov identifier: NCT01712399).,In study 1071, patients with an inadequate response to disease‐modifying antirheumatic drugs (DMARDs) received mavrilimumab (30, 100, or 150 mg) or placebo every other week plus methotrexate.,In study 1107, patients with an inadequate response to anti-tumor necrosis factor agents and/or DMARDs received 100 mg mavrilimumab every other week or 50 mg golimumab every 4 weeks plus methotrexate.,Patients entering the open‐label extension study received 100 mg mavrilimumab every other week plus methotrexate.,Long‐term safety and efficacy of mavrilimumab were assessed.,A total of 442 patients received mavrilimumab (14 of 245 patients from study 1071, 9 of 70 patients from study 1107, and 52 of 397 patients from the open‐label extension study discontinued mavrilimumab treatment throughout the studies).,The cumulative safety exposure was 899 patient‐years; the median duration of mavrilimumab treatment was 2.5 years (range 0.1-3.3 years).,The most common treatment‐emergent adverse events (AEs) were nasopharyngitis (n = 69; 7.68 per 100 patient‐years) and bronchitis (n = 51; 5.68 per 100 patient‐years).,At weeks 74 and 104, 3.5% and 6.2% of patients, respectively, demonstrated reduction in forced expiratory volume in 1 second, while 2.9% and 3.4% of patients, respectively, demonstrated reduction in forced vital capacity (>20% reduction from baseline to <80% predicted).,Most pulmonary changes were transient and only infrequently associated with AEs.,Mavrilimumab at 100 mg every other week demonstrated sustained efficacy; at week 122, 65.0% of patients achieved a Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) of <3.2, and 40.6% of patients achieved a DAS28‐CRP of <2.6.,Long‐term treatment with mavrilimumab maintained response and was well‐tolerated with no increased incidence of treatment‐emergent AEs.,Safety data were comparable with those from both phase IIb qualifying studies.

•Coronoviruses not only affect the respiratory system, but also have deleterious effects on the central nervous system.,•Most neurological diseases could be caused by coronoviruses invasion.,•Coronoviruses cause nerve damage via diverse pathways.,Coronoviruses not only affect the respiratory system, but also have deleterious effects on the central nervous system.,Most neurological diseases could be caused by coronoviruses invasion.,Coronoviruses cause nerve damage via diverse pathways.,Viral infections have detrimental impacts on neurological functions, and even to cause severe neurological damage.,Very recently, coronaviruses (CoV), especially severe acute respiratory syndrome CoV 2 (SARS-CoV-2), exhibit neurotropic properties and may also cause neurological diseases.,It is reported that CoV can be found in the brain or cerebrospinal fluid.,The pathobiology of these neuroinvasive viruses is still incompletely known, and it is therefore important to explore the impact of CoV infections on the nervous system.,Here, we review the research into neurological complications in CoV infections and the possible mechanisms of damage to the nervous system.

Dysregulation of the complement system is evident in many CNS diseases but mechanisms regulating complement activation in the CNS remain unclear.,In a recent large rat genome-wide expression profiling and linkage analysis we found co-regulation of complement C3 immediately downstream of butyrylcholinesterase (BuChE), an enzyme hydrolyzing acetylcholine (ACh), a classical neurotransmitter with immunoregulatory effects.,We here determined levels of neurofilament-light (NFL), a marker for ongoing nerve injury, C3 and activity of the two main ACh hydrolyzing enzymes, acetylcholinesterase (AChE) and BuChE, in cerebrospinal fluid (CSF) from patients with MS (n = 48) and non-inflammatory controls (n = 18).,C3 levels were elevated in MS patients compared to controls and correlated both to disability and NFL.,C3 levels were not induced by relapses, but were increased in patients with ≥9 cerebral lesions on magnetic resonance imaging and in patients with progressive disease.,BuChE activity did not differ at the group level, but was correlated to both C3 and NFL levels in individual samples.,In conclusion, we show that CSF C3 correlates both to a marker for ongoing nerve injury and degree of disease disability.,Moreover, our results also suggest a potential link between intrathecal cholinergic activity and complement activation.,These results motivate further efforts directed at elucidating the regulation and effector functions of the complement system in MS, and its relation to cholinergic tone.

Rheumatoid arthritis (RA) is the most common chronic inflammatory rheumatic condition over the world.,RA is potentially disabling because chronic inflammation of the joints leads to joint destruction.,To date, the best predictor of radiographic progression for patients with early RA is the presence of radiographic erosions at baseline, but a limited number of predictive biomarkers of structural progression are currently used in daily practice.,Here, we investigated Dickkopf-1 (DKK-1) and sclerostin (SOST) serum levels in patients with recent inflammatory arthritis from the ESPOIR cohort.,This cohort is a prospective, multicenter French cohort of 813 patients with early arthritis.,We observed that mean baseline DKK-1 level was higher among RA patients with than without radiological progression within the first 2 years of evolution.,DKK-1 level was still associated with radiographic progression in a model including other main predictors of severity (erosions at baseline, and anti-CCP antibody positivity).,This study demonstrates that increased DKK-1 level at baseline predicted structural progression after 2-year follow-up and suggests that DKK-1 might be a new structural biomarker for early RA.

Proinflammatory cytokines and growth factors, which regulate mutual interactions between immune system cells and bone tissue cells, play a major role in the formation of bone changes in rheumatoid arthritis (RA).,The aim of the work was to assess serum concentration of osteoprotegerin (OPG), RANKL, Dkk-1 and sclerostin in RA patients compared to a control group and to analyze changes of these concentrations during methotrexate (MTX) therapy.,Patients enrolled in the study were 30 women of Caucasian origin aged 30-74 years with RA.,Patients with active form of the disease were administered recommended doses of MTX for at least 6 months.,The study group was divided into subgroup I-patients with improvement; and subgroup II-patients with no improvement.,The control group consisted of 12 healthy women in the age of 41-73.,Before MTX therapy, RA patients had higher levels of RANKL (644.97 ± 477.13 vs.,255.19 ± 130.26 pmol/l), lower values of OPG/RANKL (0.01 ± 0.0101 vs.,0.02 ± 0.0078) and higher levels of Dkk-1 protein (1821.32 ± 1060.28 vs.,548.52 ± 36.35 pg/ml) compared to the control group.,In the analyzed group of patients (all patients receiving MTX regardless of responder non responder status) after 6 months of therapy, a statistically significant increase in the ratio of OPG/RANKL was found (0.0118 ± 0.0102 vs.,0.0141 ± 0.0118; p = 0.02).,The index value of OPG/RANKL differed significantly depending on the resultant effect of treatment (0.01702 ± 0.01274 in the subgroup of improvement vs.,0.00675 ± 0.00289 in the subgroup without improvement).,The difference in the mean concentrations of Dkk-1 before and after treatment with MTX between subgroups I and II was statistically significant (p = 0.002).,In subgroup I, mean concentration of Dkk-1 decreased after 6 months of treatment with MTX (2054.72 ± 1004.74 vs.,1831.70 ± 851.70 pg/ml); while in subgroup II, the mean concentration of Dkk-1 increased (1214.48 ± 738.32 vs.,2275.01 ± 1385.23 pg/ml).,There were no statistically significant changes in the mean concentrations of sclerostin before and after treatment with MTX (in whole group treatment with MTX, in subgroup I, and in subgroup II).,The results confirm the presence of disorders of bone metabolism in patients with RA.,Treatment with MTX affects the value of the ratio of OPG/RANKL and concentration of Dkk-1.

To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA-seq and flow cytometry to T cells, B cells, monocytes and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis.,Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations.,Combining mass cytometry and transcriptomics together revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ T peripheral helper (Tph) and T follicular helper (Tfh).,We defined distinct subsets of CD8+ T cells characterized by a GZMK+, GZMB+ and GNLY+ phenotype.,We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts, and IL1B production to pro-inflammatory monocytes.,These populations are potentially key mediators of RA pathogenesis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that leads to destructive arthritis.,Although the HLA class II locus is the strongest genetic risk factor for rheumatoid arthritis, the relationship between HLA class II alleles and lymphocyte activation remains unclear.,We performed immunophenotyping of peripheral blood mononuclear cells on 91 HLA-DRB1-genotyped RA patients and 110 healthy donors.,The frequency of memory CXCR4+CD4+ T cells, and not Th1 and Th17 cells, was significantly associated with disease severity by multiple linear regression analysis.,RA patients with one or more susceptible HLA-DR haplotypes (shared epitope: SE) displayed a significantly higher frequency of memory CXCR4+CD4+ T cells.,Moreover, the frequency of memory CXCR4+CD4+ T cells significantly correlated with the expression level of HLA-DR on B cells, which was elevated in RA patients with SE.,In vitro analysis and transcriptomic pathway analysis suggested that the interaction between HLA-DR and T cell receptors is an important regulator of memory CXCR4+CD4+ T cells.,Clinically, a higher frequency of memory CXCR4+CD4+ T cells predicted a better response to CTLA4-Ig.,Memory CXCR4+CD4+ T cells may serve as a powerful biomarker for unraveling the linkage between HLA-DRB1 genotype and disease activity in RA.