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Daniel et al. have previously published in JEM a study on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes.,Bergman et al. now challenge these results.,Daniel et al. (https://doi.org/10.1084/jem.20110574) have previously published in JEM a study on the preventive effect of tolerogenic vaccination with a strong agonist insulin mimetope in type 1 diabetes.,Our study now challenges these results and shows that osmotic pump delivery of the modified insulin peptide R22E did not prevent hyperglycemia, accelerated disease onset, increased its incidence, and worsened insulitis.

We report here genotyping data and type 1 diabetes association analyses for HLA class I loci (A, B, and C) on 1,753 multiplex pedigrees from the Type 1 Diabetes Genetics Consortium (T1DGC), a large international collaborative study.,Complete eight-locus HLA genotyping data were generated.,Expected patient class I (HLA-A, -B, and -C) allele frequencies were calculated, based on linkage disequilibrium (LD) patterns with observed HLA class II DRB1-DQA1-DQB1 haplotype frequencies.,Expected frequencies were compared to observed allele frequencies in patients.,Significant type 1 diabetes associations were observed at all class I HLA loci.,After accounting for LD with HLA class II, the most significantly type 1 diabetes-associated alleles were B*5701 (odds ratio 0.19; P = 4 × 10−11) and B*3906 (10.31; P = 4 × 10−10).,Other significantly type 1 diabetes-associated alleles included A*2402, A*0201, B*1801, and C*0501 (predisposing) and A*1101, A*3201, A*6601, B*0702, B*4403, B*3502, C*1601, and C*0401 (protective).,Some alleles, notably B*3906, appear to modulate the risk of all DRB1-DQA1-DQB1 haplotypes on which they reside, suggesting a class I effect that is independent of class II.,Other class I type 1 diabetes associations appear to be specific to individual class II haplotypes.,Some apparent associations (e.g., C*1601) could be attributed to strong LD to another class I susceptibility locus (B*4403).,These data indicate that HLA class I alleles, in addition to and independently from HLA class II alleles, are associated with type 1 diabetes.

Multiple Sclerosis (MS) is characterized by the pathological trafficking of leukocytes into the central nervous system (CNS).,Using the murine MS model, experimental autoimmune encephalomyelitis (EAE), we previously demonstrated that antagonism of the chemokine receptor CXCR7 blocks endothelial cell sequestration of CXCL12, thereby enhancing the abluminal localization of CXCR4-expressing leukocytes.,CXCR7 antagonism led to decreased parenchymal entry of leukocytes and amelioration of ongoing disease during EAE.,Of note, animals that received high doses of CXCR7 antagonist recovered to baseline function, as assessed by standard clinical scoring.,Because functional recovery reflects axonal integrity, we utilized diffusion tensor imaging (DTI) to evaluate axonal injury in CXCR7 antagonist- versus vehicle-treated mice after recovery from EAE.,C57BL6/J mice underwent adoptive transfer of MOG-reactive Th1 cells and were treated daily with either CXCR7 antagonist or vehicle for 28 days; and then evaluated by DTI to assess for axonal injury.,After imaging, spinal cords underwent histological analysis of myelin and oligodendrocytes via staining with luxol fast blue (LFB), and immunofluorescence for myelin basic protein (MBP) and glutathione S-transferase-π (GST-π).,Detection of non-phosphorylated neurofilament H (NH-F) was also performed to detect injured axons.,Statistical analysis for EAE scores, DTI parameters and non-phosphorylated NH-F immunofluorescence were done by ANOVA followed by Bonferroni post-hoc test.,For all statistical analysis a p < 0.05 was considered significant.,In vivo DTI maps of spinal cord ventrolateral white matter (VLWM) axial diffusivities of naïve and CXCR7 antagonist-treated mice were indistinguishable, while vehicle-treated animals exhibited decreased axial diffusivities.,Quantitative differences in injured axons, as assessed via detection of non-phosphorylated NH-F, were consistent with axial diffusivity measurements.,Overall, qualitative myelin content and presence of oligodendrocytes were similar in all treatment groups, as expected by their radial diffusivity values.,Quantitative assessment of persistent inflammatory infiltrates revealed significant decreases within the parenchyma of CXCR7 antagonist-treated mice versus controls.,These data suggest that CXCR7 antagonism not only prevents persistent inflammation but also preserves axonal integrity.,Thus, targeting CXCR7 modifies both disease severity and recovery during EAE, suggesting a role for this molecule in both phases of disease.

Murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, presents typically as ascending paralysis.,However, in mice in which interferon-gamma (IFNγ) signaling is disrupted by genetic deletion, limb paralysis is accompanied by atypical deficits, including head tilt, postural imbalance, and circling, consistent with cerebellar/vestibular dysfunction.,This was previously attributed to intense cerebellar and brainstem infiltration by peripheral immune cells and formation of neutrophil-rich foci within the CNS.,However, the exact mechanism by which IFNγ signaling prohibits the development of vestibular deficits, and whether the distribution and composition of inflammatory foci within the CNS affects the course of atypical EAE remains elusive.,We induced EAE in IFNγ-/- mice and bone marrow chimeric mice in which IFNγR is not expressed in the CNS but is intact in the periphery (IFNγRCNSKO) and vice versa (IFNγRperiKO).,Blood-brain barrier permeability was determined by Evans blue intravenous administration at disease onset.,Populations of immune cell subsets in the periphery and the CNS were quantified by flow cytometry.,CNS tissues isolated at various time points after EAE induction, were analyzed by immunohistochemistry for composition of inflammatory foci and patterns of axonal degeneration.,Incidence and severity of atypical EAE were more pronounced in IFNγRCNSKO as compared to IFNγRperiKO mice.,Contrary to what we anticipated, cerebella/brainstems of IFNγRCNSKO mice were only minimally infiltrated, while the same areas of IFNγRperiKO mice were extensively populated by peripheral immune cells.,Furthermore, the CNS of IFNγRperiKO mice was characterized by persistent neutrophil-rich foci as compared to IFNγRCNSKO.,Immunohistochemical analysis of the CNS of IFNγ-/- and IFNγR chimeric mice revealed that IFNγ protective actions are exerted through microglial STAT1.,Alterations in distribution and composition of CNS inflammatory foci are not sufficient for the onset of atypical EAE.,IFNγ dictates the course of neuroinflammatory disorders mainly through actions exerted within the CNS.,This study provides strong evidence that link microglial STAT1 inactivation to vestibular dysfunction.

Background: Rheumatoid arthritis (RA) is the most frequent autoimmune disease involving the joints.,Although anti-TNF therapies have proven effective in the management of RA, approximately one third of patients do not show a significant clinical response.,The objective of this study was to identify new genetic variation associated with the clinical response to anti-TNF therapy in RA.,Methods: We performed a sequential multi-omic analysis integrating different sources of molecular information.,First, we extracted the RNA from synovial biopsies of 11 RA patients starting anti-TNF therapy to identify gene coexpression modules (GCMs) in the RA synovium.,Second, we analyzed the transcriptomic association between each GCM and the clinical response to anti-TNF therapy.,The clinical response was determined at week 14 using the EULAR criteria.,Third, we analyzed the association between the GCMs and anti-TNF response at the genetic level.,For this objective, we used genome-wide data from a cohort of 348 anti-TNF treated patients from Spain.,The GCMs that were significantly associated with the anti-TNF response were then tested for validation in an independent cohort of 2,706 anti-TNF treated patients.,Finally, the functional implication of the validated GCMs was evaluated via pathway and cell type epigenetic enrichment analyses.,Results: A total of 149 GCMs were identified in the RA synovium.,From these, 13 GCMs were found to be significantly associated with anti-TNF response (P < 0.05).,At the genetic level, we detected two of the 13 GCMs to be significantly associated with the response to adalimumab (P = 0.0015) and infliximab (P = 0.021) in the Spain cohort.,Using the independent cohort of RA patients, we replicated the association of the GCM associated with the response to adalimumab (P = 0.0019).,The validated module was found to be significantly enriched for genes involved in the nucleotide metabolism (P = 2.41e-5) and epigenetic marks from immune cells, including CD4+ regulatory T cells (P = 0.041).,Conclusions: These findings show the existence of a drug-specific genetic basis for anti-TNF response, thereby supporting treatment stratification in the search for response biomarkers in RA.

To examine whether baseline anti-cyclic citrullinated peptide-2 (CCP2) antibody status and concentration correlated with clinical outcomes in patients treated with abatacept or adalimumab on background methotrexate (MTX) in the 2-year AMPLE (Abatacept versus adaliMumab comParison in bioLogic-naïvE rheumatoid arthritis subjects with background MTX) study.,In this exploratory analysis, anti-CCP2 antibody concentration was measured at baseline, and antibody-positive patients were divided into equal quartiles, Q1-Q4, representing increasing antibody concentrations.,Clinical outcomes analysed by baseline anti-CCP2 status and quartile included change from baseline in disease activity and disability and remission rates.,Baseline characteristics were generally comparable across quartiles and treatment groups.,In both treatment groups, anti-CCP2 antibody-negative patients responded less well than antibody-positive patients.,At year 2, improvements in disease activity and disability and remission rates were similar across Q1-Q3, but were numerically higher in Q4 in the abatacept group; in contrast, treatment effects were similar across all quartiles in the adalimumab group.,In AMPLE, baseline anti-CCP2 positivity was associated with a better response for abatacept and adalimumab.,Patients with the highest baseline anti-CCP2 antibody concentrations had better clinical response with abatacept than patients with lower concentrations, an association that was not observed with adalimumab.,NCT00929864.

In the last decades, evidence suggesting the direct or indirect involvement of B cells on multiple sclerosis (MS) pathogenesis has accumulated.,The increased amount of data on the efficacy and safety of B-cell-depleting therapies from several studies has suggested the addition of these drugs as treatment options to the current armamentarium of disease modifying therapies (DMTs) for MS.,Particularly, rituximab (RTX), a chimeric monoclonal antibody directed at CD20 positive B lymphocytes resulting in cell-mediated apoptosis, has been demonstrated to reduce inflammatory activity, incidence of relapses and new brain lesions on magnetic resonance imaging (MRI) in patients with relapsing-remitting MS (RRMS).,Additional evidence also demonstrated that patients with progressive MS (PMS) may benefit from RTX, which also showed to be well tolerated, with acceptable safety risks and favorable cost-effectiveness profile.,Despite these encouraging results, RTX is currently approved for non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, several forms of vasculitis and rheumatoid arthritis, while it can only be administered off-label for MS treatment.,Between Northern European countries exist different rules for using not licensed drug for treating MS.,The Sweden MS register reports a high rate (53.5%) of off-label RTX prescriptions in relation to other annually started DMTs to treat MS patients, while Danish and Norwegian neurologists have to use other anti-CD20 drugs, as ocrelizumab, in most of the cases.,In this paper, we review the pharmacokinetics, pharmacodynamics, clinical efficacy, safety profile and cost effectiveness aspects of RTX for the treatment of MS.,Particularly, with the approval of new anti-CD20 DMTs, the recent worldwide COVID-19 emergency and the possible increased risk of infection with this class of drugs, this review sheds light on the use of RTX as an alternative treatment option for MS management, while commenting the gaps of knowledge regarding this drug.

The nuclear factor κB (NF-κB) signaling cascade has been implicating in a broad range of biological processes, including inflammation, cell proliferation, differentiation, and apoptosis.,The past three decades have witnessed a great progress in understanding the impact of aberrant NF-κB regulation on human autoimmune and inflammatory disorders.,In this review, we discuss how aberrant NF-κB activation contributes to multiple sclerosis, a typical inflammatory demyelinating disease of the central nervous system, and its involvement in developing potential therapeutic targets.

The diagnostic criteria of neuromyelitis optica spectrum disorders (NMOSD) has been revised in the past 20 years and pathological and therapeutic data have been accumulated.,This review provides an overview of evolution and broadening of the concept of NMOSD.,NMOSD encompassing brain syndrome as well as optic neuritis and acute myelitis is now classified into aquaporine-4 (AQP)-antibody-seropositive and aquaporine-4 (AQP)-antibody-seronegative diseases, detecting more patients earlier than before.,Seronegative NMOSD includes cases of myelin oligodendrocyte glycoprotein (MOG)-antibody-seropositive disease with its unique clinical spectrum somewhat different from AQP4-antibody-seropositive NMOSD.,Pathologically, NMOSD includes AQP4-antibody-seropositive autoimmune astrocytopathic disease and MOG-antibody-seropositive inflammatory demyelinating disease.,Double seronegative group needs further research.,Therapeutic options of NMOSD has taken shape and first-ever clinical trials of monoclonal antibodies have been done.,In retrospect, relapsing NMO in the studies preceding the discovery of AQP4-antibody had features of AQP4-antibody-seropositive NMO whereas monophasic NMO was similar to AQP4-antibody-seronegative/MOG-antibody-seropositive NMO.,The clinical, pathological and therapeutic concepts of NMOSD have evolved and broadened over the last two decades following the detection of AQP4 antibodies and MOG antibodies in the patients.,Double seronegative NMOSD is a current research focus, but now we may need to reconsider how NMOSD should be defined.

Axon loss determines persistent disability in multiple sclerosis patients.,Here, we use in vivo calcium imaging in a multiple sclerosis model to show that cytoplasmic calcium levels determine the choice between axon loss and survival.,We rule out the endoplasmic reticulum, glutamate excitotoxicity, and the reversal of the sodium-calcium exchanger as sources of intra-axonal calcium accumulation and instead identify nanoscale ruptures of the axonal plasma membrane as the critical path of calcium entry.,•Cytoplasmic calcium accumulations predict axon degeneration in neuroinflammation•Release from the axoplasmic reticulum does not explain calcium accumulations•Calcium influx from the extracellular space drives axon degeneration•Nanoscale ruptures allow entry of calcium across the axonal plasma membrane,Cytoplasmic calcium accumulations predict axon degeneration in neuroinflammation,Release from the axoplasmic reticulum does not explain calcium accumulations,Calcium influx from the extracellular space drives axon degeneration,Nanoscale ruptures allow entry of calcium across the axonal plasma membrane,Witte et al. identify cytoplasmic calcium accumulations as a key driver of axon degeneration in a model of multiple sclerosis.,Calcium accumulates in the axoplasm because nanoscale ruptures of the axonal plasma membrane provide an entry path for extracellular calcium.

Sleep problems are common among children with chronic illnesses such as Juvenile Idiopathic Arthritis (or JIA).,However, little is known about the frequency and severity of sleep disturbance(s) and the factors that are associated with sleep problems in children with JIA.,The mechanism(s) of the relationships characterizing the development or exacerbation of sleep problems in children with JIA are still unknown, however studies have reported an association.,The purpose of this study was to synthesize existing research related to sleep problems in children with JIA.,The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guided the conduct and reporting of this review.,An experienced librarian conducted searches in MEDLINE, EMBASE, PsychINFO, CINAHL, and the Cochrane Central Register of Controlled Trials from inception to January 2012, to identify potentially relevant citations.,Two members independently selected, rated methodological quality using the QUIPS tool, and extracted data from included studies.,Ten studies were included and findings varied across studies; studies were mostly cross-sectional, or case-controlled designs, with only one cohort study available.,Four studies found that children and adolescents diagnosed with JIA had significantly more sleep disturbances when compared to healthy controls.,Pain was most often associated with sleep disturbances.,The heterogeneous findings highlight the complex relationships between JIA and sleep, and low methodological quality of studies in the field.,This review supports an association between poor sleep and increased symptoms related to JIA, specifically the experience of pain.,However, results need to be interpreted cautiously given the inconsistent findings regarding factors associated with sleep problems in JIA, the limited evidence available, and its low quality.,Furthermore it is not yet determined if the poor sleep patterns predate the symptoms reported with JIA.,More research is vital to understanding the factors that predict or perpetuate poor sleep in children and adolescents diagnosed with JIA.

Atherosclerosis is a chronic inflammatory disease of the arteries.,Clinical consequences of the atherosclerotic process occur in the adult population, however atherosclerotic process begins in childhood.,The classic risk factors for atherosclerosis include obesity, dyslipidaemia, age, gender or family history.,In recent years, attention has been drawn to the similarity between atherosclerotic inflammatory processes and inflammatory changes in the course of systemic connective tissue disease, in particular systemic lupus etythematosus (SLE) or rheumatoid arthritis (RA).,There is also observed the similarity of the pathogenetic background of development of atherosclerosis and juvenile idiopathic arthritis (JIA).,Elevated levels of pro-inflammatory cytokines are observed in the course of juvenile idiopathic arthritis.,Also homocysteine concentrations, which may play a significant role in the development of atherosclerotic lesions, are observed higher in patients with JIA.,Some studies revealed higher carotid intima-media thickness (IMT) index values in children with JIA.,In view of the fact that atherosclerotic process begins as early as in childhood, the introduction of appropriate preventive measures in children is a matter of utmost importance.

Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era.,Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow‐up.,Notably, “no evidence of disease activity” at 2 years did not predict long‐term stability.,Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long‐term disability accumulation.,Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year).,Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA‐DRB1*15:01 as covariates.,Relapses were associated with a transient increase in disability over 1‐year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551).,Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).,Long‐term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy.,We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS.,Ann Neurol 2019;85:653-666

See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article.,Grey matter atrophy in multiple sclerosis affects certain areas preferentially.,Eshaghi et al. use a data-driven computational model to predict the order in which regions atrophy, and use this sequence to stage patients.,Atrophy begins in deep grey matter nuclei and posterior cortical regions, before spreading to other cortical areas.,See Stankoff and Louapre (doi:10.1093/brain/awy114) for a scientific commentary on this article.,Grey matter atrophy is present from the earliest stages of multiple sclerosis, but its temporal ordering is poorly understood.,We aimed to determine the sequence in which grey matter regions become atrophic in multiple sclerosis and its association with disability accumulation.,In this longitudinal study, we included 1417 subjects: 253 with clinically isolated syndrome, 708 with relapsing-remitting multiple sclerosis, 128 with secondary-progressive multiple sclerosis, 125 with primary-progressive multiple sclerosis, and 203 healthy control subjects from seven European centres.,Subjects underwent repeated MRI (total number of scans 3604); the mean follow-up for patients was 2.41 years (standard deviation = 1.97).,Disability was scored using the Expanded Disability Status Scale.,We calculated the volume of brain grey matter regions and brainstem using an unbiased within-subject template and used an established data-driven event-based model to determine the sequence of occurrence of atrophy and its uncertainty.,We assigned each subject to a specific event-based model stage, based on the number of their atrophic regions.,Linear mixed-effects models were used to explore associations between the rate of increase in event-based model stages, and T2 lesion load, disease-modifying treatments, comorbidity, disease duration and disability accumulation.,The first regions to become atrophic in patients with clinically isolated syndrome and relapse-onset multiple sclerosis were the posterior cingulate cortex and precuneus, followed by the middle cingulate cortex, brainstem and thalamus.,A similar sequence of atrophy was detected in primary-progressive multiple sclerosis with the involvement of the thalamus, cuneus, precuneus, and pallidum, followed by the brainstem and posterior cingulate cortex.,The cerebellum, caudate and putamen showed early atrophy in relapse-onset multiple sclerosis and late atrophy in primary-progressive multiple sclerosis.,Patients with secondary-progressive multiple sclerosis showed the highest event-based model stage (the highest number of atrophic regions, P < 0.001) at the study entry.,All multiple sclerosis phenotypes, but clinically isolated syndrome, showed a faster rate of increase in the event-based model stage than healthy controls.,T2 lesion load and disease duration in all patients were associated with increased event-based model stage, but no effects of disease-modifying treatments and comorbidity on event-based model stage were observed.,The annualized rate of event-based model stage was associated with the disability accumulation in relapsing-remitting multiple sclerosis, independent of disease duration (P < 0.0001).,The data-driven staging of atrophy progression in a large multiple sclerosis sample demonstrates that grey matter atrophy spreads to involve more regions over time.,The sequence in which regions become atrophic is reasonably consistent across multiple sclerosis phenotypes.,The spread of atrophy was associated with disease duration and with disability accumulation over time in relapsing-remitting multiple sclerosis.

Vitamin D3 (cholecalciferol) is a secosteroid and prohormone which is metabolized in various tissues to the biologically most active vitamin D hormone 1,25(OH)2D3 (calcitriol).,1,25(OH)2D3 has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases.,In this context, the latest research has revealed clinical benefits of high dose vitamin D3 therapy in autoimmune diseases.,The necessity of high doses of vitamin D3 for treatment success can be explained by the concept of an acquired form of vitamin D resistance.,Its etiology is based on the one hand on polymorphisms within genes affecting the vitamin D system, causing susceptibility towards developing low vitamin D responsiveness and autoimmune diseases; on the other hand it is based on a blockade of vitamin D receptor signaling, e.g. through pathogen infections.,In this paper, we review observational and mechanistic evidence for the acquired vitamin D resistance hypothesis.,We particularly focus on its clinical confirmation from our experience of treating multiple sclerosis patients with the so-called Coimbra protocol, in which daily doses up to 1000 I.U. vitamin D3 per kg body weight can be administered safely.,Parathyroid hormone levels in serum thereby provide the key information for finding the right dose.,We argue that acquired vitamin D resistance provides a plausible pathomechanism for the development of autoimmune diseases, which could be treated using high-dose vitamin D3 therapy.

Vitamin K2 (VK2) belongs to the vitamin K family and comprises a number of subtypes differing in length of side chains consisting of isoprenoid groups (menaquinone-n, MK-n).,It is essential for a number of physiological functions although the full spectrum of activity has not yet been elucidated.,Due to its role in protection of mitochondrial damage, VK2 could be relevant in preventing disease progress in multiple sclerosis (MS).,We measured VK2 serum levels by the double antibody sandwich Enzyme-linked Immunosorbent Assay (ELISA) technique in MS patients and age and sex matched controls, both under vitamin D supplementation, and related it to disease characteristics and treatment.,Overall, 45 MS patients (31 females and 39 of the relapsing-remitting type) and 29 healthy controls (19 females) were included in the analysis.,The MS patients had vastly lower VK2 blood levels than controls (235 ± 100 ng/ml vs. 812 ± 154 ng/ml, respectively).,Female patients had significantly lower VK2 levels than males and a decrease with age by approximately 10% per decade was found.,The VK2 levels were lower with increasing numbers of attacks per year and were higher in patients with optic nerve lesions.,No consistent relationship with medications was detected.,The substantially lower levels of VK2 in MS patients could be due to depletion, lower production in the gut, diminished absorption or, less likely, reduced intake of precursor vitamin K1.,The role of VK2 in MS development and progress deserves further study.,The online version of this article (10.1007/s00508-018-1328-x) contains supplementary material, which is available to authorized users.

Myasthenic crisis (MC) and disease exacerbation in myasthenia gravis (MG) are associated with significant lethality and continue to impose a high disease burden on affected patients.,Therefore, we sought to determine potential predictors for MC and exacerbation as well as to identify factors affecting outcome.,We examined a retrospective, observational cohort study of patients diagnosed with MG between 2000 and 2021 with a mean follow-up of 62.6 months after diagnosis from eight tertiary hospitals in Germany.,A multivariate Cox regression model with follow-up duration as the time variable was used to determine independent risk factors for MC and disease exacerbation.,815 patients diagnosed with MG according to national guidelines were included.,Disease severity at diagnosis (quantitative MG score or Myasthenia Gravis Foundation of America class), the presence of thymoma and anti-muscle specific tyrosine kinase-antibodies were independent predictors of MC or disease exacerbation.,Patients with minimal manifestation status 12 months after diagnosis had a lower risk of MC and disease exacerbation than those without.,The timespan between diagnosis and the start of immunosuppressive therapy did not affect risk.,Patients with a worse outcome of MC were older, had higher MGFA class before MC and at admission, and had lower vital capacity before and at admission.,The number of comorbidities, requirement for intubation, prolonged mechanical ventilation, and MC triggered by infection were associated with worse outcome.,No differences between outcomes were observed comparing treatments with IVIG (intravenous immunoglobulin) vs. plasma exchange vs.,IVIG together with plasma exchange.,MC and disease exacerbations inflict a substantial burden of disease on MG patients.,Disease severity at diagnosis and antibody status predicted the occurrence of MC and disease exacerbation.,Intensified monitoring with emphasis on the prevention of infectious complications could be of value to prevent uncontrolled disease in MG patients.,The online version contains supplementary material available at 10.1186/s12974-022-02448-4.

The Coronavirus disease-19 (COVID-19) pandemic continues to expand across the world.,This pandemic has had a significant impact on patients with chronic diseases.,Among patients with demyelinating diseases of the central nervous system (CNS), such as Multiple Sclerosis (MS) or Neuromyelitis Optica Spectrum Disorder (NMOSD), concerns remain about the potential impact of COVID-19 on these patients given their treatment with immunosuppressive or immunomodulatory therapies.,In this study, we review the existing literature investigating the impact of disease-modifying therapies(DMT) on COVID-19 risks in this group of patients.,For this systematic review, we searched PubMed from January 1, 2020, to December 3, 2020.,The following keywords were used: “COVID-19” AND “Multiple Sclerosis” OR “Neuromyelitis Optica.”,Articles evaluating COVID-19 in patients with demyelinating diseases of CNS were included.,This study evaluates the different aspects of the DMTs in these patients during the COVID-19 era.,A total of 262 articles were found.,After eliminating duplicates and unrelated research papers, a total of 84 articles met the final inclusion criteria in our study.,Overall, the experiences of 2493 MS patients and 37 NMOSD patients with COVID-19 were included in this review.,Among them, 46(1.8%) MS patients died(the global death-to-case ratio of Covid-19 was reported about 2.1%).,Among DMTs, Rituximab had the highest mortality rate (4%).,Despite controversies, especially concerning anti-CD20 monoclonal antibody therapies, a relation between DMT-use and COVID-19 disease- course was not found in many studies.,This observation reinforces the recommendation of not stopping current DMTs.,Other variables such as age, higher expanded disability status scale (EDSS) scores, cardiac comorbidities, and obesity were independent risk factors for severe COVID-19.,Despite the risks of infection, most patients were willing to continue their DMT during the pandemic because of more significant concern about the risk of relapse or worsening MS symptoms.,After the infection, an immune response's attenuation was seen in the patients on Fingolimod and anti-CD20 monoclonal antibodies.,This may be a critical finding in future vaccinations.

Autoantibodies, such as anti-citrullinated protein antibodies (ACPAs), have been described as inducing bone loss in rheumatoid arthritis (RA), which can also be reflected by bone mineral density (BMD).,We therefore examined the association between osteoporosis and autoantibodies in two independent RA cohorts.,Dual x‐ray absorptiometry (DXA) of the lumbar spine and left hip was performed in 408 Dutch patients with early RA during 5 years of follow‐up and in 198 Swedish patients with early RA during 10 years of follow‐up.,The longitudinal effect of ACPAs and other autoantibodies on several BMD measures was assessed using generalized estimating equations.,In the Dutch cohort, significantly lower BMD at baseline was observed in ACPA‐positive patients compared to ACPA‐negative patients, with an estimated marginal mean BMD in the left hip of 0.92 g/cm2 (95% confidence interval [95% CI] 0.91-0.93) versus 0.95 g/cm2 (95% CI 0.93-0.97) (P = 0.01).,In line with this, significantly lower Z scores at baseline were noted in the ACPA‐positive group compared to the ACPA‐negative group (estimated marginal mean Z score in the left hip of 0.18 [95% CI 0.08-0.29] versus 0.48 [95% CI 0.33-0.63]) (P < 0.01).,However, despite clear differences at baseline, ACPA positivity was not associated with greater decrease in absolute BMD or Z scores over time.,Furthermore, there was no association between BMD and higher levels of ACPAs or other autoantibodies (rheumatoid factor and anti-carbamylated protein antibodies).,In the Swedish cohort, ACPA‐positive patients tended to have a higher prevalence of osteopenia at baseline (P = 0.04), but again, ACPA positivity was not associated with an increased prevalence of osteopenia or osteoporosis over time.,The presence of ACPAs is associated with significantly lower BMD at baseline, but not with greater BMD loss over time in treated RA patients.,These results suggest that ACPAs alone do not appear to contribute to bone loss after disease onset when disease activity is well‐managed.

Rheumatoid arthritis (RA) is known to cause secondary osteoporosis and fragility fractures.,This study aimed to identify biomarkers predictive of bone mineral density (BMD) change at three anatomical sites in patients with RA.,We conducted a prospective longitudinal study in patients with RA.,In 2012, we recruited 379 patients from an RA cohort, 329 of whom underwent evaluation of blood and urine biomarkers together with measurement of BMD in the lumbar spine, proximal femur, and distal forearm.,The BMD in these three regions was reassessed in 2014.,We performed multivariate linear regression analysis to identify those factors associated with BMD change.,The averages of age, body mass index, and disease activity score in 28 joints (DAS28) at baseline were 63.2 (minimum to maximum, 32-85), 21.3 (12.3-30.0), and 3.2 (0.1-5.9), respectively.,Univariate analysis showed that the annual BMD change was significantly associated with the use of steroid, bisphosphonate (BP) or vitamin D (VitD), and serum homocysteine in the lumber spine; DAS28, the use of BP or VitD, CRP, and anti-cyclic citrullinated peptide antibody (ACPA) in the proximal femur; and the dosage of MTX, the use of BP or VitD, and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) in the distal forearm, respectively.,Predictive biomarkers for BMD change in RA patients differ at each anatomical site.,Practitioners should treat each anatomical site with different markers and prescribe osteoporosis drugs to prevent fractures for RA patients.

Accumulating evidence suggests an important role for interleukin 17 (IL-17) in the pathogenesis of several inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA).,Accordingly, clinical trials aimed at blocking IL-17 have been initiated, but clinical results between patients and across different diseases have been highly variable.,The objective was to determine the variability in expression of IL-17A, IL-17F and their receptors IL-17RA and IL-17RC in the synovia of patients with arthritis.,Synovial biopsies were obtained from patients with RA (n = 11), PsA (n = 15) and inflammatory osteoarthritis (OA, n = 14).,For comparison, synovia from noninflamed knee joints (n = 7) obtained from controls were included.,Frozen sections were stained for IL-17A, IL-17F, IL-17RA and IL-17RC and evaluated by digital image analysis.,We used confocal microscopy to determine which cells in the synovium express IL-17A and IL-17F, double-staining with CD4, CD8, CD15, CD68, CD163, CD31, von Willebrand factor, peripheral lymph node address in, lymphatic vessel endothelial hyaluronan receptor 1, mast cell tryptase and retinoic acid receptor-related orphan receptor γt (RORγt).,IL-17A, IL-17F, IL-17RA and IL-17RC were abundantly expressed in synovial tissues of all patient groups.,Whereas IL-17RA was present mostly in the synovial sublining, IL-17RC was abundantly expressed in the intimal lining layer.,Digital image analysis showed a significant (P < 0.05) increase of only IL-17A in arthritis patients compared to noninflamed control tissues.,The expression of IL-17A, IL-17F and their receptors was similar in the different patient groups, but highly variable between individual patients.,CD4+ and CD8+ cells coexpressed IL-17A, and few cells coexpressed IL-17F.,IL-17A and IL-17F were not expressed by CD15+ neutrophils.,Mast cells were only occasionally positive for IL-17A or IL-17F.,Interestingly, IL-17A and IL-17F staining was also observed in macrophages, as well as in blood vessels and lymphatics.,This staining probably reflects receptor-bound cytokine staining.,Many infiltrated cells were positive for the transcription factor RORγt.,Colocalisation between RORγt and IL-17A and IL-17F indicates local IL-17 production.,Increased expression of IL-17A is not restricted to synovial tissues of RA and PsA patients; it is also observed in inflammatory OA.,The heterogeneous expression levels may explain nonresponse to anti-IL-17 therapy in subsets of patients.,The online version of this article (doi:10.1186/s13075-014-0426-z) contains supplementary material, which is available to authorized users.

Although previous studies found that cigarette smoking is associated with risk of rheumatoid arthritis (RA), the dose-response relationship remains unclear.,This meta-analysis quantitatively summarizes accumulated evidence regarding the association of lifelong exposure to cigarette smoking assessed as pack-years with the risk of RA.,Relevant studies were identified by a search of MEDLINE and EMBASE from 1966 to October 2013, with no restrictions.,Reference lists from retrieved articles were also reviewed.,Studies that reported relative risks (RR) or odds ratio (OR) estimates with 95% confidence intervals (CIs) for the association between pack-years of cigarette smoking and rheumatoid arthritis were included in a dose-response random-effects meta-regression analysis.,We included 3 prospective cohorts and 7 case-control studies in the meta-analysis.,They included a total of 4,552 RA cases.,There was no indication of heterogeneity (Pheterogeneity = 0.32) and publication bias did not affect the results.,Compared to never smokers, the risk of developing RA increased by 26% (RR = 1.26, 95% CI 1.14 to 1.39) among those who smoked 1 to 10 pack-years and doubled among those with more than 20 pack-years (RR for 21 to 30 pack years = 1.94, 95% CI 1.65 to 2.27).,The risk of RA was not increasing further for higher exposure levels (RR for >40 pack-years = 2.07, 95% CI 1.15 to 3.73).,The risk of RA was statistically significantly higher among rheumatoid factor (RF)-positive RA cases (RR = 2.47, 95% CI 2.02 to 3.02) compared to RF-negative (RR = 1.58, 95% CI 1.15 to 2.18) when comparing the highest versus lowest category of pack-years for the individual studies.,Lifelong cigarette smoking was positively associated with the risk of RA even among smokers with a low lifelong exposure.,The risk of RA did not further increase with an exposure higher than 20 pack-years.

To determine if there is an association between sarcopenia, physical function and self-reported fatigue in osteoarthritis (OA) and rheumatoid arthritis (RA).,A cross-sectional analysis of measurements from a cohort of 157 participants with OA or RA was performed.,The relationship between muscle mass (appendicular muscle index (AMI)), physical function (timed up and go, 30-seconds sit-to-stand test, 40-meter fast-paced walk test and grip-strength) and two fatigue measures (Multidimensional Assessment of Fatigue (MAF) and a fatigue Visual Analogue Scale (VAS)) was explored using hierarchical linear regression or logistic regression with established AMI cut-offs for sarcopenia.,There were no significant differences for perceived fatigue-related variables between OA or RA sarcopenic or non-sarcopenic participants.,Participants with OA had worse physical function (TUG; P = 0.029, STS; P = 0.004, WS; P = 0.003), but participants with RA had lower grip strength (P<0.001).,The RA group had higher CRP (P = 0.006), were more likely to receive glucocorticoids (P<0.001), and experienced worse fatigue (P = 0.050).,The hierarchical multiple regression showed that self-reported fatigue (VAS/MAF-distress) had a significant but weak association with AMI in RA.,Participants with higher percentage body fat had a significantly stronger association with sarcopenia in both OA and RA.,Sarcopenia, when assessed by AMI, does not appear to be strongly associated with self-reported fatigue or physical function in participants with either OA or RA.,Higher body fat had a moderately strong association with sarcopenia in this cross-sectional study, suggesting that body composition may be an important factor in the health of patients with longstanding OA or RA.

The link between body mass index (BMI) and disease characteristics in rheumatoid arthritis (RA) remains controversial.,Body composition (BC) has been more frequently recommended to be used instead of BMI for more accurate assessment.,Our study aimed to investigate the characteristics of BC in RA patients and their associations with disease characteristics.,Body composition was assessed in consecutive Chinese RA patients and control subjects by bioelectric impedance analysis.,Overfat was defined by body fat percentage (BF%) as ≥25% for men and ≥35% for women.,Myopenia was defined by appendicular skeletal muscle mass index (ASMI) ≤7.0 kg/m2 in men and ≤5.7 kg/m2 in women.,BMI and clinical data including disease activity, function, and radiographic assessment were collected.,Active disease was defined by disease activity score in 28 joints with four variables including C‐reactive protein (DAS28‐CRP) ≥2.6.,Functional limitation was defined as Stanford health assessment questionnaire disability index (HAQ‐DI) >1.,Radiographic joint damage (RJD) was defined as the Sharp/van der Heijde modified sharp score (mTSS) >10.,There were 457 RA patients (mean age 49.5 ± 13.1 years old with 82.7% women) and 1860 control subjects (mean age 34.3 ± 9.9 years old with 51.2% women) recruited.,Comparisons of BMI and BC between RA patients and control subjects in age and gender stratification showed that lower BMI with 17.7% underweight and lower ASMI with 45.1% myopenia are the main characteristics in RA patients.,Compared with those without myopenia, RA patients with myopenia had significantly higher DAS28‐CRP (median 3.5 vs.,3.0), higher HAQ‐DI (median 0.38 vs.,0.13) with higher rate of functional limitation (24.8% vs.,7.6%), and higher mTSS (median 22.3 vs.,9.0) with more RJD (71.8% vs.,45.8%) (all P < 0.001).,Multivariate logistic regression analysis showed myopenia were positively associated with functional limitation (OR = 2.546, 95% CI: 1.043-6.217) and RJD (OR = 2.660, 95% CI: 1.443-4.904).,All RA patients were divided into four BC subgroups according to overfat and myopenia.,Those with both overfat and myopenia had the worst disease characteristics.,After adjustment for confounding factors, significant additive interactions were observed between overfat and myopenia in active disease (AP = 0.528, 95% CI: 0.086-0.971), functional limitation (AP = 0.647, 95% CI: 0.356-0.937), and RJD (AP = 0.514, 95% CI: 0.139-0.890).,Myopenia is very common in RA patients that is associated with functional limitation and joint damage in RA.,Further research on the underlying mechanism and the effect of skeletal muscle mass improvement in RA management are worth exploring in the future.

Infections are considered important environmental triggers of autoimmunity and can contribute to autoimmune disease onset and severity.,Nucleic acids and the complexes that they form with proteins-including chromatin and ribonucleoproteins-are the main autoantigens in the autoimmune disease systemic lupus erythematosus (SLE).,How these nuclear molecules become available to the immune system for recognition, presentation, and targeting is an area of research where complexities remain to be disentangled.,In this review, we discuss how bacterial infections participate in the exposure of nuclear autoantigens to the immune system in SLE.,Infections can instigate pro-inflammatory cell death programs including pyroptosis and NETosis, induce extracellular release of host nuclear autoantigens, and promote their recognition in an immunogenic context by activating the innate and adaptive immune systems.,Moreover, bacterial infections can release bacterial DNA associated with other bacterial molecules, complexes that can elicit autoimmunity by acting as innate stimuli of pattern recognition receptors and activating autoreactive B cells through molecular mimicry.,Recent studies have highlighted SLE disease activity-associated alterations of the gut commensals and the expansion of pathobionts that can contribute to chronic exposure to extracellular nuclear autoantigens.,A novel field in the study of autoimmunity is the contribution of bacterial biofilms to the pathogenesis of autoimmunity.,Biofilms are multicellular communities of bacteria that promote colonization during chronic infections.,We review the very recent literature highlighting a role for bacterial biofilms, and their major components, amyloid/DNA complexes, in the generation of anti-nuclear autoantibodies and their ability to stimulate the autoreactive immune response.,The best studied bacterial amyloid is curli, produced by enteric bacteria that commonly cause infections in SLE patients, including Escherichia coli and Salmonella spps.,Evidence suggests that curli/DNA complexes can trigger autoimmunity by acting as danger signals, molecular mimickers, and microbial chaperones of nucleic acids.

The aim of our study was to assess the associations of HSP90AB1 copy number variations (CNVs) with systemic lupus erythematosus (SLE) risk and glucocorticoids (GCs) efficacy, as well as the relationship between HSP90AB1 single‐nucleotide polymorphisms (SNPs) and GCs efficacy.,HSP90AB1 CNVs and SLE risk were analysed in 519 patients and 538 controls.,Patients treated with GCs were followed up for 12 weeks and were divided into sensitive and insensitive groups to investigate the effects of CNVs (419 patients) and SNPs (457 patients) on the efficacy of GCs.,Health‐related quality of life (HRQoL) was also measured by SF‐36 at baseline and week 12 to explore the relationship between CNVs/SNPs and HRQoL improvements in Chinese SLE patients.,Our results indicated a statistically significant association between HSP90AB1 CNVs and SLE (P BH = 0.039), and this association was more pronounced in the female subgroup (P BH = 0.039).,However, we did not detect association of HSP90AB1 CNVs/SNPs with efficacy of GCs.,But we found a marginal association between SNP rs13296 and improvement in Role‐emotional, while this association was not strong enough to survive in the multiple testing corrections.,Collectively, our findings suggest that the copy number of HSP90AB1 is associated with SLE susceptibility.,But copy number and polymorphisms of HSP90AB1 may not be associated with efficacy of GCs.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS).,The activation of inflammatory cells is crucial for the development of MS and is shown to induce intracellular glycolytic metabolism in pro-inflammatory microglia and macrophages, as well as CNS-resident astrocytes.,Advanced glycation endproducts (AGEs) are stable endproducts formed by a reaction of the dicarbonyl compounds methylglyoxal (MGO) and glyoxal (GO) with amino acids in proteins, during glycolysis.,This suggests that, in MS, MGO-derived AGEs are formed in glycolysis-driven cells.,MGO and MGO-derived AGEs can further activate inflammatory cells by binding to the receptor for advanced glycation endproducts (RAGE).,Recent studies have revealed that AGEs are increased in the plasma and brain of MS patients.,Therefore, AGEs might contribute to the inflammatory status in MS.,Moreover, the main detoxification system of dicarbonyl compounds, the glyoxalase system, seems to be affected in MS patients, which may contribute to high MGO-derived AGE levels.,Altogether, evidence is emerging for a contributing role of AGEs in the pathology of MS.,In this review, we provide an overview of the current knowledge on the involvement of AGEs in MS.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration.,The mechanisms of tissue injury are currently poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process.,Since mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, we analysed by immunocytochemistry the presence and cellular location of oxidized lipids and oxidized DNA in lesions and in normal-appearing white matter of 30 patients with multiple sclerosis and 24 control patients without neurological disease or brain lesions.,As reported before in biochemical studies, oxidized lipids and DNA were highly enriched in active multiple sclerosis plaques, predominantly in areas that are defined as initial or ‘prephagocytic’ lesions.,Oxidized DNA was mainly seen in oligodendrocyte nuclei, which in part showed signs of apoptosis.,In addition, a small number of reactive astrocytes revealed nuclear expression of 8-hydroxy-d-guanosine.,Similarly, lipid peroxidation-derived structures (malondialdehyde and oxidized phospholipid epitopes) were seen in the cytoplasm of oligodendrocytes and some astrocytes.,In addition, oxidized phospholipids were massively accumulated in a fraction of axonal spheroids with disturbed fast axonal transport as well as in neurons within grey matter lesions.,Neurons stained for oxidized phospholipids frequently revealed signs of degeneration with fragmentation of their dendritic processes.,The extent of lipid and DNA oxidation correlated significantly with inflammation, determined by the number of CD3 positive T cells and human leucocyte antigen-D expressing macrophages and microglia in the lesions.,Our data suggest profound oxidative injury of oligodendrocytes and neurons to be associated with active demyelination and axonal or neuronal injury in multiple sclerosis.

Interleukin (IL)-17-producing T helper cells (TH17) are a recently identified CD4+ T cell subset distinct from T helper type 1 (TH1) and T helper type 2 (TH2) cells1.,TH17 cells can drive antigen specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE)2, the mouse model for multiple sclerosis.,The factors that are needed for the generation of TH17 cells have been well-characterized3-6.,However, where and how the immune system controls TH17 cells in vivo remains unclear.,Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory TH17 cells can be redirected to and controlled in the small intestine.,TH17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis.,Moreover, we found that TH17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen and simultaneously pro-inflammatory TH17 cells acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rTH17).,These results identify mechanisms limiting TH17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of TH17 cells.

We describe a reporter mouse strain designed to fate-map cells that have activated IL-17A.,Here we show that TH17 cells show distinct plasticity in different inflammatory settings.,Chronic inflammatory conditions in EAE caused a switch to alternative cytokines in TH17 cells, whereas acute cutaneous infection with Candida albicans, did not result in deviation of TH17 to alternative cytokine production, although IL-17A production was shut off in the course of the infection.,During development of EAE, IFN-γ and other pro-inflammatory cytokines in the spinal cord were produced almost exclusively by ‘ex-TH17’ cells whose conversion was driven by IL-23.,Thus, this model allows relating the actual functional fate of effector T cells to TH17 developmental origin irrespective of IL-17 expression.

To compare the performance of the new 2016 American College of Rheumatology (ACR)-European League Against Rheumatism (EULAR) classification criteria for primary Sjögren's syndrome (SS) with 1999 revised Japanese Ministry of Health criteria for diagnosis of SS (JPN), 2002 American-European Consensus Group classification criteria for SS (AECG) and 2012 ACR classification criteria for SS (ACR) in Japanese patients.,The study subjects were 499 patients with primary SS (pSS) or suspected pSS who were followed up in June 2012 at 10 hospitals in Japan.,All patients had been assessed for all four criteria of JPN (pathology, oral, ocular, anti-SS-A/SS-B antibodies).,The clinical diagnosis by the physician in charge was set as the ‘gold standard’.,pSS was diagnosed in 302 patients and ruled out in 197 patients by the physician in charge.,The sensitivity of the ACR-EULAR criteria in the diagnosis of pSS (95.4%) was higher than those of the JPN, AECG and ACR (82.1%, 89.4% and 79.1%, respectively), while the specificity of the ACR-EULAR (72.1%) was lower than those of the three sets (90.9%, 84.3% and 84.8%, respectively).,The differences of sensitivities and specificities between the ACR-EULAR and other three sets of criteria were statistically significant (p<0.001).,Eight out of 302 patients with pSS and 11 cases out of 197 non-pSS cases satisfied only the ACR-EULAR criteria, compared with none of the other three sets.,The ACR-EULAR criteria had significantly higher sensitivity and lower specificity in diagnosis of pSS, compared with the currently available three sets of criteria.

Increasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS).,The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls.,Genome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies.,Gene expression was analysed in CD19+ B cells by RNA-sequencing.,Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed.,We identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations.,Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed.,We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression.,In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2.,Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders.,Evidence for genetic control of methylation levels at known pSS risk loci was observed.,Our study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings.,The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.

The Juvenile Diabetes Research Foundation (JDRF) Network for Pancreatic Organ Donors with Diabetes (JDRF nPOD) was established to obtain human pancreata and other tissues from organ donors with type 1 diabetes (T1D) in support of research focused on disease pathogenesis.,Since 2007, nPOD has recovered tissues from over 100 T1D donors and distributed specimens to approximately 130 projects led by investigators worldwide.,More recently, nPOD established a programmatic expansion that further links the transplantation world to nPOD, nPOD-Transplantation; this effort is pioneering novel approaches to extend the study of islet autoimmunity to the transplanted pancreas and to consent patients for postmortem organ donation directed towards diabetes research.,Finally, nPOD actively fosters and coordinates collaborative research among nPOD investigators, with the formation of working groups and the application of team science approaches.,Exciting findings are emerging from the collective work of nPOD investigators, which covers multiple aspects of islet autoimmunity and beta cell biology.

Islet leukocytic infiltration (insulitis) is first obvious at around 4 weeks of age in the NOD mouse - a model for human type 1 diabetes (T1D).,The molecular events that lead to insulitis and initiate autoimmune diabetes are poorly understood.,Since TID is caused by numerous genes, we hypothesized that multiple molecular pathways are altered and interact to initiate this disease.,We evaluated the molecular phenotype (mRNA and protein expression) and molecular networks of ex vivo unfractionated spleen leukocytes from 2 and 4 week-old NOD mice in comparison to two control strains.,Analysis of the global gene expression profiles and hierarchical clustering revealed that the majority (∼90%) of the differentially expressed genes in NOD mice were repressed.,Furthermore, analysis using a modern suite of multiple bioinformatics approaches identified abnormal molecular pathways that can be divided broadly into 2 categories: metabolic pathways, which were predominant at 2 weeks, and immune response pathways, which were predominant at 4 weeks.,Network analysis by Ingenuity pathway analysis identified key genes/molecules that may play a role in regulating these pathways.,These included five that were common to both ages (TNF, HNF4A, IL15, Progesterone, and YWHAZ), and others that were unique to 2 weeks (e.g.,MYC/MYCN, TGFB1, and IL2) and to 4 weeks (e.g.,IFNG, beta-estradiol, p53, NFKB, AKT, PRKCA, IL12, and HLA-C).,Based on the literature, genes that may play a role in regulating metabolic pathways at 2 weeks include Myc and HNF4A, and at 4 weeks, beta-estradiol, p53, Akt, HNF4A and AR.,Our data suggest that abnormalities in regulation of metabolic pathways in the immune cells of young NOD mice lead to abnormalities in the immune response pathways and as such may play a role in the initiation of autoimmune diabetes.,Thus, targeting metabolism may provide novel approaches to preventing and/or treating autoimmune diabetes.

We conducted a retrospective cohort study in Kaiser Permanente Southern California from 1 January 2020 to 30 September 2020.,We found that rituximab‐treated persons with multiple sclerosis (pwMS, n = 1895) were more likely be hospitalized (n = 8, 33.3%), but not die (n = 0) from COVID‐19, compared to the 4.81 million non‐MS population (5.8% and 1.4%, respectively).,Time in months (adjusted OR = 0.32, 95% CI = 0.15-0.69, p = 0.0033) and receiving 1000 mg compared to lower doses at last infusion (adjusted OR = 6.28, 95% CI = 1.38-28.5, p = 0.0173) were independent predictors of COVID‐19 severity.,Rituximab‐treated pwMS should be counseled to take extra precautions in the 5 months following each infusion.,Using extended dosing intervals and lower doses could be considered.

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.

Systemic lupus erythematosus (SLE) is a complex trait characterised by the production of a range of auto-antibodies and a diverse set of clinical phenotypes.,Currently, ∼8% of the genetic contribution to SLE in Europeans is known, following publication of several moderate-sized genome-wide (GW) association studies, which identified loci with a strong effect (OR>1.3).,In order to identify additional genes contributing to SLE susceptibility, we conducted a replication study in a UK dataset (870 cases, 5,551 controls) of 23 variants that showed moderate-risk for lupus in previous studies.,Association analysis in the UK dataset and subsequent meta-analysis with the published data identified five SLE susceptibility genes reaching genome-wide levels of significance (Pcomb<5×10−8): NCF2 (P comb = 2.87×10−11), IKZF1 (P comb = 2.33×10−9), IRF8 (P comb = 1.24×10−8), IFIH1 (P comb = 1.63×10−8), and TYK2 (P comb = 3.88×10−8).,Each of the five new loci identified here can be mapped into interferon signalling pathways, which are known to play a key role in the pathogenesis of SLE.,These results increase the number of established susceptibility genes for lupus to ∼30 and validate the importance of using large datasets to confirm associations of loci which moderately increase the risk for disease.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disorder.,The study of diverse mouse models of lupus has provided clues to the etiology of SLE.,Spontaneous mouse models of lupus have led to identification of numerous susceptibility loci from which several candidate genes have emerged.,Meanwhile, induced models of lupus have provided insight into the role of environmental factors in lupus pathogenesis as well as provided a better understanding of cellular mechanisms involved in the onset and progression of disease.,The SLE-like phenotypes present in these models have also served to screen numerous potential SLE therapies.,Due to the complex nature of SLE, it is necessary to understand the effect specific targeted therapies have on immune homeostasis.,Furthermore, knowledge gained from mouse models will provide novel therapy targets for the treatment of SLE.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) in which oligodendrocytes, the CNS cells that stain most robustly for iron and myelin are the targets of injury.,Metals are essential for normal CNS functioning, and metal imbalances have been linked to demyelination and neurodegeneration.,Using a multidisciplinary approach involving synchrotron techniques, iron histochemistry and immunohistochemistry, we compared the distribution and quantification of iron and zinc in MS lesions to the surrounding normal appearing and periplaque white matter, and assessed the involvement of these metals in MS lesion pathogenesis.,We found that the distribution of iron and zinc is heterogeneous in MS plaques, and with few remarkable exceptions they do not accumulate in chronic MS lesions.,We show that brain iron tends to decrease with increasing age and disease duration of MS patients; reactive astrocytes organized in large astrogliotic areas in a subset of smoldering and inactive plaques accumulate iron and safely store it in ferritin; a subset of smoldering lesions do not contain a rim of iron-loaded macrophages/microglia; and the iron content of shadow plaques varies with the stage of remyelination.,Zinc in MS lesions was generally decreased, paralleling myelin loss.,Iron accumulates concentrically in a subset of chronic inactive lesions suggesting that not all iron rims around MS lesions equate with smoldering plaques.,Upon degeneration of iron-loaded microglia/macrophages, astrocytes may form an additional protective barrier that may prevent iron-induced oxidative damage.,The online version of this article (doi:10.1007/s00401-017-1696-8) contains supplementary material, which is available to authorized users.

The pathological hallmark of multiple sclerosis (MS) is myelin phagocytosis.,It remains unclear why microglia and macrophages demyelinate axons in MS, but previously found or yet-unknown changes in the myelin of MS patients could contribute to this process.,We therefore studied whether myelin from normal-appearing white matter (NAWM) of MS donors is phagocytosed more efficiently than myelin from control donors.,Myelin was isolated from 11 MS and 12 control brain donors and labeled with the pH-sensitive fluorescent dye pHrodo to quantify uptake in lysosomes.,Phagocytosis by differentiated THP-1 macrophages and by primary human microglia was quantified with flow cytometry.,Whereas myelin uptake by THP-1 macrophages reached a plateau after approximately 24 hours, uptake by primary human microglia showed an almost linear increase over a 72-hour period.,Data were statistically analyzed with the Mann-Whitney U test.,MS-derived myelin was phagocytosed more efficiently by THP-1 macrophages after 6-hour incubation (P = 0.001 for the percentage of myelin-phagocytosing cells and P = 0.0005 for total myelin uptake) and after 24-hour incubation (P = 0.0006 and P = 0.0001, respectively), and by microglia after 24-hour incubation (P = 0.0106 for total myelin uptake).,This enhanced uptake was not due to differences in the oxidation status of the myelin.,Interestingly, myelin phagocytosis correlated negatively with the age of myelin donors, whereas the age of microglia donors showed a positive trend with myelin phagocytosis.,Myelin isolated from normal-appearing white matter of MS donors was phagocytosed more efficiently than was myelin isolated from control brain donors by both THP-1 macrophages and primary human microglia.,These data indicate that changes in MS myelin might precede phagocyte activation and subsequent demyelination in MS.,Identifying these myelin changes responsible for enhancing phagocytic ability could be an interesting therapeutic target to prevent or inhibit formation or expansion of MS lesions.,Moreover, during aging, microglia enhance their phagocytic capacity for myelin phagocytosis, but myelin reduces its susceptibility for uptake.

To evaluate the efficacy and safety of sarilumab plus conventional synthetic disease‐modifying antirheumatic drugs (DMARDs) in patients with active moderate‐to‐severe rheumatoid arthritis (RA) who had an inadequate response or intolerance to anti-tumor necrosis factor (anti‐TNF) therapy.,Patients were randomly allocated to receive sarilumab 150 mg, sarilumab 200 mg, or placebo every 2 weeks for 24 weeks with background conventional synthetic DMARDs.,The co‐primary end points were the proportion of patients achieving a response according to the American College of Rheumatology 20% criteria for improvement (ACR20) at week 24, and change from baseline in the Health Assessment Questionnaire disability index (HAQ DI) at week 12.,Each sarilumab dose was evaluated against placebo; differences between the 2 sarilumab doses were not assessed.,The baseline characteristics of the treatment groups were similar.,The ACR20 response rate at week 24 was significantly higher with sarilumab 150 mg and sarilumab 200 mg every 2 weeks compared with placebo (55.8%, 60.9%, and 33.7%, respectively; P < 0.0001).,The mean change from baseline in the HAQ DI score at week 12 was significantly greater for sarilumab (least squares mean change: for 150 mg, −0.46 [P = 0.0007]; for 200 mg, −0.47 [P = 0.0004]) versus placebo (−0.26).,Infections were the most frequently reported treatment‐emergent adverse events.,Serious infections occurred in 1.1%, 0.6%, and 1.1% of patients receiving placebo, sarilumab 150 mg, and sarilumab 200 mg, respectively.,Laboratory abnormalities included decreased absolute neutrophil count and increased transaminase levels in both sarilumab groups compared with placebo.,In this study, reductions in the absolute neutrophil count were not associated with an increased incidence of infections or serious infections.,Sarilumab 150 mg and sarilumab 200 mg every 2 weeks plus conventional synthetic DMARDs improved the signs and symptoms of RA and physical function in patients with an inadequate response or intolerance to anti‐TNF agents.,Safety data were consistent with interleukin‐6 receptor blockade and the known safety profile of sarilumab.

To evaluate the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) Risk Score for serious infections in patients with rheumatoid arthritis (RA).,The RABBIT Risk Score for serious infections was developed in 2011 on a cohort of RA patients enrolled in the German biologics register RABBIT between 2001 and 2007.,To evaluate this score, we used data from patients enrolled in RABBIT after 1 January 2009.,Expected numbers of serious infections and expected numbers of patients with at least one serious infection per year were calculated by means of the RABBIT Risk Score and compared with observed numbers in the evaluation sample.,The evaluation of the score in an independent cohort of 1522 RA patients treated with tumour necrosis factor α (TNFα) inhibitors and 1468 patients treated with non-biological disease-modifying antirheumatic drugs (DMARDs) showed excellent agreement between observed and expected rates of serious infections.,For patients exposed to TNF inhibitors, expected as well as observed numbers of serious infections were 3.0 per 100 patient-years (PY).,For patients on non-biological DMARDs the expected and observed numbers were 1.5/100 PY and 1.8/100 PY, respectively.,The score was highly predictive in groups of patients with low as well as with high infection risk.,The RABBIT Risk Score is a reliable instrument which determines the risk of serious infection in individual patients based on clinical and treatment information.,It helps the rheumatologist to balance benefits and risks of treatment, to avoid high-risk treatment combinations and thus to make informed clinical decisions.

To determine whether genetic variation within genes related to the Toll-like receptor, inflammasome and interferon-γ pathways contributes to the differences in treatment response to tumour necrosis factor inhibitors (anti-TNF) in patients with rheumatoid arthritis (RA).,In a retrospective case-case study, we assessed 23 functional single nucleotide polymorphisms (SNPs) in 15 genes.,We included 538 anti-TNF naïve Danish RA patients from the nationwide DANBIO database.,Multivariable logistic regression analyses were performed to detect associations (p-value<0.05) between genotypes and European League Against Rheumatism (EULAR) treatment responses.,False Discovery Rate corrections for multiple testing (q-value) and stratified analyses were performed to investigate association with individual therapies and IgM-rheumatoid factor (RF) status.,Six of twenty successfully genotyped polymorphisms were nominally associated with EULAR treatment response.,Three of these were in weak to moderate linkage disequilibrium with polymorphisms previously reported associated with anti-TNF treatment response.,TLR5(rs5744174) variant allele carriers (odds ratio(OR) = 1.7(1.1-2.5),p = 0.010,q = 0.46) and TLR1(rs4833095) homozygous variant carriers (OR = 2.8(1.1-7.4),p = 0.037,q = 0.46) had higher odds for a positive treatment response.,NLRP3(rs10754558) variant allele carriers (odds ratio(OR) = 0.6(0.4-1.0),p = 0.045,q = 0.46) were more likely to have a negative treatment response.,The association in TLR5(rs5744174) remained significant after correction for multiple comparisons among patients negative for RF (OR = 6.2(2.4-16.3),p = 0.0002,q = 0.024).,No other association withstood correction for multiple testing.,Post hoc analyses showed that change in Patient Global score on a visual analogue scale (VAS) and change in pain VAS were the main factors responsible for the association.,We reproduced previously reported associations between genetic variation in the TLR10/1/6 gene cluster, TLR5, and NLRP3 loci and response to anti-TNF treatment in RA.,Changes in VAS pain and patient global scores were the main contributors to the association found for TLR5.,Furthermore, we identified other candidate genes that require replication in independent cohorts.

Faced with an increasing number of choices for biologic therapies, rheumatologists have a critical need for better tools to inform rheumatoid arthritis (RA) disease management.,The ability to identify patients who are unlikely to respond to first-line biologic anti-TNF therapies prior to their treatment would allow these patients to seek alternative therapies, providing faster relief and avoiding complications of disease.,We identified a gene expression classifier to predict, pre-treatment, which RA patients are unlikely to respond to the anti-TNF infliximab.,The classifier was trained and independently evaluated using four published whole blood gene expression data sets, in which RA patients (n = 116 = 44 + 15 + 30 + 27) were treated with infliximab, and their response assessed 14-16 months post treatment according to the European League Against Rheumatism (EULAR) response criteria.,For each patient, prior knowledge was used to group gene expression measurements into disease-relevant biological signaling mechanisms that were used as the input features for regularized logistic regression.,The classifier produced a substantial enrichment of non-responders (59 %, given by the cross validated test precision) compared to the full population (27 % non-responders), while identifying nearly a third of non-responders.,Given this classifier performance, treatment of predicted non-responders with alternative biologics would decrease their chance of non-response by between a third and a half, substantially improving their odds of effective treatment and stemming further disease progression.,The classifier consisted of 18 signaling mechanisms, which together indicated that higher inflammatory signaling mediated by TNF and other cytokines was present pre-treatment in the blood of patients who responded to infliximab treatment.,In contrast, non-responders were classified by relatively higher levels of specific metabolic activities in the blood prior to treatment.,We were able to successfully produce a classifier to identify a population of RA patients significantly enriched in anti-TNF non-responders across four different patient cohorts.,Additional prospective studies are needed to validate and refine the classifier for clinical use.,The online version of this article (doi:10.1186/s12920-015-0100-6) contains supplementary material, which is available to authorized users.

Pemphigus is a blistering disease characterized by pemphigus autoantibodies (PVIgG) directed mostly against desmogleins (Dsgs), resulting in the loss of keratinocyte adhesion (acantholysis).,Yet, the mechanisms underlying blister formation remain to be clarified.,We have shown previously that anti-Fas ligand (FasL) antibody (Ab) prevents PVIgG-induced caspase-8 activation and Dsg cleavage in human keratinocytes, and that sera from pemphigus patients contain abnormally increased levels of FasL.,Here, we demonstrate that recombinant FasL induces the activation of caspases prior to Dsg degradation, and anti-FasL Ab prevents acantholysis in cultured keratinocytes.,Moreover, the silencing of FasL reduces PVIgG-induced caspase-8 activation and Dsg3 cleavage.,Following injection of PVIgG into mice, FasL is upregulated at 1-3 h and is followed by caspase-8-mediated keratinocyte apoptosis, before blister formation.,The administration of anti-FasL Ab after PVIgG injection blocks blister formation in mice.,Furthermore, we injected PVIgG into two different gene-targeted mutant mice that selectively lack either secreted soluble FasL (sFasL), FasLΔs/Δs mice, or the membrane-bound form of FasL (mFasL), FasLΔm/Δm mice.,After PVIgG treatment, blisters are only visible in FasLΔm/Δm animals, lacking mFasL, but still producing sFasL, similar to wild-type (C57BL/6) animals.,By contrast, a significant decrease in the relative acantholytic area is observed in the FasLΔs/Δs animals.,These results demonstrate that soluble FasL plays a crucial role in the mechanisms of blister formation, and blockade of FasL could be an effective therapeutic approach for pemphigus.

Bullous pemphigoid (BP) is an autoimmune bullous disease caused by autoantibodies against BP180 in the epidermal basement membrane.,Autoantibody-mediated complement activation is an important process in BP pathogenesis.,CD46, a crucial complement regulatory protein in the complement activation, has been reported to be involved in several autoimmune diseases.,In the present study, we investigated whether CD46 plays a role in BP development.,We found that sCD46 expression was significantly increased in the serum and blister fluids of BP patients and correlated with the levels of anti-BP180 NC16A antibody and C3a.,Otherwise, the level of mCD46 was decreased in lesions of BP patients, whereas the complement activation was enhanced.,We also found that CD46 knockdown in HaCaT human keratinocytes enhanced autoantibody-mediated complement activation.,Importantly, exogenous CD46 blocked complement activation in both healthy skin sections and keratinocytes induced by exposure to pathogenic antibodies from BP patients.,These data suggest that CD46 deficiency is an important factor in BP pathogenesis and that increasing CD46 levels might be an effective treatment for BP.

Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal.,Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes.,In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy.,Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA.,We ran two trials in parallel for pregnant participants and for participants planning pregnancy.,In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone.,Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c).,The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments.,Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation.,This trial is registered with ClinicalTrials.gov, number NCT01788527.,Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy).,We found a small difference in HbA1c in pregnant women using CGM (mean difference −0·19%; 95% CI −0·34 to −0·03; p=0·0207).,Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10).,Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091).,We found no apparent benefit of CGM in women planning pregnancy.,Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial.,Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control).,The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial.,The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy).,Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia.,CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy.,This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use.,Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research.

Intense exercise is a major challenge to the management of type 1 diabetes (T1D).,Closed-loop control (CLC) systems (artificial pancreas) improve glycemic control during limited intensity and short duration of physical activity (PA).,However, CLC has not been tested during extended vigorous outdoor exercise common among adolescents.,Skiing presents unique metabolic challenges: intense prolonged PA, cold, altitude, and stress/fear/excitement.,In a randomized controlled trial, 32 adolescents with T1D (ages 10-16 years) participated in a 5-day ski camp (∼5 h skiing/day) at two sites: Wintergreen, VA, and Breckenridge, CO.,Participants were randomized to the University of Virginia CLC system or remotely monitored sensor-augmented pump (RM-SAP).,The CLC and RM-SAP groups were coarsely paired by age and hemoglobin A1c (HbA1c).,All subjects were remotely monitored 24 h per day by the study physicians and clinical team.,Compared with physician-monitored open loop, percent time in range (70-180 mg/dL) improved using CLC: 71.3 vs.,64.7% (+6.6% [95% CI 1-12]; P = 0.005), with maximum effect late at night.,Hypoglycemia exposure and carbohydrate treatments were improved overall (P = 0.001 and P = 0.007) and during the daytime with strong ski level effects (P = 0.0001 and P = 0.006); ski/snowboard proficiency was balanced between groups but with a very strong site effect: naive in Virginia and experienced in Colorado.,There was no adverse event associated with CLC; the participants’ feedback was overwhelmingly positive.,CLC in adolescents with T1D improved glycemic control and reduced exposure to hypoglycemia during prolonged intensive winter sport activities, despite the added challenges of cold and altitude.

Increased osteoclast (OC) differentiation and activity is the critical event that results in bone loss and joint destruction in common pathological bone conditions, such as osteoporosis and rheumatoid arthritis (RA).,RANKL and its decoy receptor, osteoprotegerin (OPG), control OC differentiation and activity.,However, there is a specific concern of a rebound effect of denosumab discontinuation in treating osteoporosis.,TNFα can induce OC differentiation that is independent of the RANKL/RANK system.,In this review, we discuss the factors that negatively and positively regulate TNFα induction of OC formation, and the mechanisms involved to inform the design of new anti-resorptive agents for the treatment of bone conditions with enhanced OC formation.,Similar to, and being independent of, RANKL, TNFα recruits TNF receptor-associated factors (TRAFs) to sequentially activate transcriptional factors NF-κB p50 and p52, followed by c-Fos, and then NFATc1 to induce OC differentiation.,However, induction of OC formation by TNFα alone is very limited, since it also induces many inhibitory proteins, such as TRAF3, p100, IRF8, and RBP-j.,TNFα induction of OC differentiation is, however, versatile, and Interleukin-1 or TGFβ1 can enhance TNFα-induced OC formation through a mechanism which is independent of RANKL, TRAF6, and/or NF-κB.,However, TNFα polarized macrophages also produce anabolic factors, including insulin such as 6 peptide and Jagged1, to slow down bone loss in the pathological conditions.,Thus, the development of novel approaches targeting TNFα signaling should focus on its downstream molecules that do not affect its anabolic effect.

Rheumatoid arthritis (RA) is a chronic disabling disease that is associated with increased localized and generalized osteoporosis (OP).,Previous studies estimated that approximately one-third of the RA population experience bone loss.,Moreover, RA patients suffer from a doubled fracture incidence depending on several clinical factors, such as disease severity, age, glucocorticoid (GC) use, and immobility.,As OP fractures are related to impaired quality of life and increased mortality rates, OP has an enormous impact on global health status.,Therefore, there is an urgent need for a holistic approach in daily clinical practice.,In other words, both OP- and RA-related factors should be taken into account in treatment guidelines for OP in RA.,First, to determine the actual fracture risk, dual-energy X-ray absorptiometry (DXA), including vertebral fracture assessment (VFA) and calculation of the 10-year fracture risk with FRAX®, should be performed.,In case of high fracture risk, calcium and vitamin D should be supplemented alongside anti-osteoporotic treatment.,Importantly, RA treatment should be optimal, aiming at low disease activity or remission.,Moreover, GC treatment should be at the lowest possible dose.,In this way, good fracture risk management will lead to fracture risk reduction in RA patients.,This review provides a practical guide for clinicians regarding pharmacological treatment options in RA patients with OP, taking into account both osteoporotic-related factors and factors related to RA.

To compare the efficacy of disease activity score in 28 joints (DAS28ESR)-driven therapy with anti-tumour necrosis factor (patients from the GUEPARD trial) and routine care in patients with recent-onset rheumatoid arthritis (patients of the ESPOIR cohort).,After matching GUEPARD and ESPOIR patients on the basis of a propensity score and a 1:2 ratio, at baseline all patients had comparable demographic characteristics, rheumatoid factor, anticyclic citrullinated peptide antibody positivity and clinical disease activity parameters: erythrocyte sedimentation rate, C-reactive protein, mean DAS (6.26±0.87), Sharp/van der Heijde radiographic score (SHS), health assessment questionnaire (HAQ).,Disease duration was longer in GUEPARD patients (5.6±4.6 vs 3.5±2.0 months, p<0.001).,After 1 year, the percentage of patients in remission with an HAQ (<0.5) and an absence of radiological progression was higher in the tight control group (32.3% vs 10.2%, p=0.011) as well as the percentage of patients in low DAS with an HAQ (<0.5) and an absence of radiological progression (36.1% vs 18.9%, p=0.045).,However, there was no difference in the decrease in DAS, nor in the percentage of EULAR (good and moderate), ACR20, ACR50 and ACR70 responses.,More patients in the tight control group had an HAQ below 0.5 (70.2% vs 45.2%, p=0.005).,Overall, pain, patient and physician assessment and fatigue decreased more in the tight control group.,The mean SHS progression was similar in the two groups as was the percentage of patients without progression.,In patients with recent onset active rheumatoid arthritis, a tight control of disease activity allows more patients to achieve remission without disability and radiographic progression.

Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available.,In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described.,The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues.,The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process.,Levels of evidence, strength of recommendations and levels of agreement were derived.,Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed.,Cost effectiveness of the treatments was additionally examined.,These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that is characterized by motor deficits, fatigue, pain, cognitive impairment, and sensory and visual dysfunction.,Secondary progressive multiple sclerosis (SPMS) is a progressive form of MS that develops from relapsing-remitting MS.,Repulsive guidance molecule-a (RGMa) has diverse functions, including axon growth inhibition and immune regulation.,Here, we show inhibiting RGMa had therapeutic effects in mouse models of SPMS.,We induced experimental autoimmune encephalomyelitis in nonobese diabetic mice (NOD-EAE mice) and treated them with humanized anti-RGMa monoclonal antibody.,This treatment significantly suppressed secondary progression of disease and inflammation, demyelination and axonal degeneration.,In addition, treatment with anti-RGMa antibody promoted the growth of corticospinal tracts and motor recovery in targeted EAE mice with inflammatory lesions in the spinal cord.,Collectively, these results show that a humanized anti-RGMa antibody has therapeutic effects in mouse models of SPMS.

It is known that oxidative stress produced by proinflammatory myeloid cells plays an important role in demyelination and neuronal injury in progressive multiple sclerosis (MS).,Myeloperoxidase (MPO) is a pro-oxidative enzyme released from myeloid cells during inflammation.,It has been shown that MPO-dependent oxidative stress plays important roles in inducing tissue injury in many inflammatory diseases.,In this report, we treated NOD experimental autoimmune encephalomyelitis (EAE) mice, a murine model of progressive MS, with N-acetyl lysyltyrosylcysteine amide (KYC), a novel specific MPO inhibitor.,Our data showed that KYC treatment not only attenuated MPO-mediated oxidative stress but also reduced demyelination and axonal injury in NOD EAE mice.,More importantly, we found that KYC treatment increased oligodendrocyte regeneration and neurogenesis in NOD EAE mice.,Taken together, our data suggests that targeting MPO should be a good therapeutic approach for reducing oxidative injury and preserving neuronal function in progressive MS patients.

The study of endogenous insulin secretion may provide relevant insight into the comparison of the natural history of adult onset latent autoimmune diabetes (LADA) with types 1 and 2 diabetes mellitus.,The aim of this study was to compare the results of the C-peptide response to mixed-meal stimulation in LADA patients with different disease durations and subjects with type 2 and adult-onset type 1 diabetes.,Stimulated C-peptide secretion was assessed using the mixed-meal tolerance test in patients with LADA (n = 32), type 1 diabetes mellitus (n = 33) and type 2 diabetes mellitus (n = 30).,All patients were 30 to 70 years old at disease onset.,The duration of diabetes in all groups ranged from 6 months to 10 years.,The recruitment strategy was predefined to include at least 10 subjects in the following 3 disease onset categories for each group: 6 to 18 months, 19 months to 5 years and 5 to 10 years.,At all time-points of the mixed-meal tolerance test, patients with LADA had a lower stimulated C-peptide response than the type 2 diabetes group and a higher response than the type 1 diabetes group.,The same results were found when the peak or area under the C-peptide curve was measured.,When the results were stratified by time since disease onset, a similar pattern of residual insulin secretory capacity was observed.,The present study shows that the magnitude of stimulated insulin secretion in LADA is intermediate between that of type 1 and type 2 diabetes mellitus.,The online version of this article (doi:10.1186/1472-6823-15-1) contains supplementary material, which is available to authorized users.

The optimal treatment of latent autoimmune diabetes in adults (LADA) is not established.,We explored whether early insulin treatment, which has shown beneficial effects in rodents and in human pilot studies, would result in better preservation of β-cell function or metabolic control, compared with conventional treatment.,Glucagon-stimulated C-peptide and HbAlc were evaluated at baseline and after 12, 24 and 36 months in 37 patients recently diagnosed with diabetes, aged ≥30 years, non-insulin-requiring and GADAb and/or ICA positive.,Twenty patients received early insulin and 17 received conventional treatment (diet±oral hypoglycaemic agents (OHA), metformin, some and/or sulfonylurea) and insulin when necessary.,Level of metabolic control, HbAlc, was preserved in the early insulin treated, while it significantly deteriorated in the conventionally treated.,There was no significant difference between the groups in C-peptide after 12, 24 or 36 months, or in the decline of C-peptide.,Only baseline C-peptide predicted a C-peptide of ≥0.5 nmol/l at 36 months.,Gender, body mass index, antibody titres or HbAlc did not influence the levels of C-peptide or HbAlc at baseline or end-of-study, or the decline in C-peptide.,Among the diet±OHA-treated, 5/17 (30%) developed insulin dependency during the follow-up.,No major hypoglycaemic events occurred.,Early insulin treatment in LADA leads to better preservation of metabolic control and was safe.,Superior preservation of C-peptide could not be significantly demonstrated.,Only baseline level of C-peptide significantly influenced C-peptide level after 3 years.,Further studies exploring the best treatment in LADA are warranted.

•A case of an acute demyelinating polyneuropathy during infection by SARS-CoV-2.,•SARS-CoV-2 has also been shown to affect the peripheral nervous system.,•Guillain-Barré syndrome (GBS) due to SARS-CoV-2 is a rare complication.,•Some GBS have led to hypothesize a possible parainfectious pathogenesis.,A case of an acute demyelinating polyneuropathy during infection by SARS-CoV-2.,SARS-CoV-2 has also been shown to affect the peripheral nervous system.,Guillain-Barré syndrome (GBS) due to SARS-CoV-2 is a rare complication.,Some GBS have led to hypothesize a possible parainfectious pathogenesis.,In recent months, the new beta-coronavirus has caused a pandemic with symptoms affecting mainly the respiratory system.,It is established that the virus may play a neurotropic role and in recent months several cases of Guillain-Barré-Strohl syndrome (GBS) have been reported in patients infected with COVID-19.,We report the case of a 54-year-old patient with acute demyelinating polyneuropathy during infection by SARS-CoV-2 who progressed clinically to require assisted ventilation.,After several weeks of specific symptomatic treatment, the patient had a favorable outcome.,In conclusion, despite being a rare complication, we think it is important to consider the possibility of diffuse involvement of the peripheral nervous system in patients with COVID-19 to adjust clinical monitoring and treatment in these cases.

For a long time, viruses have been shown to modify the clinical picture of several autoimmune diseases, including type 1 diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), herpetic stromal keratitis (HSK), celiac disease (CD), and multiple sclerosis (MS).,Best examples of viral infections that have been proposed to modulate the induction and development of autoimmune diseases are the infections with enteric viruses such as Coxsackie B virus (CVB) and rotavirus, as well as influenza A viruses (IAV), and herpesviruses.,Other viruses that have been studied in this context include, measles, mumps, and rubella.,Epidemiological studies in humans and experimental studies in animal have shown that viral infections can induce or protect from autoimmunopathologies depending on several factors including genetic background, host-elicited immune responses, type of virus strain, viral load, and the onset time of infection.,Still, data delineating the clear mechanistic interaction between the virus and the immune system to induce autoreactivity are scarce.,Available data indicate that viral-induced autoimmunity can be activated through multiple mechanisms including molecular mimicry, epitope spreading, bystander activation, and immortalization of infected B cells.,Contrarily, the protective effects can be achieved via regulatory immune responses which lead to the suppression of autoimmune phenomena.,Therefore, a better understanding of the immune-related molecular processes in virus-induced autoimmunity is warranted.,Here we provide an overview of the current understanding of viral-induced autoimmunity and the mechanisms that are associated with this phenomenon.

The pro-inflammatory activities of the calgranulins and HMGB1 can be counteracted by sRAGE, the soluble form of their shared receptor.,To understand the role of these molecules in AAV and their potential as therapeutic targets we have studied (i) the relationship between these DAMPS and disease activity; (ii) the expression of RAGE and sRAGE in biopsy tissue and peripheral blood; and (iii) the effect of these molecules on ANCA-mediated cytokine production.,We examined circulating levels of calgranulins (S100A8/A9 and S100A12), HMGB1 and sRAGE by ELISA.,RAGE was examined in AAV kidney and lung biopsies by immunohistochemistry and RAGE expression was monitored in peripheral blood by qPCR.,In vitro, the effect of co-stimulating PBMC with ANCA and S100A8/A9 on cytokine production was studied by ELISA.,We found significantly raised levels of calgranulins and HMGB1 in active AAV regardless of clinical phenotype (PR3+/MPO+ AAV).,Levels of calgranulins showed significant correlations with each other.,RAGE protein and message was raised in peripheral blood and in cells infiltrating kidney and lung biopsy tissue, while sRAGE was lowered.,Furthermore, ANCA-mediated production of IL-8 from PBMC was significantly enhanced by the presence of S100A8/A9 in a RAGE/TLR4-dependent manner.,Raised circulating calgranulins provide a good marker of disease activity in AAV and are unlikely to be counteracted by sRAGE.,Increased RAGE expression in AAV indicates receptor stimulation in active disease that may exacerbate ANCA-induced cytokine production.,Targeting the RAGE pathway may provide a useful therapeutic approach in AAV.

ANCA-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).,While systemic vasculitis is a hallmark of all AAV, GPA is characterized by extravascular granulomatous inflammation, preferentially affecting the respiratory tract.,The mechanisms underlying the emergence of neutrophilic microabscesses; the appearance of multinucleated giant cells; and subsequent granuloma formation, finally leading to scarred or destroyed tissue in GPA, are still incompletely understood.,This review summarizes findings describing the presence and function of molecules and cells contributing to granulomatous inflammation in the respiratory tract and to renal inflammation observed in GPA.,In addition, factors affecting or promoting the development of granulomatous inflammation such as microbial infections, the nasal microbiome, and the release of damage-associated molecular patterns (DAMP) are discussed.,Further, on the basis of numerous results, we argue that, in situ, various ways of exposure linked with a high number of infiltrating proteinase 3 (PR3)- and myeloperoxidase (MPO)-expressing leukocytes lower the threshold for the presentation of an altered PR3 and possibly also of MPO, provoking the local development of ANCA autoimmune responses, aided by the formation of ectopic lymphoid structures.,Although extravascular granulomatous inflammation is unique to GPA, similar molecular and cellular patterns can be found in both the respiratory tract and kidney tissue of GPA and MPA patients; for example, the antimicrobial peptide LL37, CD163+ macrophages, or regulatory T cells.,Therefore, we postulate that granulomatous inflammation in GPA or PR3-AAV is intertwined with autoimmune and destructive mechanisms also seen at other sites.

Multiple sclerosis is the most common inflammatory neurological disease in young adults.,The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic method of quantifying various effects of a given condition by demographic variables and geography.,In this systematic analysis, we quantified the global burden of multiple sclerosis and its relationship with country development level.,We assessed the epidemiology of multiple sclerosis from 1990 to 2016.,Epidemiological outcomes for multiple sclerosis were modelled with DisMod-MR version 2.1, a Bayesian meta-regression framework widely used in GBD epidemiological modelling.,Assessment of multiple sclerosis as the cause of death was based on 13 110 site-years of vital registration data analysed in the GBD's cause of death ensemble modelling module, which is designed to choose the optimum combination of mathematical models and predictive covariates based on out-of-sample predictive validity testing.,Data on prevalence and deaths are summarised in the indicator, disability-adjusted life-years (DALYs), which was calculated as the sum of years of life lost (YLLs) and years of life lived with a disability.,We used the Socio-demographic Index, a composite indicator of income per person, years of education, and fertility, to assess relations with development level.,In 2016, there were 2 221 188 prevalent cases of multiple sclerosis (95% uncertainty interval [UI] 2 033 866-2 436 858) globally, which corresponded to a 10·4% (9·1 to 11·8) increase in the age-standardised prevalence since 1990.,The highest age-standardised multiple sclerosis prevalence estimates per 100 000 population were in high-income North America (164·6, 95% UI, 153·2 to 177·1), western Europe (127·0, 115·4 to 139·6), and Australasia (91·1, 81·5 to 101·7), and the lowest were in eastern sub-Saharan Africa (3·3, 2·9-3·8), central sub-Saharan African (2·8, 2·4 to 3·1), and Oceania (2·0, 1·71 to 2·29).,There were 18 932 deaths due to multiple sclerosis (95% UI 16 577 to 21 033) and 1 151 478 DALYs (968 605 to 1 345 776) due to multiple sclerosis in 2016.,Globally, age-standardised death rates decreased significantly (change −11·5%, 95% UI −35·4 to −4·7), whereas the change in age-standardised DALYs was not significant (−4·2%, −16·4 to 0·8).,YLLs due to premature death were greatest in the sixth decade of life (22·05, 95% UI 19·08 to 25·34).,Changes in age-standardised DALYs assessed with the Socio-demographic Index between 1990 and 2016 were variable.,Multiple sclerosis is not common but is a potentially severe cause of neurological disability throughout adult life.,Prevalence has increased substantially in many regions since 1990.,These findings will be useful for resource allocation and planning in health services.,Many regions worldwide have few or no epidemiological data on multiple sclerosis, and more studies are needed to make more accurate estimates.,Bill & Melinda Gates Foundation.

We investigated potential interactions between human leukocyte antigen (HLA) genotype and body mass index (BMI) status in relation to the risk of developing multiple sclerosis (MS).,We used 2 case-control studies, one with incident cases (1,510 cases, 2,017 controls) and one with prevalent cases (937 cases, 609 controls).,Subjects with different genotypes and BMI were compared with regard to incidence of MS by calculating odds ratios (ORs) with 95% confidence intervals (CIs) employing logistic regression.,Potential interactions between genotypes and BMI were evaluated by calculating the attributable proportion due to interaction.,In both cohorts, a significant interaction was observed between HLA-DRB1*15 and obesity, regardless of HLA-A*02 status.,Similarly, there was a significant interaction between absence of A*02 and obesity, regardless of DRB1*15 status.,In the incident cohort, obese subjects with the most susceptible genotype (carriage of DRB1*15 and absence of A*02) had an OR of 16.2 (95% CI 7.5-35.2) compared to nonobese subjects without the genetic risk factors.,The corresponding OR in the prevalent study was 13.8 (95% CI 4.1-46.8).,We observed striking interactions between BMI status and HLA genotype with regard to MS risk.,Hypothetically, a low-grade inflammatory response inherent to obesity synergizes with the adaptive, HLA molecule-restricted arm of the immune system, causing MS.,Prevention of adolescent obesity may thus lower the risk of developing MS, predominantly among people with a genetic susceptibility to the disease.

Galactose-deficient IgA1 (Gd-IgA1) is a critical pathogenic factor for IgA nephropathy (IgAN), but its value as a disease-specific biomarker remains controversial.,We aimed to clarify the clinical significance of Gd-IgA1 in patients with IgAN.,We retrospectively reviewed 111 patients who were diagnosed with IgAN based on the findings of renal biopsies (RB) at Showa University Hospital since 2007.,Serum Gd-IgA1 (s-Gd-IgA1) at the time of RB was compared among 111 IgAN patients, 18 Henoch-Schönlein purpura nephritis (HSPN) patients, 29 lupus nephritis (LN) patients, 28 ANCA-associated vasculitis (AAV) patients, and 13 minimal change disease (MCD) patients using ELISA with an anti-human Gd-IgA1-specific monoclonal antibody (KM55).,We also immunohistochemically stained paraffin-embedded sections for mesangial Gd-IgA1 (m-Gd-IgA1) deposition using KM55.,Although levels of s-Gd-IgA1 were comparable among IgAN and HSPN, s-Gd-IgA1 levels were significantly elevated in patients with IgAN compared with LN, AAV and MCD (IgAN vs.,HSPN, LN, AAV, and MCD: 16.2 ± 9.1 vs.,14.2 ± 10.8, p = 0.263; 12.7 ± 9.4, p = 0.008; 13.1 ± 7.3, p = 0.059; and 8.2 ± 4.8 μg/mL, p<0.001, respectively).,Mesangial-Gd-IgA1 deposition was specifically detected in IgAN or HSPN.,The increase in s-Gd-IgA1 significantly correlated with m-Gd-IgA1 positivity in patients with IgAN, and s-Gd-IgA1 elevation and m-Gd-IgA1 deposition were evident in patients with histopathologically advanced IgAN.,Moreover, s-Gd-IgA1 levels were significantly higher in IgAN patients with glomerular sclerosis and tubulo-interstitial lesions.,Mesangial-Gd-IgA1 intensity negatively correlated with eGFR in IgAN.,Multivariate analysis selected s-Gd-IgA1 elevation as a significant risk factor for a 30%-reduction in eGFR in IgAN (HR, 1.37; 95% CI, 1.02-1.89; p = 0.038).,Although IgAN and HSPN remain difficult to differentiate, s-Gd-IgA1 elevation and m-Gd-IgA1 deposition are reliable diagnostic factors that reflect IgAN severity.,Serum-Gd-IgA1 could serve as a predictor of renal outcomes in IgAN.,Thus, Gd-IgA1 could be significant biomarker for patients with IgAN.

Streptococcus mutans is a major pathogen of human dental caries.,Strains harbouring the cnm gene, which encodes Cnm, a collagen-binding protein, contribute to the development of several systemic diseases.,In this study, we analysed S. mutans strains isolated from the oral cavity of immunoglobulin (Ig)A nephropathy (IgAN) patients to determine potential relationships between cnm and caries status as well as IgAN conditions.,Saliva specimens were collected from 109 IgAN patients and the cnm status of isolated S. mutans strains was determined using PCR.,In addition, the dental caries status (decayed, missing or filled teeth [DMFT] index) in patients who agreed to dental consultation (n = 49) was evaluated.,The DMFT index and urinary protein levels in the cnm-positive group were significantly higher than those in the cnm-negative group (p < 0.05).,Moreover, the urinary protein levels in the high DMFT (≥15) group were significantly higher than those in the low DMFT (<15) group (p < 0.05).,Our results show that isolation of cnm-positive S. mutans strains from the oral cavity may be associated with urinary protein levels in IgAN patients, especially those with a high dental caries status.

Type 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction.,A gut microbiota-immunological interplay is involved in the pathophysiology of T1D.,We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT).,Patients with recent-onset (<6 weeks) T1D (18-30 years of age) were randomised into two groups to receive three autologous or allogenic (healthy donor) FMTs over a period of 4 months.,Our primary endpoint was preservation of stimulated C peptide release assessed by mixed-meal tests during 12 months.,Secondary outcome parameters were changes in glycaemic control, fasting plasma metabolites, T cell autoimmunity, small intestinal gene expression profile and intestinal microbiota composition.,Stimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months.,Small intestinal Prevotella was inversely related to residual beta cell function (r=−0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively).,Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics.,FMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset.,Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function.,This study provides insight into the role of the intestinal gut microbiome in T1D.,NTR3697.

Susceptibility to many human autoimmune diseases is under strong genetic control by class II human leukocyte antigen (HLA) allele combinations.,These genes remain by far the greatest risk factors in the development of type 1 diabetes and celiac disease.,Despite this, little is known about HLA influences on the composition of the human gut microbiome, a potential source of environmental influence on disease.,Here, using a general population cohort from the All Babies in Southeast Sweden study, we report that genetic risk for developing type 1 diabetes autoimmunity is associated with distinct changes in the gut microbiome.,Both the core microbiome and beta diversity differ with HLA risk group and genotype.,In addition, protective HLA haplotypes are associated with bacterial genera Intestinibacter and Romboutsia.,Thus, general population cohorts are valuable in identifying potential environmental triggers or protective factors for autoimmune diseases that may otherwise be masked by strong genetic control.,HLA alleles and microbiome alterations have been separately associated with human autoimmunity.,Here the authors identify differences in stool microbiome between healthy carriers of HLA alleles conferring low- and high-risk for type 1 diabetes, suggesting that HLA shaping of microbiome may contribute to HLA impact on autoimmunity risks.

In Graves' disease (GD), autoantibodies to the thyroid stimulating hormone receptor (TSHR) cause hyperthyroidism.,The condition is often associated with eye signs including proptosis, oedema, and diplopia (collectively termed Graves' orbitopathy [GO]).,The safety profile of K1‐70TM (a human monoclonal TSHR specific autoantibody, which blocks ligand binding and stimulation of the receptor) in patients with GD was evaluated in a phase I clinical trial.,Eighteen GD patients stable on antithyroid drug medication received a single intramuscular (IM) or intravenous (IV) dose of K1‐70TM during an open label phase I ascending dose, safety, tolerability, pharmacokinetic and pharmacodynamic (PD) study.,Immunogenic effects of K1‐70TM were also determined.,K1‐70TM was well‐tolerated in all subjects at all doses and no significant immunogenic response was observed.,There were no deaths or serious adverse events.,Increased systemic exposure to K1‐70TM was observed following a change to IV dosing, indicating this was the correct dosage route.,Expected PD effects occurred after a single IM dose of 25 mg or single IV dose of 50 mg or 150 mg with fT3, fT4, and TSH levels progressing into hypothyroid ranges.,There were also clinically significant improvements in symptoms of both GD (reduced tremor, improved sleep, improved mental focus, reduced toilet urgency) and GO (reduced exophthalmos measurements, reduced photosensitivity).,K1‐70TM was safe, well tolerated and produced the expected PD effects with no immunogenic responses.,It shows considerable promise as a new drug to block the actions of thyroid stimulators on the TSHR.

Thyroid-associated ophthalmoapthy (TAO) is the most common orbital disease.,As an autoimmune disorder, it is caused by self-reactive lymphocytes that escape immune tolerance, but the mechanism is not fully understood.,The basic process of TAO is the infiltration of immune cells in orbital tissues, the activation of orbital fibroblasts (OFs), and the proliferation and differentiation of OFs and lymphocytes.,Activated OFs secrete inflammatory regulators, growth factors, and chemokines, thereby maintaining and amplifying the immune responses.,The interactions between OFs and lymphocytes lead to the expansion and the remodeling of the orbital tissues, presenting the clinical manifestations of TAO.,This review will focus on the role of T cell subsets (Type 1, Type 2, Type 17 helper T cells, and regulatory T cells) in the pathogenesis of TAO.,However, we still need further studies to unravel the pathogenesis, to confirm current hypotheses, and to provide novel ideas for appropriate clinical treatment of TAO.

PTPN22 is a tyrosine phosphatase and functions as a damper of TCR signals.,A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human PTPN22 cDNA and converting an arginine (R620) to tryptophan (W620) confers the highest risk of rheumatoid arthritis among non-HLA genetic variations that are known to be associated with this disease.,The effect of the R-to-W conversion on the phosphatase activity of PTPN22 protein and the impact of the minor T allele of the C1858T SNP on the activation of T cells has remained controversial.,In addition, how the overall activity of PTPN22 is regulated and how the R-to-W conversion contributes to rheumatoid arthritis is still poorly understood.,Here we report the identification of an alternative splice form of human PTPN22, namely PTPN22.6.,It lacks the nearly entire phosphatase domain and can function as a dominant negative isoform of the full length PTPN22.,Although conversion of R620 to W620 in the context of PTPN22.1 attenuated T cell activation, expression of the tryptophan variant of PTPN22.6 reciprocally led to hyperactivation of human T cells.,More importantly, the level of PTPN22.6 in peripheral blood correlates with disease activity of rheumatoid arthritis.,Our data depict a model that can reconcile the conflicting observations on the functional impact of the C1858T SNP and also suggest that PTPN22.6 is a novel biomarker of rheumatoid arthritis.

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage.,By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33×10−11, OR = 1.29; WDFY4: rs7097397, P = 8.15×10−12, OR = 1.30).,ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes.,SNP rs1128334 is located in the 3′-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele.,WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein.,Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians.,These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.

It is well recognised that a state of autoimmunity, in which immunological tolerance is broken, precedes the development of symptoms in the majority of patients with rheumatoid arthritis (RA).,For individuals who will later develop seropositive disease, this manifests as autoantibodies directed against proteins that have undergone specific post-translational modifications.,There is evidence that the induction of this autoantibody response occurs at peripheral extra-articular mucosal sites, such as the periodontium and lung.,In addition to their utility as diagnostic markers, these autoantibodies may have a pathogenic role that helps localise disease to the synovium.,Alongside the development of autoantibodies, other factors contributing to pre-symptomatic autoimmunity may include dysbiosis of the gastrointestinal tract, abnormal development of lymphoid tissue, and dysregulated autonomic and lipid-mediated anti-inflammatory signalling.,These factors combine to skew the balance between pro-inflammatory and anti-inflammatory signalling in a manner that is permissive for the development of clinical arthritis.,We present data to support the concept that the transitions from at-risk states to systemic autoimmunity and then to classifiable RA depend on multiple “switches”.,However, further prospective studies are necessary to define the molecular basis of these switches and the specific features of pre-symptomatic autoimmunity, so that preventative treatments can be targeted to individuals at high risk for RA.,In this review, we analyse mechanisms that may contribute to the development of autoimmunity in at-risk individuals and discuss the relationship between this pre-symptomatic state and subsequent development of RA.

Patients with rheumatoid arthritis (RA) are at increased risk of developing comorbid conditions.,To evaluate the prevalence of comorbidities and compare their management in RA patients from different countries worldwide.,Study design: international, cross-sectional.,Patients: consecutive RA patients.,Data collected: demographics, disease characteristics (activity, severity, treatment), comorbidities (cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and psychiatric disorders).,Of 4586 patients recruited in 17 participating countries, 3920 were analysed (age, 56±13 years; disease duration, 10±9 years (mean±SD); female gender, 82%; DAS28 (Disease Activity Score using 28 joints)-erythrocyte sedimentation rate, 3.7±1.6 (mean±SD); Health Assessment Questionnaire, 1.0±0.7 (mean±SD); past or current methotrexate use, 89%; past or current use of biological agents, 39%.,The most frequently associated diseases (past or current) were: depression, 15%; asthma, 6.6%; cardiovascular events (myocardial infarction, stroke), 6%; solid malignancies (excluding basal cell carcinoma), 4.5%; chronic obstructive pulmonary disease, 3.5%.,High intercountry variability was observed for both the prevalence of comorbidities and the proportion of subjects complying with recommendations for preventing and managing comorbidities.,The systematic evaluation of comorbidities in this study detected abnormalities in vital signs, such as elevated blood pressure in 11.2%, and identified conditions that manifest as laboratory test abnormalities, such as hyperglycaemia in 3.3% and hyperlipidaemia in 8.3%.,Among RA patients, there is a high prevalence of comorbidities and their risk factors.,In this multinational sample, variability among countries was wide, not only in prevalence but also in compliance with recommendations for preventing and managing these comorbidities.,Systematic measurement of vital signs and laboratory testing detects otherwise unrecognised comorbid conditions.

Here we looked for possible mechanisms regulating the progression of type 1 diabetes mellitus (T1DM).,In this disease, autoaggressive T cells (T conventional cells, Tconvs) not properly controlled by T regulatory cells (Tregs) destroy pancreatic islets.,We compared the T-cell compartment of patients with newly diagnosed T1DM (NDT1DM) with long-duration T1DM (LDT1DM) ones.,The third group consisted of patients with LDT1DM treated previously with polyclonal Tregs (LDT1DM with Tregs).,We have also looked if the differences might be dependent on the antigen specificity of Tregs expanded for clinical use and autologous sentinel Tconvs.,Patients with LDT1DM were characterized by T-cell immunosenescence-like changes and expansion of similar vβ/T-cell receptor (TCR) clones in Tconvs and Tregs.,The treatment with Tregs was associated with some inhibition of these effects.,Patients with LDT1DM possessed an increased percentage of various proinsulin-specific T cells but not GAD65-specific ones.,The percentages of all antigen-specific subsets were higher in the expansion cultures than in the peripheral blood.,The proliferation was more intense in proinsulin-specific Tconvs than in specific Tregs but the levels of some proinsulin-specific Tregs were exceptionally high at baseline and remained higher in the expanded clinical product than the levels of respective Tconvs in sentinel cultures.,T1DM is associated with immunosenescence-like changes and reduced diversity of T-cell clones.,Preferential expansion of the same TCR families in both Tconvs and Tregs suggests a common trigger/autoantigen responsible.,Interestingly, the therapy with polyclonal Tregs was associated with some inhibition of these effects.,Proinsulin-specific Tregs appeared to be dominant in the immune responses in patients with T1DM and probably associated with better control over respective autoimmune Tconvs.,EudraCT 2014-004319-35.

The dysfunction of FOXP3-positive regulatory T cells (Tregs) plays a key role in the pathogenesis of autoimmune diseases, including type 1 diabetes (T1D).,However, previous studies analyzing the peripheral blood Treg compartment in patients with T1D have yielded partially conflicting results.,Moreover, the phenotypic complexity of peripheral blood Tregs during the development of human T1D has not been comprehensively analyzed.,Here, we used multi-color flow cytometry to analyze the frequency of distinct Treg subsets in blood samples from a large cohort comprising of 74 children with newly diagnosed T1D, 76 autoantibody-positive children at-risk for T1D and 180 age- and HLA-matched control children.,The frequency of CD4+CD25+CD127lowFOXP3+ Tregs was higher in children with T1D compared to control children, and this change was attributable to a higher proportion of naïve Tregs in these subjects.,Further longitudinal analyses demonstrated that the increase in Treg frequency correlated with disease onset.,The frequencies of the minor subsets of CD25+FOXP3low memory Tregs as well as CD25lowCD127lowFOXP3+ Tregs were also increased in children with T1D.,Moreover, the ratio of CCR6-CXCR3+ and CCR6+CXCR3- memory Tregs was altered and the frequency of proliferating Ki67-positive and IFN-γ producing memory Tregs was decreased in children with T1D.,The frequency of CXCR5+FOXP3+ circulating follicular T regulatory cells was not altered in children with T1D.,Importantly, none of the alterations observed in children with T1D were observed in autoantibody-positive at-risk children.,In conclusion, our study reveals multiple alterations in the peripheral blood Treg compartment at the diagnosis of T1D that appear not to be features of early islet autoimmunity.

To evaluate the efficacy of denosumab in suppressing joint destruction when added to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy in patients with rheumatoid arthritis (RA).,This was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase 3 study in Japan.,Patients with RA aged ≥20 years receiving csDMARDs were randomly assigned (1:1:1) to denosumab 60 mg every 3 months (Q3M), denosumab 60 mg every 6 months (Q6M) or placebo.,The change in the modified total Sharp score (mTSS) and effect on bone mineral density (BMD) at 12 months was evaluated.,In total, 654 patients received the trial drugs.,Denosumab groups showed significantly less progression of joint destruction.,The mean changes in the mTSS at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p=0.0235) and 0.72 (95% CI 0.41 to 1.03) in the Q3M group (p=0.0055).,The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p=0.0104) and 0.22 (95% CI 0.09 to 0.34) in the Q3M group (p=0.0001).,No significant between-group difference was observed in the joint space narrowing score.,The per cent change in lumbar spine (L1-L4) BMD in the placebo, Q6M and Q3M groups were −1.03%, 3.99% (p<0.0001) and 4.88% (p<0.0001).,No major differences were observed among safety profiles.,Denosumab inhibits the progression of joint destruction, increases BMD and is well tolerated in patients with RA taking csDMARD.

To determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA).,Patients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks.,The primary outcome was safety.,Of the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively).,Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group.,The most common AE was nasopharyngitis.,In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject.,Both patients recovered fully.,In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo.,MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters.,MOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA.,The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases.,NCT01023256

Lood et al. find that neutrophil TLR7/8 activation shifts neutrophils from phagocytosis of immune complexes to NETosis.,Reduced phagocytosis of immune complexes is associated with partial proteolytic cleavage of FcgRIIA.,Cleaved FcgRIIA is found in SLE neutrophils ex vivo.,Neutrophils play a crucial role in host defense.,However, neutrophil activation is also linked to autoimmune diseases such as systemic lupus erythematosus (SLE), where nucleic acid-containing immune complexes (IC) drive inflammation.,The role of Toll-like receptor (TLR) signaling in processing of SLE ICs and downstream inflammatory neutrophil effector functions is not known.,We observed that TLR7/8 activation leads to a furin-dependent proteolytic cleavage of the N-terminal part of FcgRIIA, shifting neutrophils away from phagocytosis of ICs toward the programmed form of necrosis, NETosis.,TLR7/8-activated neutrophils promoted cleavage of FcgRIIA on plasmacytoid dendritic cells and monocytes, resulting in impaired overall clearance of ICs and increased complement C5a generation.,Importantly, ex vivo derived activated neutrophils from SLE patients demonstrated a similar cleavage of FcgRIIA that was correlated with markers of disease activity, as well as complement activation.,Therapeutic approaches aimed at blocking TLR7/8 activation would be predicted to increase phagocytosis of circulating ICs, while disarming their inflammatory potential.

Toll-like receptors (TLRs) are transmembrane proteins acting mainly as sensors of microbial components.,Triggering TLRs results in increased expression of multiple inflammatory genes, which then play a protective role against infection.,However, aberrant activation of TLR signaling has a significant impact on the onset of cancer, allergy, sepsis and autoimmunity.,Various adaptor proteins, including MyD88, IRAKs, TIRAP, TRIF, and TRAM, are involved in specific TLR signaling pathways.,This article reviews the role of these molecules in TLR signaling, and discusses the impact of this pathway on various disease scenarios.,Given their important role in infectious and non-infectious disease settings, TLRs and their signaling pathways emerge as attractive targets for therapeutics.

The genetic and immunological factors that contribute to differences in susceptibility and progression between sub-types of inflammatory and autoimmune diseases continue to be elucidated.,Inflammatory bowel disease and juvenile idiopathic arthritis are both clinically heterogeneous and known to be due in part to abnormal regulation of gene activity in diverse immune cell types.,Comparative genomic analysis of these conditions is expected to reveal differences in underlying genetic mechanisms of disease.,We performed RNA-Seq on whole blood samples from 202 patients with oligoarticular, polyarticular, or systemic juvenile idiopathic arthritis, or with Crohn’s disease or ulcerative colitis, as well as healthy controls, to characterize differences in gene expression.,Gene ontology analysis combined with Blood Transcript Module and Blood Informative Transcript analysis was used to infer immunological differences.,Comparative expression quantitative trait locus (eQTL) analysis was used to quantify disease-specific regulation of transcript abundance.,A pattern of differentially expressed genes and pathways reveals a gradient of disease spanning from healthy controls to oligoarticular, polyarticular, and systemic juvenile idiopathic arthritis (JIA); Crohn’s disease; and ulcerative colitis.,Transcriptional risk scores also provide good discrimination of controls, JIA, and IBD.,Most eQTL are found to have similar effects across disease sub-types, but we also identify disease-specific eQTL at loci associated with disease by GWAS.,JIA and IBD are characterized by divergent peripheral blood transcriptomes, the genetic regulation of which displays limited disease specificity, implying that disease-specific genetic influences are largely independent of, or downstream of, eQTL effects.,The online version of this article (10.1186/s13073-018-0558-x) contains supplementary material, which is available to authorized users.

The non-receptor tyrosine phosphatase PTPN22 has a vital function in inhibiting antigen-receptor signaling in T cells, while polymorphisms in the PTPN22 gene are important risk alleles in human autoimmune diseases.,We recently reported that a key physiological function of PTPN22 was to prevent naïve T cell activation and effector cell responses in response to low affinity antigens.,PTPN22 also has a more general role in limiting T cell receptor-induced proliferation.,Here we present new data emphasizing this dual function for PTPN22 in T cells.,Furthermore, we show that T cell activation modulates the expression of PTPN22 and additional inhibitory phosphatases.,We discuss the implication of these findings for our understanding of the roles of PTPN22 in regulating T cell responses and in autoimmunity.

Lupus nephritis is one of the most serious complications of systemic lupus erythematosus and manifests with considerable phenotypic and histological heterogeneity.,In particular, diffuse proliferative lupus nephritis (DPLN) and membranous lupus nephritis (MLN) represent morphologic forms that are polar opposites.,DPLN is associated with autoimmune responses dominated by Th1 immune response associated with high levels of interferon (IFN)-γ.,In contrast, a Th2 cytokine response is associated with the pathogenesis of MLN.,MRL/lpr mice develop human LN-like immune complex-associated nephritis and provide a suitable histological model for human DPLN.,Infection with Schistosoma mansoni skewed a Th2-type immune response induction and IL-10 in MRL/lpr mice, drastically changing the pathophysiology of glomerulonephritis from DPLN to MLN accompanied by increased IgG1 and IgE in the sera.,T cells in 32-week-old MRL/lpr mice infected with S. mansoni expressed significantly more IL-4 and IL-10 than T cells of uninfected mice; T cells with IFN-γ were comparable between infected and uninfected MR/lpr mice.,Thus, the helminthic infection modified the cytokine microenvironment and altered the pathological phenotype of autoimmune nephritis.

There is growing evidence that interleukin 17 (IL-17) producing T cells are involved in the pathogenesis of systemic lupus erythematosus (SLE).,Previous studies showed that increased percentages of T-cell subsets expressing the costimulatory molecules CD80 and CD134 are associated with disease activity and renal involvement in SLE.,The aim of this study was to investigate the distribution and phenotypical characteristics of IL-17 producing T-cells in SLE, in particular in patients with lupus nephritis, with emphasis on the expression of CD80 and CD134.,Thirty-four patients (3 male, 31 female, mean age 41 ± 15 years) fulfilling at least four of the American College of Rheumatology (ACR) revised criteria for the diagnosis of SLE and 24 healthy controls were enrolled.,T-cells from the peripheral blood were analysed by fluorescence activated cell sorting (FACS) for their expression levels of CD80, CD134 and CCR6.,In vitro stimulated CD3+IL17+ cells were also investigated for the expression of these costimulatory markers.,Finally, renal biopsies from SLE patients were evaluated for the presence of CD134 expressing T-cells.,Percentages of IL-17 expressing T-cells were significantly increased in patients with active disease as compared to healthy controls (1.46 ± 0.58% versus 0.93 ± 0.30%, P = 0.007).,The percentage of IL-17 producing T-cells was correlated with disease activity as assessed by systemic lupus erythematosus disease activity index (SLEDAI) (r = 0.53, P = 0.003).,In patients, most of the IL-17 producing T-cells were confined to the CCR6+ T-cell subset (80 ± 13%).,Expression of CD80 and CD134 on the IL-17 producing T-cell subset was higher in SLE than in healthy controls (HC) (CD134: 71.78 ± 14.51% versus 51.45 ± 16.58%, P = 0.002; CD80: 25.5 ± 14.99% versus 14.99 ± 5.74%, P = 0.02).,Also, patients with lupus nephritis expressed higher levels of CD134+ on CD3+IL-17+ cells as compared to HC (72.69 ± 11.54% versus 51.45 ± 16.58%, P = 0.006).,Furthermore, renal biopsies of lupus nephritis patients showed infiltration of CD134+ T cells.,Percentages of IL-17 expressing T-cells correlate with disease activity.,Further, these cells show increased expression of costimulatory markers such as CD134 and CD80.,The presence of CD134+ T-cells in renal biopsies of lupus nephritis patients suggest that these cells migrate to the kidney and might contribute to inflammatory processes through IL-17 secretion.

STING is essential for control of infections and for tumor immunosurveillance, but can also drive pathological inflammation.,STING resides on the endoplasmic reticulum (ER), and traffics following stimulation to ERGIC/Golgi where signaling occurs.,Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood.,Here we identify STEEP as a positive regulator of STING signaling.,STEEP was associated with STING and promoted trafficking from the ER.,This was mediated through stimulation of phosphatidylinositol-3-phosphate (PI3P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING.,Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases.,Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP leading to increased ER PI3P levels and membrane curvature.,Thus, STEEP enables STING signaling by promoting ER exit.

Interferon α (IFNα) is a prompt and efficient orchestrator of host defense against nucleic acids but upon chronicity becomes a potent mediator of autoimmunity.,Sustained IFNα signaling is linked to pathogenesis of systemic lupus erythematosus (SLE), an incurable autoimmune disease characterized by aberrant self-DNA sensing that culminates in anti-DNA autoantibody-mediated pathology.,IFNα instructs monocytes differentiation into autoinflammatory dendritic cells (DCs) than potentiates the survival and expansion of autoreactive lymphocytes, but the molecular mechanism bridging sterile IFNα-danger alarm with adaptive response against self-DNA remains elusive.,Herein, we demonstrate IFNα-mediated deregulation of mitochondrial metabolism and impairment of autophagic degradation, leading to cytosolic accumulation of mtDNA that is sensed via stimulator of interferon genes (STING) to promote induction of autoinflammatory DCs.,Identification of mtDNA as a cell-autonomous enhancer of IFNα signaling underlines the significance of efficient mitochondrial recycling in the maintenance of peripheral tolerance.,Antioxidant treatment and metabolic rescue of autolysosomal degradation emerge as drug targets in SLE and other IFNα-related pathologies.,•IFNα obstructs autophagic flux in SLE monocytes through lysosomal alkalinization•IFNα signaling induces oxidative stress that affects lysosomal pH through mTOR•Impaired clearance of damaged mitochondria leads to cytosolic mtDNA accumulation•Autophagic escape of mtDNA is sensed by STING and primes monocytes autoimmunity,IFNα obstructs autophagic flux in SLE monocytes through lysosomal alkalinization,IFNα signaling induces oxidative stress that affects lysosomal pH through mTOR,Impaired clearance of damaged mitochondria leads to cytosolic mtDNA accumulation,Autophagic escape of mtDNA is sensed by STING and primes monocytes autoimmunity,In lupus, sustained IFNα signaling leads to anti-DNA autoimmunity.,Gkirtzimanaki et al. propose that excessive IFNα damages mitochondrial respiration, leading to oxidative stress that impairs lysosomal degradation and obstructs autophagic clearance.,Undegraded mtDNA escapes in the cytoplasm and is sensed, priming monocytes cell-autonomously to initiate an anti-viral-like response against self-DNA.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, which exhibits multiple B cell abnormalities including expanded populations of memory B cells and elevated levels of autoantibodies.,Belimumab is a monoclonal antibody targeting the B cell cytokine BAFF (a.k.a.,BLyS), approved for the treatment of SLE.,In this prospective cohort study, B cells from peripheral blood of 23 SLE patients initiating belimumab treatment and followed longitudinally for up to three years, were assessed using mass cytometry.,B cells decreased during the study period, with a rapid decrease of both naïve and CD11c+CD21− B cells at the first follow-up visit, followed by a continuous reduction at subsequent follow-ups.,In contrast, plasma cells and switched memory B cells remained stable throughout the study.,The observed immunological changes correlated with early, but not late, clinical improvements.,Moreover, high baseline B cell counts were predictive of failure to attain low disease activity.,In summary, our data unveiled both rapid and gradual later therapy-associated alterations of both known and unforeseen B cell phenotypes.,Our results suggest that evaluation of B cell counts might prove useful prior to initiation of belimumab treatment and that early treatment evaluation and discontinuation might underestimate delayed clinical improvements resultant of late B cell changes.

Epratuzumab, a humanized anti-CD22 monoclonal antibody, is under investigation as a therapeutic antibody in non-Hodgkin's lymphoma and systemic lupus erythematosus (SLE), but its mechanism of action on B-cells remains elusive.,Treatment of SLE patients with epratuzumab leads to a reduction of circulating CD27negative B-cells, although epratuzumab is weakly cytotoxic to B-cells in vitro.,Therefore, potential effects of epratuzumab on adhesion molecule expression and the migration of B-cells have been evaluated.,Epratuzumab binding specificity and the surface expression of adhesion molecules (CD62L, β7 integrin and β1 integrin) after culture with epratuzumab was studied on B-cell subsets of SLE patients by flow cytometry.,In addition, in vitro transwell migration assays were performed to analyze the effects of epratuzumab on migration towards different chemokines such as CXCL12, CXCL13 or to CXCR3 ligands, and to assess the functional consequences of altered adhesion molecule expression.,Epratuzumab binding was considerably higher on B-cells relative to other cell types assessed.,No binding of epratuzumab was observed on T-cells, while weak non-specific binding of epratuzumab on monocytes was noted.,On B-cells, binding of epratuzumab was particularly enhanced on CD27negative B-cells compared to CD27positive B-cells, primarily related to a higher expression of CD22 on CD27negative B-cells.,Moreover, epratuzumab binding led to a decrease in the cell surface expression of CD62L and β7 integrin, while the expression of β1 integrin was enhanced.,The effects on the pattern of adhesion molecule expression observed with epratuzumab were principally confined to a fraction of the CD27negative B-cell subpopulation and were associated with enhanced spontaneous migration of B-cells.,Furthermore, epratuzumab also enhanced the migration of CD27negative B-cells towards the chemokine CXCL12.,The current data suggest that epratuzumab has effects on the expression of the adhesion molecules CD62L, β7 integrin and β1 integrin as well as on migration towards CXCL12, primarily of CD27negative B-cells.,Therefore, induced changes in migration appear to be part of the mechanism of action of epratuzumab and are consistent with the observation that CD27negative B-cells were found to be preferentially reduced in the peripheral blood under treatment.

A characteristic pathology of early onset myasthenia gravis is thymic hyperplasia with ectopic germinal centers (GC).,However, the mechanisms that trigger and maintain thymic hyperplasia are poorly characterized.,Dysregulation of small, non-coding microRNAs (miRNAs) and their target genes has been identified in the pathology of several autoimmune diseases.,We assessed the miRNA and mRNA profiles of the MG thymus and have investigated their role in GC formation and maintenance.,MG thymus samples were assessed by histology and grouped based upon the appearance of GC; GC positive and GC negative.,A systems biology approach was used to study the differences between the groups.,Our study included miRNA and mRNA profiling, quantitative real-time PCR validation, miRNA target identification, pathway analysis, miRNA-mRNA reciprocal expression pairing and interaction.,Thirty-eight mature miRNAs and forty-six annotated mRNA transcripts were differentially expressed between the two groups (>1.5 fold change, ANOVA p<0.05).,The miRNAs were found to be involved in immune response pathways and identified in other autoimmune diseases.,The cellular and molecular functions of the mRNAs showed involvement in cell death and cell survival, cellular proliferation, cytokine signaling and extra-cellular matrix reorganization.,Eleven miRNA and mRNA pairs were reciprocally regulated.,The Regulator of G protein Signalling 13 (RGS13), known to be involved in GC regulation, was identified in specimens with GC and was paired with downregulation of miR-452-5p and miR-139-5p.,MiRNA target sites were validated by dual luciferase assay.,Transfection of miRNA mimics led to down regulation of RGS13 expression in Raji cells.,Our study indicates a distinct miRNA and mRNA expression pattern in ectopic GC in MG thymus.,These miRNAs and mRNAs are involved in regulatory pathways common to inflammation and immune response, cell cycle regulation and anti-apoptotic pathways suggesting their involvement in support of GC formation in the thymus.,We demonstrate for the first time that miR-139-5p and miR-452-5p negatively regulate RGS13 expression.

Self‐estimated health can be used for comparison of different diseases between countries.,It is important to elaborate on whether disparities in self‐estimated health are due to disease‐specific parameters or socioeconomic differences.,In this study, we aimed at evaluating clinical and social similarities and differences in myasthenia gravis (MG) patients between comparable regions in two Baltic Sea countries, Estonia and Sweden.,This cross‐sectional study included southern counties in Sweden and Estonia of comparable size.,All patients with a confirmed MG diagnosis were asked to answer two questionnaires including demographic and disease‐specific data, lifestyle issues, and mental fatigue (Fatigue Severity Scale [FSS]).,Clinical fatigue was assessed objectively through the Quantitative Myasthenia Gravis Score (QMG).,Thirty‐six of 92 identified patients in Estonia and 40 of 70 identified MG patients in Sweden chose to participate in the study.,The demographic characteristics and symptoms reported by the patients were similar.,QMG score did not differ; however, the Estonian patients scored their current subjective disease severity significantly higher (5.6 ± 2.8) compared to the Swedish patients (3.4 ± 2.3, p = .0005).,Estonian patients also had significantly higher FSS scores (5.0 ± 1.7) than Swedish patients (3.5 ± 1.6; p = .001).,Swedish patients were more active and performed physical activity more regularly (29.1% in Estonia and 74.2% in Sweden, p = .004).,Although, the patients had comparable clinical fatigue, Estonian patients evaluated their health state as being more severe and reported more mental fatigue than Swedish patients.,These data indicate large regional differences in disease perception of MG, which is important to consider in international studies.

To evaluate the outcomes of immunosuppressive therapy (IST) discontinuation in patients with neuromyelitis optica spectrum disorder (NMOSD) after a sustained remission period.,We retrospectively reviewed the medical records of 17 patients with antiaquaporin-4 antibody-positive NMOSD who discontinued IST after a relapse-free period of ≥3 years.,IST was discontinued at a median age of 40 years (interquartile range [IQR], 32-51) after a median relapse-free period of 62 months (IQR, 52-73).,Among the 17 enrolled patients, 14 (82%) relapsed at a median interval of 6 months (IQR, 4-34) after IST discontinuation, 3 (18%) of whom experienced severe attacks; notably, all 3 of these patients had a history of severe attack before IST.,These 3 patients received steroids, followed by plasma exchange for acute treatment, but 2 exhibited poor recovery and significant disability worsening at 6 months after relapse.,IST discontinuation may increase the risk of relapse in seropositive patients with NMOSD even after 5 years of remission.,Given the potentially devastating consequence of a single attack of NMOSD, caution is advised with IST discontinuation, particularly in patients with severe attack before IST.

Mycophenolate mofetil (MMF) is an immunosuppressive agent (IS) which is widely prescribed in neuromyelitis optica spectrum disorder (NMOSD) patients.,We aim to assess the efficacy and safety of MMF in controlling relapse and disease severity.,Eligible studies obtained from the EMBASE and Ovid MEDLINE databases were studies of NMOSD patients treated with MMF, which reported treatment outcomes as Annualized Relapse Rate (ARR) or Expanded Disability Status Scale (EDSS) before and after treatment.,Fifteen studies included 1047 patients, of whom 915 (87.4%) were aquaporin-4 immunoglobulin seropositive.,The total number of patients that received MMF was 799.,A meta-analysis on ARR was conducted in 200 patients from 4 studies and on EDSS in 158 patients from 3 studies.,The result showed a significant improvement with a mean reduction of 1.13 [95% confidence interval (CI) 0.60-1.65] in ARR, and a mean reduction of 0.85 (95% CI 0.36-1.34) in EDSS after MMF therapy.,Adverse events occurred in 106 (17.8%) of 594 patients during MMF therapy.,This systematic review and meta-analysis showed that using MMF as a preventive therapy in NMOSD patients can significantly reduce relapse rates and improve disease severity with acceptable tolerability.

Lim et al. demonstrate that protein deacetylase, Sirtuin 1, promotes autoimmunity by deacetylating RORγt increasing its transcriptional activity and promoting Th17 differentiation and function.,Blockade or loss of Sirtuin 1 results in protection from multiple sclerosis-like disease in mice.,The balance of effector and regulatory T cell function, dependent on multiple signals and epigenetic regulators, is critical to immune self-tolerance.,Dysregulation of T helper 17 (Th17) effector cells is associated with multiple autoimmune diseases, including multiple sclerosis.,Here, we report that Sirtuin 1 (SIRT1), a protein deacetylase previously reported to have an antiinflammatory function, in fact promotes autoimmunity by deacetylating RORγt, the signature transcription factor of Th17 cells.,SIRT1 increases RORγt transcriptional activity, enhancing Th17 cell generation and function.,Both T cell-specific Sirt1 deletion and treatment with pharmacologic SIRT1 inhibitors suppress Th17 differentiation and are protective in a mouse model of multiple sclerosis.,Moreover, analysis of infiltrating cell populations during disease induction in mixed hematopoietic chimeras shows a marked bias against Sirt1-deficient Th17 cells.,These findings reveal an unexpected proinflammatory role of SIRT1 and, importantly, support the possible therapeutic use of SIRT1 inhibitors against autoimmunity.

In EAE (experimental autoimmune encephalomyelitis), agonists of PPARs (peroxisome proliferator-activated receptors) provide clinical benefit and reduce damage.,In contrast with PPARγ, agonists of PPARδ are more effective when given at later stages of EAE and increase myelin gene expression, suggesting effects on OL (oligodendrocyte) maturation.,In the present study we examined effects of the PPARδ agonist GW0742 on OPCs (OL progenitor cells), and tested whether the effects involve modulation of BMPs (bone morphogenetic proteins).,We show that effects of GW0742 are mediated through PPARδ since no amelioration of EAE clinical scores was observed in PPARδ-null mice.,In OPCs derived from E13 mice (where E is embryonic day), GW0742, but not the PPARγ agonist pioglitazone, increased the number of myelin-producing OLs.,This was due to activation of PPARδ since process formation was reduced in PPARδ-null compared with wild-type OPCs.,In both OPCs and enriched astrocyte cultures, GW0742 increased noggin protein expression; however, noggin mRNA was only increased in astrocytes.,In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes.,These findings demonstrate that PPARδ plays a role in OPC maturation, mediated, in part, by regulation of BMP and BMP antagonists.

•Covid-19 pandemic can have implications for MS and neuroimmunology patients and potentially their adherence to disease modifying therapies (DMTs).,•A large proportion of patients receiving DMT's for their MS expressed some degree of concern regarding the COVID-19 pandemic and their therapy in one MS centre in Australia.,•The level of concern in most patients was at most mild however.,•Patients ascribed similar concern to the risk of a relapse of their disease compared to the risk of contracting COVID-19, perhaps underscoring a willingness to continue their DMT despite the pandemic.,Covid-19 pandemic can have implications for MS and neuroimmunology patients and potentially their adherence to disease modifying therapies (DMTs).,A large proportion of patients receiving DMT's for their MS expressed some degree of concern regarding the COVID-19 pandemic and their therapy in one MS centre in Australia.,The level of concern in most patients was at most mild however.,Patients ascribed similar concern to the risk of a relapse of their disease compared to the risk of contracting COVID-19, perhaps underscoring a willingness to continue their DMT despite the pandemic.,Objective: Patients with Multiple Sclerosis (MS) and on disease modifying therapies (DMTs) that can be immunosuppressive or immunomodulatory form a special group where risk of continuation of DMT needs to be taken into account with risk of contracting Covid-19.,This concept can pose a degree of anxiety for patients as well as neurologists.,We aimed to evaluate patient perspectives regarding the use of Natalizumab and anti-CD20 therapies (Rituximab and Ocrelizumab) in the context of the COVID-19 pandemic.,Methods: cross-sectional study conducted via voluntary survey filled in by patients with MS and related disorders receiving their infusional treatment in one MS centre in Australia, exploring their concerns regarding their therapy, their therapy and COVID-19, precautions undertaken in response to the pandemic, and factors impacting their decision-making.,Results: 170 patients completed the survey.,Of patients on Natalizumab, the majority had either no or mild concern regarding their DMT and COVID-19, and of patients on B-cell depleting therapies, again, the majority had no or mild concern, though a slightly higher proportion had a moderate level of concern.,Asked to delineate their concerns, an increased risk of contracting COVID-19 was more commonly conveyed than MS-specific factors or poor outcomes pertaining to COVID-19 if contracted, by patients in both groups.,Conversely, being invited to specifically consider the possibility of contracting COVID-19 or experience a relapse of MS, almost half of the cohort rated both of equal of concern.,More than half of the cohort were self-isolating more stringently than general government advice and government-related resources followed by information provided by patient's neurologist where the commonest means of information to guide decision making.,Conclusions: Whilst a large proportion of patients had some concern regarding the impact of their DMT on COVID-19, whether on their risk of contracting COVID-19 or a theoretical risk for more severe disease, the overall level of concern in most cases was at most mild.,Patients on B-cell depleting therapies were more inclined to express a higher level of concern.,A similar concern was ascribed to a risk of a relapse or worsening MS symptoms compared to the risk of contracting COVID-19.,Such attitudes may underscore a willingness of patients to continue their DMT where benefits outweigh risks during future phases of the COVID-19 pandemic.

The outbreak of a severe acute respiratory syndrome caused by a novel coronavirus (COVID-19), has raised health concerns for patients with multiple sclerosis (MS) who are commonly on long-term immunotherapies.,Managing MS during the pandemic remains challenging with little published experience and no evidence-based guidelines.,We present five teriflunomide-treated patients with MS who subsequently developed active COVID-19 infection.,The patients continued teriflunomide therapy and had self-limiting infection, without relapse of their MS.,These observations have implications for the management of MS in the setting of the COVID-19 pandemic.

MicroRNAs fine-tune the regulation of Th1/Th17 lymphocyte subsets in multiple sclerosis.,We investigated the expression of miRNAs (previously associated with mycobacterial and viral infections) in MS patients and healthy donors (HD) following 6 months natalizumab therapy.,In addition, Th1/Th17 cytokines and the presence of anti-EBNA1/VCA IgG in MS patients with different pattern of miRNA expression have been evaluated.,MiR-155, miR-26a, miR-132, miR-146a and Th1/Th17 cytokines expression was detected by RT-real time PCR; moreover anti-EBNA1 and VCA IgG titres were measured by ELISA.,We observed an up-regulation of miR-155 (p value = 0.009) and miR-132 (p value = 0.04) in MS patients compared to HD.,In MS patients, IL-17a (p = 0.037), IFN γ (p = 0.012) and TNFα (p = 0.015) but not IL-6 were over-expressed compared to HD.,Two different miRNAs patterns associated to the expression of different cytokines were observed in the MS cohort.,Moreover, a down-regulation of miR-155 and miR-26a was seen in MS patients during and after natalizumab therapy.,MS patients that over-expressed miR-155 showed a higher EBNA1 IgG titer than MS patients with high levels of miR-26a.,In conclusions the expression of particular miRNAs modulates the pro-inflammatory cytokine expression and the humoral response against EBV and this expression is natalizumab regulated.

Demyelination and failure of remyelination are core mechanisms in the pathogenesis of multiple sclerosis (MS); the factor(s) modulating these processes are still mostly unknown.,MicroRNA 572 (miR-572) is deregulated in MS and is suggested to targets neural cell adhesion molecule (NCAM), a glycoprotein involved in CNS reparative mechanisms.,The aim of this study is to analyze miR-572 in patients with different clinical phenotypes of MS.,qPCR quantification of miR-572 isolated from serum was performed in 16 primary progressive (PP), 15 secondary progressive (SP), 31 relapsing remitting (RR) MS patients and 15 sex-and age-matched healthy controls.,miR-572 expression was reduced overall in MS patients (p < 0.05) compared to HC; this miRNA was significantly upregulated in SPMS and in RRMS during disease relapse, whereas it was downregulated in PPMS and in quiescent phases of RRMS. miR-572 expression correlated with EDSS scores (RSp = 0.491; p < 0.05) independently of the clinical phenotype.,The results suggest that this miRNA might be a tool that helps distinguishing between PPMS and SPMS and between relapsing and remitting phases in RRMS.,Evaluation of miR-572 may serve as a non-invasive biomarker for remyelination.,The online version of this article (doi:10.1186/s12967-015-0504-2) contains supplementary material, which is available to authorized users.

Fatigue is a very common and debilitating symptom in patients with systemic lupus erythematosus (SLE), even among those with a mild or inactive disease.,The objective of this study is to define fatigue determinants and describe the impact of fatigue on health-related quality of life (HRQoL) and illness perception in a monocentric cohort of patients with SLE.,This is a cross-sectional study.,Adult patients with SLE were included.,For each patient, demographics, medications, comorbidities, organ damage (Systemic Lupus International Collaborating Clinics Damage Index), active disease manifestations and Systemic Lupus Disease Activity Index scores were collected.,It was evaluated if each patient met the definitions of remission and low disease activity.,At enrolment, each patient completed the Short Form-36 (SF-36), Functional Assessment Chronic Illness Therapy-Fatigue (FACIT-F), Lupus Impact Tracker (LIT), Systemic Lupus Activity Questionnaire (SLAQ) and Brief Index of Lupus Damage (BILD).,The FACIT-F questionnaire was also administered to a group of healthy controls.,223 patients were included (mean age 44.9±13.2 years, median disease duration 13 years).,18.2% had an active disease, 43.5% met the definition of remission on treatment, and 11.8% had a concomitant fibromyalgia.,The median FACIT-F score of our cohort was significantly lower compared with that of healthy controls (40 vs 47; p<0.001).,FACIT-F scores were irrespective of age, disease duration, disease activity and damage.,FACIT-F score was significantly lower in patients with fibromyalgia (p<0.01).,FACIT-F scores demonstrated a significant correlation with all other patient-reported outcomes: SF-36 (r=0.53-0.77), LIT (r=−0.78), SLAQ (r=−0.72) and BILD (r=−0.28).,Fatigue in patients with SLE has a strong negative impact on HRQoL and patient perception of the disease burden.,Fatigue seems irrespective of disease activity but significantly influenced by the presence of fibromyalgia.

To assess the effect of upper limb exercise on hand function, daily activities performance and quality of life of patients with systemic lupus erythematosus (SLE).,We performed a pilot randomised, 24-week follow-up, unmasked controlled trial.,Inclusion criteria were upper limb arthralgias, a Disabilities of Arm, Shoulder and Hand (DASH) questionnaire score >10 and a stable treatment over the past 3 months.,Patients were randomly allocated in the routine care (control) or exercise group that received an individually tailored 30-min daily upper-limb exercise programme by a hand therapist for 12 weeks.,We evaluated at 0, 6, 12 and 24 weeks the performance of daily activities for both groups with DASH questionnaire and Health Assessment Questionnaire (HAQ), the grip and pinch strength with Jamar dynamometer and pinch gauge tool, respectively, the dexterity with Purdue pegboard test, the quality of life with Lupus Quality of Life (LupusQoL) Questionnaire and the pain level by Visual Analogue Scale (VAS) score.,From 293 consecutive SLE patients, data from 32 patients allocated to the exercise group and 30 to the control group were analysed.,There was a significant difference between the two groups in percentage changes of DASH, HAQ, grip strength, pinch strength, LupusQoL-physical health and fatigue, and VAS scores from baseline to 6, 12 and 24 weeks, and from baseline to 12 weeks for dexterity test (p<0.001).,No interaction was observed between exercise and disease activity or medication use at baseline and during the observation period.,Upper-limb exercise significantly improves hand function, pain, daily activity performance and quality of life in SLE.,NCT03802578.

Objective: To evaluate the lifetime prevalence of infectious, inflammatory, and autoimmune disorders in a multisite study of probands with childhood-onset obsessive compulsive disorder (OCD) and their first-degree relatives.,Methods: Medical questionnaires were completed by 1401 probands and 1045 first-degree relatives in the OCD Collaborative Genetics Association Study.,Lifetime prevalence of immune-related diseases was compared with the highest available population estimate and reported as a point estimate with 95% adjusted Wald interval.,Worst-episode OCD severity and symptom dimensions were assessed with the Yale-Brown Obsessive Compulsive Scale (YBOCS) and Symptom Checklist (YBOCS-CL).,Results: Probands reported higher-than-expected prevalence of scarlet fever (4.0 [3.1-5.2]% vs.,1.0%-2.0%, z = 1.491, p < 0.001, n = 1389), encephalitis or meningitis (1.4 [0.9-2.1]% vs.,0.1%-0.4%, z = 5.913, p < 0.001, n = 1393), rheumatoid arthritis (1.1 [0.6-2.0]% vs.,0.2%-0.4%, z = 3.416, p < 0.001, n = 949) and rheumatic fever (0.6 [0.3-1.2]% vs.,0.1%-0.2%, z = 3.338, p < 0.001, n = 1390), but not systemic lupus erythematosus, diabetes, asthma, multiple sclerosis, psoriasis, or inflammatory bowel disease.,First-degree relatives reported similarly elevated rates of scarlet fever, rheumatic fever, and encephalitis or meningitis independent of OCD status.,There was no association between worst-episode severity and immune-related comorbidities, although probands reporting frequent ear or throat infections had increased severity of cleaning-/contamination-related symptoms (mean factor score 2.5 ± 0.9 vs.,2.3 ± 1.0, t = 3.183, p = 0.002, n = 822).,Conclusion: These data suggest high rates of streptococcal-related and other immune-mediated diseases in patients with childhood-onset OCD and are consistent with epidemiological studies in adults noting familial clustering.,Limitations include potential reporting bias and absence of a control group, underscoring the need for further prospective studies characterizing medical and psychiatric disease clusters and their interactions in children.,Such studies may ultimately improve our understanding of OCD pathogenesis and aid in the development of adjunctive immune-modulating therapeutic strategies.

Pediatric autoimmune neuropsychiatric disorder after streptococcal infection (PANDAS) is a specific autoimmune response to group-A streptococcal infections in children and adolescents with a sudden onset of obsessive-compulsive disorders or tic-like symptoms.,Cerebral metabolic changes of patients have not yet been observed.,We present a case of an 18-year old male with a PANDAS-like condition after developing tic-like symptoms and involuntary movements three weeks after cardiac surgery.,The patient had suffered from pharyngotonsillitis before the symptoms started.,The anti-streptolysin O (ASO) titer was elevated (805 kU/l).,Antibiotic therapy did not improve his condition.,Intravenous immunoglobulins and high-dose cortisone therapy had minor beneficial effects on his involuntary movements.,18F-Fluorodeoxyglucose positron emission tomography/ computer tomography (18F-FDG PET/CT) demonstrated pronounced hypermetabolism of the basal ganglia and cortical hypometabolism.,The patient was treated with five cycles of plasmapheresis.,A marked clinical improvement was observed after four months.,Cerebral metabolic alterations had completely normalized.,This is the first report of cerebral metabolic changes observed on FDG-PET/CT in a patient with a PANDAS-like condition with a normalization following immunomodulatory treatment.,Cerebral FDG-PET/CT might be a promising tool in the diagnosis of PANDAS.

A working group on the Oxford classification of IgA nephropathy (IgAN) recently reported that crescents detected in kidney tissue predicted a worse renal outcome.,However, this finding must be validated in independent cohorts before it can be widely applied to clinical practice.,Biopsy-proven IgAN patients were continuously recruited from two large renal centers in China from 1989 to 2014.,All patients were followed for more than 1 year unless end stage renal disease (ESRD) occurred within 12 months.,Crescents were defined as focal cellular or fibrocellular crescent formations.,IgAN patients without detectable crescents were recruited to the C0 group.,Patients with crescents in less than or more than 1/4 of all glomeruli were recruited to the C1 or C2 group, respectively.,Primary outcome was defined as the time to ESRD, and the secondary outcome was defined as the time to an estimated glomerular filtration rate (eGFR) decline equal to or greater than 50% or to ESRD.,In total, 1152 IgAN patients were recruited in this study.,Among all patients, 53.7% were in the C0 group, 38.8% were in the C1 group, and 7.5% were in the C2 group.,Compared to patients in the C0 group, patients in the C1 or C2 group were younger, had more urinary protein excretion and lower eGFR, and presented with more severe mesangial hypercellularity, endocapillary proliferation or tubular atrophy/interstitial fibrosis.,After 45 months of follow-up, ESRD had occurred in 80 (12.9%), 46 (10.3%) and 18 (20.9%) of patients in the C0, C1 and C2 groups, respectively.,By multivariable Cox regression analysis, inclusion in the C1 (HR = 1.07, 95% CI 0.71-1.63), C2 (HR = 0.84, 95% CI 0.41-1.73), or C1 or C2 group (HR = 1.02, 95% CI 0.68-1.52) was not associated with a higher rate of ESRD than inclusion in the C0 group after adjusting for age, gender, eGFR, mean arterial pressure (MAP), MEST scores, and immunosuppressive treatment.,However, in patients with nephrotic-range proteinuria, patients in either the C1 or C2 group had a higher rate of the primary outcome, ESRD (HR = 2.54, 95% CI 1.14-5.66) after adjusting for age, gender, eGFR, MAP, MEST scores, and immunosuppressive treatment.,Similar results were found when we evaluated the association between crescents and the secondary outcome.,IgAN patients with crescents had more severe clinical and pathological manifestations than those without crescents.,However, we failed to replicate the association between crescents and renal function progression in Chinese IgAN patients followed for more than 1 year.,The online version of this article (10.1186/s12967-018-1488-5) contains supplementary material, which is available to authorized users.

Research on the prognosis of IgA nephropathy (IgAN) has focused on renal survival, with little information being available on patient survival.,Hence, this investigation aimed to explore long-term patient outcome in IgAN patients.,Clinical and pathological characteristics at the time of renal biopsy were reviewed in 1,364 IgAN patients from 1979 to 2008.,The outcomes were patient death and end stage renal disease (ESRD) progression.,Overall, 71 deaths (5.3%) and 277 cases of ESRD (20.6%) occurred during 13,916 person-years.,Ten-, 20-, and 30-year patient survival rates were 96.3%, 91.8%, and 82.7%, respectively.,More than 50% patient deaths occurred without ESRD progression.,Overall mortality was elevated by 43% from an age/sex-matched general population (GP) (standardized mortality ratio [SMR], 1.43; 95% confidence interval [CI], 1.04-1.92).,Men had comparable mortality to GP (SMR, 1.22; 95% CI, 0.82-1.75), but, in women, the mortality rate was double (SMR, 2.17; 95% CI, 1.21-3.57).,Patients with renal risk factors such as initial renal dysfunction (estimated glomerular filgration rate <60 ml/min per 1.73m2; SMR, 1.70; 95% CI, 1.13-2.46), systolic blood pressure ≥140 mmHg (SMR, 1.88; 95% CI, 1.19-2.82) or proteinuria ≥1 g/day (SMR, 1.66; 95% CI, 1.16-2.29) had an elevated mortality rate.,Patients with preserved renal function, normotension, and proteinuria <1 g/day, however, had a similar mortality rate to GP.,When risk stratification was performed by counting the number of major risk factors present at diagnosis, low-risk IgAN patients had a mortality rate equal to that of GP, whereas high-risk patients had a mortality rate higher than that of GP.,This investigation demonstrated that overall mortality in IgAN patients was higher than that of GP.,Women and patients with renal risk factors had a higher mortality than that of GP, Therefore, strategies optimized to alleviate major renal risk factors are warranted to reduce patient mortality.

Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens.,Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability.,Our study comprised 7,219 cases and 15,991 controls of European ancestry: a new GWAS, meta-analysis with a published GWAS and a replication study.,We have mapped 43 susceptibility loci, including 10 novel associations.,Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes.,Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells.,We found an over-representation (n=16) of transcription factors among SLE susceptibility genes.,This supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage.,By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33×10−11, OR = 1.29; WDFY4: rs7097397, P = 8.15×10−12, OR = 1.30).,ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes.,SNP rs1128334 is located in the 3′-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele.,WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein.,Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians.,These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.

IgG4‐related disease (IgG4‐RD) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production.,In addition, recent studies have implicated the Toll‐like receptor (TLR) pathway.,This study was undertaken to examine the expression of TLRs in salivary glands (SGs) from patients with IgG4‐RD.,SGs from 15 patients with IgG4‐RD, 15 patients with Sjögren's syndrome (SS), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically.,TLR family gene expression (TLR‐1 through TLR‐10) was analyzed by DNA microarray in the submandibular glands (SMGs).,Up‐regulation of TLRs was confirmed in SGs from patients with IgG4‐RD.,Finally, the phenotype of human TLR‐7 (huTLR‐7)-transgenic C57BL/6 mice was assessed before and after stimulation with TLR agonist.,In patients with IgG4‐RD, TLR‐4, TLR‐7, TLR‐8, and TLR‐9 were overexpressed.,Polymerase chain reaction validated the up‐regulation of TLR‐7 in IgG4‐RD compared with the other groups.,Immunohistochemical analysis confirmed strong infiltration of TLR‐7-positive cells in the SGs of patients with IgG4‐RD.,Double immunohistochemical staining showed that TLR‐7 expression colocalized with CD163+ M2 macrophages.,After in vitro stimulation with a TLR‐7 agonist, CD163+ M2 macrophages produced higher levels of interleukin‐33 (IL‐33), which is a Th2‐activating cytokine.,In huTLR‐7-transgenic mice, the focus and fibrosis scores in SMGs, pancreas, and lungs were significantly higher than those in wild‐type mice (P < 0.05).,Moreover, the concentration of serum IgG, IgG1, and IL‐33 in huTLR‐7-transgenic mice was distinctly increased upon stimulation with a TLR‐7 agonist (P < 0.05).,TLR‐7-expressing M2 macrophages may promote the activation of Th2 immune responses via IL‐33 secretion in IgG4‐RD.

B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) play a crucial role in B cell development, survival, and antibody production.,Here we analyzed the serum levels of BAFF and APRIL and their respective clinical associations in patients with an immunoglobulin (Ig) G4-related disease (IgG4-RD).,We measured serum levels of BAFF and APRIL in patients with IgG4-RD, primary Sjögren's syndrome (pSS), and healthy individuals.,Serum BAFF and APRIL levels in IgG4-RD were assessed for correlations with serological parameters, including Ig, particularly IgG4, and the number of affected organs.,Serum BAFF and APRIL levels in IgG4-RD were monitored during glucocorticoid (GC) therapy.,Serum BAFF and APRIL levels in patients with IgG4-RD were significantly higher (P < 0.01) than in healthy individuals.,The BAFF levels of patients with IgG4-RD were comparable to those of patients with pSS.,Although clinical parameters, such as serum IgG4 and the number of affected organs, were not correlated with the levels of BAFF, serum APRIL levels were inversely correlated with serum IgG4 levels (r = -0.626, P < 0.05).,While serum BAFF levels decreased following GC therapy, serum APRIL levels increased during follow-up.,These results indicate that BAFF and APRIL might be useful markers for predicting disease activity in IgG4-RD.,Further studies are needed to elucidate the role of BAFF and APRIL in the pathogenesis of IgG4-RD.

Infections with human herpesvirus 6A (HHV‐6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development.,For EBV, late infection has been proposed as a risk factor, but serological support is lacking.,The objective of this study was to investigate how age affects the EBV and HHV‐6A associated risks of developing MS.,In this nested case-control study, Swedish biobanks were accessed to find pre‐symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls.,A bead‐based multiplex assay was used to determine serological response against EBV and HHV‐6A.,Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals.,Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020).,The age of transition was estimated to be 18.8 years.,In contrast, HHV‐6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7).,This study suggests EBV infection after adolescence and age independent HHV‐6A infection as risk factors for MS.,Epstein-Barr virus infection after adolescence and age independent human herpesvirus 6A infection are risk factors for multiple sclerosis.

Recent evidence suggests that the primary progressive form of multiple sclerosis (PP-MS) may present with specific immunological alterations.,In this study we focused our attention on CD161, an NK and T cell marker upregulated in relapsing-remitting MS, and investigated its transcript and protein levels in blood cells from PP-MS and healthy individuals.,We demonstrated transcriptional downregulation of CD161 in PP-MS and described concomitant mRNA reduction for RORgt, CCR6, CXCR6, KLRK1/NKG2D and many other markers typical of mucosa associated invariant T (MAIT) cells.,Targeted multiparametric flow cytometry on fresh blood cells from an independent cohort of case-control subjects confirmed the selective loss of circulating CD8 CD161high T cells, which consist mainly of MAIT cells, and not of CD8 CD161int T cells in PP-MS.,These data demonstrate alterations in a specific circulating immune cell subset in MS patients with progressive onset.

Systemic lupus erythematosus (SLE) is characterized by abnormalities in B cell and T cell function, but the role of disturbances in the activation status of macrophages (Mϕ) has not been well described in human patients.,To address this, gene expression profiles from isolated lymphoid and myeloid populations were analyzed to identify differentially expressed (DE) genes between healthy controls and patients with either inactive or active SLE.,While hundreds of DE genes were identified in B and T cells of active SLE patients, there were no DE genes found in B or T cells from patients with inactive SLE compared to healthy controls.,In contrast, large numbers of DE genes were found in myeloid cells (MC) from both active and inactive SLE patients.,Among the DE genes were several known to play roles in Mϕ activation and polarization, including the M1 genes STAT1 and SOCS3 and the M2 genes STAT3, STAT6, and CD163.,M1-associated genes were far more frequent in data sets from active versus inactive SLE patients.,To characterize the relationship between Mϕ activation and disease activity in greater detail, weighted gene co-expression network analysis (WGCNA) was used to identify modules of genes associated with clinical activity in SLE patients.,Among these were disease activity-correlated modules containing activation signatures of predominantly M1-associated genes.,No disease activity-correlated modules were enriched in M2-associated genes.,Pathway and upstream regulator analysis of DE genes from both active and inactive SLE MC were cross-referenced with high-scoring hits from the drug discovery Library of Integrated Network-based Cellular Signatures (LINCS) to identify new strategies to treat both stages of SLE.,A machine learning approach employing MC gene modules and a generalized linear model was able to predict the disease activity status in unrelated gene expression data sets.,In summary, altered MC gene expression is characteristic of both active and inactive SLE.,However, disease activity is associated with an alteration in the activation of MC, with a bias toward the M1 proinflammatory phenotype.,These data suggest that while hyperactivity of B cells and T cells is associated with active SLE, MC potentially direct flare-ups and remission by altering their activation status toward the M1 state.

Microvesicles (MVs) are emerging as a novel means to enact cell-to-cell communication in inflammation.,Here, we aimed to ascertain the ability of neutrophil-derived MVs to modulate target cell behaviour, the focus being the macrophage.,MVs were generated in response to tumour necrosis factor-α, from healthy control neutrophils or those from rheumatoid arthritis patients.,MVs were used to stimulate human monocyte-derived macrophages in vitro, or administered intra-articularly in the K/BxN mouse model of arthritis.,A macrophage/fibroblast-like synoviocyte co-culture system was used to study the effects of vesicles on the crosstalk between these cells.,We demonstrate a direct role for phosphatidylserine and annexin-A1 exposed by the MVs to counteract classical activation of the macrophages, and promote the release of transforming growth factor-β, respectively.,Classically-activated macrophages exposed to neutrophil MVs no longer activated fibroblast-like synoviocytes in subsequent co-culture settings.,Finally, intra-articular administration of neutrophil MVs from rheumatoid arthritis patients in arthritic mice affected the phenotype of joint macrophages.,Altogether these data, with the identification of specific MV determinants, open new opportunities to modulate on-going inflammation in the synovia - mainly by affecting macrophage polarization and potentially also fibroblast-like synoviocytes - through the delivery of autologous or heterologous MVs produced from neutrophils.,•Neutrophil microvesicles restrict the inflammatory activation of macrophages by presenting phosphatidylserine to Mer.,•Annexin A1 expressed on neutrophil microvesicles induces macrophage release of TGFβ by activating FPR2.,•Neutrophil microvesicles restrict the ability of macrophages to activate fibroblast-like synoviocytes.,Neutrophil microvesicles restrict the inflammatory activation of macrophages by presenting phosphatidylserine to Mer.,Annexin A1 expressed on neutrophil microvesicles induces macrophage release of TGFβ by activating FPR2.,Neutrophil microvesicles restrict the ability of macrophages to activate fibroblast-like synoviocytes.,All cells release small, spherical parcels of information, called vesicles, that they use to send signals between each other.,One immune cell type, the neutrophil, has been shown to release vesicles which prevents other immune cells from becoming hyperactive: herein we focus on rheumatoid arthritis.,This paper demonstrates that vesicles released from neutrophils are able to prevent another immune cell type, the macrophage, from becoming activated.,The importance of this is that this mechanism is occurring naturally, and if we can understand it, we may be able to use our own bodies' mechanisms to control chronic inflammation.

Sjögren syndrome (SS) is an immunologically complex, chronic autoimmune disease targeting lacrimal and salivary glands.,Nonobese diabetic (NOD) mice spontaneously develop inflammation of lacrimal and salivary glands with histopathological features similar to SS in humans including focal lymphocytic infiltrates in the affected glands.,The innate immune signals driving lymphocytic infiltration of these glands are not well-defined.,Here we evaluate the role of Toll-like receptor (TLR) 7 in the development of SS-like manifestations in NOD mice.,We created a Tlr7 knockout NOD mouse strain and performed histological and gene expression studies to characterize the effects of TLR7 on autoimmunity development.,TLR7 was required for male-specific lacrimal gland inflammation but not for female-specific salivary gland inflammation.,Moreover, TLR7 was required for type 1 diabetes development in male but not female NOD mice.,RNA sequencing demonstrated that TLR7 was associated with a type I interferon (IFN) response and a type I IFN-independent B cell response in the lacrimal glands.,Together these studies identify a previously unappreciated pathogenic role for TLR7 in lacrimal gland autoimmunity and T1D development in male NOD mice adding to the growing body of evidence supporting sex differences in mechanisms of autoimmune disease in NOD mice.

Monogenic causes of autoimmunity give key insights to the complex regulation of the immune system.,We report a new monogenic cause of autoimmunity resulting from de novo germline activating STAT3 mutations in 5 individuals with a spectrum of early-onset autoimmune disease including type 1 diabetes.,These findings emphasise the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in Hyper IgE syndrome.

Epratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells.,The aim of this study was to report the results of 2 phase III multicenter randomized, double‐blind, placebo‐controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE).,Patients met ≥4 of the American College of Rheumatology revised classification criteria for SLE, were positive for antinuclear antibodies and/or anti-double‐stranded DNA antibodies, had an SLE Disease Activity Index 2000 (SLEDAI‐2K) score of ≥6 (increased disease activity), had British Isles Lupus Assessment Group 2004 index (BILAG‐2004) scores of grade A (severe disease activity) in ≥1 body system or grade B (moderate disease activity) in ≥2 body systems (in the mucocutaneous, musculoskeletal, or cardiorespiratory domains), and were receiving standard therapy, including mandatory treatment with corticosteroids (5-60 mg/day).,BILAG‐2004 grade A scores in the renal and central nervous system domains were excluded.,Patients were randomized 1:1:1 to receive either placebo, epratuzumab 600 mg every week, or epratuzumab 1,200 mg every other week, with infusions delivered for the first 4 weeks of each 12‐week dosing cycle, for 4 cycles.,Patients across all 3 treatment groups also continued with their standard therapy.,The primary end point was the response rate at week 48 according to the BILAG‐based Combined Lupus Assessment (BICLA) definition, requiring improvement in the BILAG‐2004 score, no worsening in the BILAG‐2004 score, SLEDAI‐2K score, or physician's global assessment of disease activity, and no disallowed changes in concomitant medications.,Patients who discontinued the study medication were classified as nonresponders.,In the EMBODY 1 and EMBODY 2 trials of epratuzumab, 793 patients and 791 patients, respectively, were randomized, 786 (99.1%) and 788 (99.6%), respectively, received study medication, and 528 (66.6%) and 533 (67.4%), respectively, completed the study.,There was no statistically significant difference in the primary end point between the groups, with the week 48 BICLA response rates being similar between the epratuzumab groups and the placebo group (response rates ranging from 33.5% to 39.8%).,No new safety signals were identified.,In patients with moderate or severely active SLE, treatment with epratuzumab + standard therapy did not result in improvements in response rates over that observed in the placebo + standard therapy group.

Epratuzumab, a humanized anti-CD22 monoclonal antibody, is under investigation as a therapeutic antibody in non-Hodgkin's lymphoma and systemic lupus erythematosus (SLE), but its mechanism of action on B-cells remains elusive.,Treatment of SLE patients with epratuzumab leads to a reduction of circulating CD27negative B-cells, although epratuzumab is weakly cytotoxic to B-cells in vitro.,Therefore, potential effects of epratuzumab on adhesion molecule expression and the migration of B-cells have been evaluated.,Epratuzumab binding specificity and the surface expression of adhesion molecules (CD62L, β7 integrin and β1 integrin) after culture with epratuzumab was studied on B-cell subsets of SLE patients by flow cytometry.,In addition, in vitro transwell migration assays were performed to analyze the effects of epratuzumab on migration towards different chemokines such as CXCL12, CXCL13 or to CXCR3 ligands, and to assess the functional consequences of altered adhesion molecule expression.,Epratuzumab binding was considerably higher on B-cells relative to other cell types assessed.,No binding of epratuzumab was observed on T-cells, while weak non-specific binding of epratuzumab on monocytes was noted.,On B-cells, binding of epratuzumab was particularly enhanced on CD27negative B-cells compared to CD27positive B-cells, primarily related to a higher expression of CD22 on CD27negative B-cells.,Moreover, epratuzumab binding led to a decrease in the cell surface expression of CD62L and β7 integrin, while the expression of β1 integrin was enhanced.,The effects on the pattern of adhesion molecule expression observed with epratuzumab were principally confined to a fraction of the CD27negative B-cell subpopulation and were associated with enhanced spontaneous migration of B-cells.,Furthermore, epratuzumab also enhanced the migration of CD27negative B-cells towards the chemokine CXCL12.,The current data suggest that epratuzumab has effects on the expression of the adhesion molecules CD62L, β7 integrin and β1 integrin as well as on migration towards CXCL12, primarily of CD27negative B-cells.,Therefore, induced changes in migration appear to be part of the mechanism of action of epratuzumab and are consistent with the observation that CD27negative B-cells were found to be preferentially reduced in the peripheral blood under treatment.

Ubiquitin is highly conserved across eukaryotes and is essential for normal eukaryotic cell function.,The bacterium Bacteroides fragilis is a member of the normal human gut microbiota, and the only bacterium known to encode a homologue of eukaryotic ubiquitin.,The B. fragilis gene sequence indicates a past horizontal gene transfer event from a eukaryotic source.,It encodes a protein (BfUbb) with 63% identity to human ubiquitin which is exported from the bacterial cell.,The aim of this study was (i) to determine if there was antigenic cross‐reactivity between B. fragilis ubiquitin and human ubiquitin and (ii) to determine if humans produced antibodies to BfUbb.,Molecular model comparisons of BfUbb and human ubiquitin predicted a high level (99·8% confidence) of structural similarity.,Linear epitope mapping identified epitopes in BfUbb and human ubiquitin that cross‐react.,BfUbb also has epitope(s) that do not cross‐react with human ubiquitin.,The reaction of human serum (n = 474) to BfUbb and human ubiquitin from the following four groups of subjects was compared by enzyme‐linked immunosorbent assay (ELISA): (1) newly autoantibody‐positive patients, (2) allergen‐specific immunoglobulin (Ig)E‐negative patients, (3) ulcerative colitis patients and (4) healthy volunteers.,We show that the immune system of some individuals has been exposed to BfUbb which has resulted in the generation of IgG antibodies.,Serum from patients referred for first‐time testing to an immunology laboratory for autoimmune disease are more likely to have a high level of antibodies to BfUbb than healthy volunteers.,Molecular mimicry of human ubiquitin by BfUbb could be a trigger for autoimmune disease.

Systemic lupus erythematosus (SLE) is the prototypical systemic autoimmune disease in humans and is characterized by the presence of hyperactive immune cells and aberrant antibody responses to nuclear and cytoplasmic antigens, including characteristic anti-double-stranded DNA antibodies.,We performed a cross-sectional study in order to determine if an SLE-associated gut dysbiosis exists in patients without active disease.,A group of 20 SLE patients in remission, for which there was strict inclusion and exclusion criteria, was recruited, and we used an optimized Ion Torrent 16S rRNA gene-based analysis protocol to decipher the fecal microbial profiles of these patients and compare them with those of 20 age- and sex-matched healthy control subjects.,We found diversity to be comparable based on Shannon’s index.,However, we saw a significantly lower Firmicutes/Bacteroidetes ratio in SLE individuals (median ratio, 1.97) than in healthy subjects (median ratio, 4.86; P < 0.002).,A lower Firmicutes/Bacteroidetes ratio in SLE individuals was corroborated by quantitative PCR analysis.,Notably, a decrease of some Firmicutes families was also detected.,This dysbiosis is reflected, based on in silico functional inference, in an overrepresentation of oxidative phosphorylation and glycan utilization pathways in SLE patient microbiota.,Growing evidence suggests that the gut microbiota might impact symptoms and progression of some autoimmune diseases.,However, how and why this microbial community influences SLE remains to be elucidated.,This is the first report describing an SLE-associated intestinal dysbiosis, and it contributes to the understanding of the interplay between the intestinal microbiota and the host in autoimmune disorders.

Measurement of MRP8/14 serum levels has shown potential in predicting clinical response to different biological agents in rheumatoid arthritis (RA).,We aimed to develop a treatment algorithm based on a prediction score using MRP8/14 measurements and clinical parameters predictive for response to different biological agents.,Baseline serum levels of MRP8/14 were measured in 170 patients starting treatment with infliximab, adalimumab or rituximab.,We used logistic regression analysis to develop a predictive score for clinical response at 16 weeks.,MRP8/14 levels along with clinical variables at baseline were investigated.,We also investigated how the predictive effect of MRP8/14 was modified by drug type.,A treatment algorithm was developed based on categorizing the expected response per drug type as high, intermediate or low for each patient and optimal treatment was defined.,Finally, we present the utility of using this treatment algorithm in clinical practice.,The probability of response increased with higher baseline MRP8/14 complex levels (OR = 1.39), differentially between the TNF-blockers and rituximab (OR of interaction term = 0.78), and also increased with higher DAS28 at baseline (OR = 1.28).,Rheumatoid factor positivity, functional disability (a higher HAQ), and previous use of a TNF-inhibitor decreased the probability of response.,Based on the treatment algorithm 80 patients would have been recommended for anti-TNF treatment, 8 for rituximab, 13 for another biological treatment (other than TNFi or rituximab) and for 69 no recommendation was made.,The predicted response rates matched the observed response in the cohort well.,On group level the predicted response based on the algorithm resulted in a modest 10% higher response rate in our cohort with much higher differences in response probability in individual patients treated contrary to treatment recommendation.,Prediction of response using MRP8/14 levels along with clinical predictors has potential in personalizing treatment for RA patients starting biological anti-rheumatic treatment, and might increase cost-effectiveness.

There has been no report in the literature of a soluble form of interleukin (IL)-18 receptor α (IL-18Rα).,In this study, we evaluated the levels and characteristics of soluble IL-18Rα (sIL-18Rα) in the sera of patients with rheumatoid arthritis (RA) and compared these results to control populations.,The sIL-18Rα complex was isolated from pooled human blood serum using an anti-IL-18Rα monoclonal antibody affinity column.,The purified sIL-18Rα was then examined using Western blot analysis and used in experiments to evaluate the effects on an IL-18-responsive natural killer (NK) human cell line, NK0.,An enzyme-linked immunosorbent assay was developed, and sera from 145 patients with RA, 6 patients with adult-onset Still's disease, 31 patients with osteoarthritis (OA), 39 patients with systemic lupus erythematosus (SLE) and 67 controls were tested, along with levels of immunoglobulin M, rheumatoid factor, anticyclic citrullinated peptide antibody, IL-18, IL-13 and interferon (IFN)-γ.,Area under the receiver operating characteristic curve (ROC-AUC) analysis was used to evaluate the diagnostic utility of the sIL-18Rα complex.,The isolated sIL-18Rα complex can be associated with IL-18 and the soluble form of the IL-18Rβ chain.,The sIL-18Rα complex bound to the surface to the NK0 cell line, antagonized the stimulatory effects of IL-18 and IL-2 on the NK0 cell line and inhibited IFN-γ production by the cells.,The serum levels of sIL-18Rα complex in RA (186.0 ± 33.5 ng/mL, n = 145) and adult-onset Still's disease (98.2 ± 8.9 ng/mL, n = 6) were significantly (P < 0.001) higher than those in the healthy controls (52.3 ± 8.5 ng/mL, n = 67), OA (38.6 ± 5.4 ng/mL, n = 31), SLE (44.6 ± 3.2 ng/mL, n = 39).,The serum level of sIL-18Rα complex was not significantly different between RA and adult-onset Still's disease patients.,The serum levels of IL-18, IL-13 and IFN-γ in the RA patients were significantly (P < 0.01) higher than in OA and SLE patients as well as healthy controls.,ROC-AUC analysis of the serum concentration of sIL-18Rα indicated that it was significantly diagnostic of RA.,Moreover, a tumor necrosis factor inhibitor, etanercept, significantly (P < 0.0001) decreased levels of sIL-18Rα in the sera of 29 RA patients 6 months after treatment.,The sIL-18Rα complex could be a potentially useful biomarker for the diagnosis of RA.

IgA nephropathy (IgAN) is a common cause of end-stage renal disease (ESRD) in Asia.,In this study, based on a large cohort of Chinese patients with IgAN, we aim to identify independent predictive factors associated with disease progression to ESRD.,We collected retrospective clinical data and renal outcomes on 619 biopsy-diagnosed IgAN patients with a mean follow-up time of 41.3 months.,In total, 67 individuals reached the study endpoint defined by occurrence of ESRD necessitating renal replacement therapy.,In the fully adjusted Cox proportional hazards model, there were four baseline variables with a significant independent effect on the risk of ESRD.,These included: eGFR [HR = 0.96(0.95-0.97)], serum albumin [HR = 0.47(0.32-0.68)], hemoglobin [HR = 0.79(0.72-0.88)], and SBP [HR = 1.02(1.00-1.03)].,Based on these observations, we developed a 4-variable equation of a clinical risk score for disease progression.,Our risk score explained nearly 22% of the total variance in the primary outcome.,Survival ROC curves revealed that the risk score provided improved prediction of ESRD at 24th, 60th and 120th month of follow-up compared to the three previously proposed risk scores.,In summary, our data indicate that IgAN patients with higher systolic blood pressure, lower eGFR, hemoglobin, and albumin levels at baseline are at a greatest risk of progression to ESRD.,The new progression risk score calculated based on these four baseline variables offers a simple clinical tool for risk stratification.

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide and an important cause of kidney disease in young adults.,Highly variable clinical presentation and outcome of IgAN suggest that this diagnosis may encompass multiple subsets of disease that are not distinguishable by currently available clinical tools.,Marked differences in disease prevalence between individuals of European, Asian, and African ancestry suggest the existence of susceptibility genes that are present at variable frequencies in these populations.,Familial forms of IgAN have also been reported throughout the world but are probably underrecognized because associated urinary abnormalities are often intermittent in affected family members.,Of the many pathogenic mechanisms reported, defects in IgA1 glycosylation that lead to formation of immune complexes have been consistently demonstrated.,Recent data indicates that these IgA1 glycosylation defects are inherited and constitute a heritable risk factor for IgAN.,Because of the complex genetic architecture of IgAN, the efforts to map disease susceptibility genes have been difficult, and no causative mutations have yet been identified.,Linkage-based approaches have been hindered by disease heterogeneity and lack of a reliable noninvasive diagnostic test for screening family members at risk of IgAN.,Many candidate-gene association studies have been published, but most suffer from small sample size and methodological problems, and none of the results have been convincingly validated.,New genomic approaches, including genome-wide association studies currently under way, offer promising tools for elucidating the genetic basis of IgAN.,The online version of this article (doi:10.1007/s00467-010-1500-7) contains supplementary material, which is available to authorized users.

The steep increase in the incidence of type 1 diabetes (T1D), in the Western world after World War II, cannot be explained solely by genetic factors but implies that this rise must be due to crucial interactions between predisposing genes and environmental changes.,Three parallel phenomena in early childhood - the dynamic development of the immune system, maturation of the gut microbiome, and the appearance of the first T1D-associated autoantibodies - raise the question whether these phenomena might reflect causative relationships.,Plenty of novel data on the role of the microbiome in the development of T1D has been published over recent years and this review summarizes recent findings regarding the associations between islet autoimmunity, T1D, and the intestinal microbiota.

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.

Myasthenia gravis is a chronic, autoimmune, neuromuscular junction disorder characterized by skeletal muscle weakness.,Current therapies for myasthenia gravis are associated with significant side effects.,The objective of this study was to characterize the side effects, and associated health-related quality of life and treatment impacts, of traditional myasthenia gravis treatments.,This study had two phases; a Phase 1 interview and a 2-part web-based survey in Phase 2 that included brainstorming (Step 1) and rating (Step 2) exercises using group concept mapping.,In Phase 1, all 14 participants reported experiencing side effects from myasthenia gravis treatments which had significant impacts on daily life.,In Phase 2, 246 participants contributed to Step 1; 158 returned for Step 2.,The brainstorming exercise produced 874 statements about side effects and their impact, which were reduced to 35 side effects and 23 impact-on-daily life statements.,When rating these statements on severity, frequency, and tolerability, blood clots, infections/decreased immunity, weight gain, and diarrhea were the least tolerable and most severely rated.,The most frequent and severe impacts were sleep interference and reduced physical and social activities.,Based on these findings, there appears to be a need for better and more tolerable treatments for myasthenia gravis patients.

Emerging evidence suggests that fatigue in myasthenia gravis (MG) is a relevant problem that negatively impacts activities of daily living (ADL).,The relationship between fatigue and quality of life (QoL) has never been systematically explored in MG patients.,The study aimed to assess the prevalence of fatigue and its relation to ADL and QoL as well as to identify factors associated with fatigue in MG.,This was a cross‐sectional observational study in patients with confirmed diagnosis of MG independent of disease severity.,Prevalence of fatigue was assessed using the Chalder Fatigue Scale (CFQ).,Impact of fatigue on ADL and QoL was assessed by the MG activities of daily living profile (MG‐ADL) and the MG‐specific quality‐of‐life instrument (MG‐QoL), respectively.,Association of fatigue with sociodemographics, clinical characteristics of MG, and comorbidities including mood and anxiety disorders as well as sleep disorders was investigated using multivariable logistic regression analyses.,Overall, 200 MG patients were included.,The observed rate of fatigue was 56.1%, of those 70.4% fulfilled the criteria of chronic fatigue (CF) with a duration of ≥6 months.,Relevant fatigue was strongly associated to ADL and QoL.,Factors associated with relevant fatigue were disease severity and depressive state.,Furthermore, positive muscle‐specific tyrosine kinase (MuSK) antibody status showed a strong association with relevant fatigue.,MG patients have a high prevalence of fatigue which negatively impacts ADL and QoL.,MG‐specific clinical characteristics are related to fatigue and might help to identify MG patients at risk for fatigue.

Diabetic peripheral neuropathy (DPN) involves sensory and motor nerves, resulting in demyelination as well as axonal degeneration.,This study was conducted to describe the pattern of lower limb nerve involvement in children with type 1 diabetes mellitus (DM) based on the parameters of nerve conduction study (NCS).,This cross-sectional study recruited 50 children with type 1 DM having mean disease duration of 4.92 ± 3.84 years who attended the referred clinic in Sudan Childhood Diabetes Center.,Their mean age was 15.00 ± 2.19 years, 42% were males, and 58% were females.,Twenty six matched healthy control subjects were involved; their mean age was 13.88 ± 2.46 years, 38.46% were males, and 61.54% were females.,Bilateral NCS of the sensory and motor lower limb nerves was performed using Medelec Synergy machine.,Interpretation of the patients' results was based on our own control reference values.,Data was analysed using IBM SPSS statistics.,Out of the 50 diabetic patients, 44 (88%) had electrophysiological evidence of peripheral neuropathy (abnormalities in at least two of the electrophysiological parameters).,The majority (68.2%) had motor involvement and 31.8% had sensorimotor, while none of them (0%) had pure sensory involvement.,Regarding abnormal NCS parameters (conduction velocity vs. amplitude of the compound action potential), conduction slowing feature predominated in 61.4% and only few (6.8%) showed amplitude reduction, while 31.8% showed mixed features.,The most frequently affected nerve was the common peroneal, followed by posterior tibial, and the least was the sural nerve.,The most sensitive parameter was the common peroneal conduction velocity.,Motor precedes sensory nerve involvement.,The most frequent neurophysiological abnormality was the conduction slowing, and the common peroneal was the most vulnerable nerve.,These findings signify generation of a protocol for early screening of neuropathy in children with type 1 diabetes.

The effectiveness of an intervention in clinical practice is often reduced compared to the efficacy demonstrated in a randomised controlled trial (RCT).,In this comparative effectiveness study, the RCT-proven efficacy of a diabetes education programme for type 1 diabetic patients (PRIMAS) was compared to the effectiveness observed in an implementation trial (IT) under routine care conditions.,75 patients with type 1 diabetes received PRIMAS through an RCT, whereas 179 patients were observed in an implementation trial.,Baseline characteristics and treatment outcomes at the 6-month follow-up (improvement of HbA1c, hypoglycaemia problems, and diabetes-related distress) were compared.,At baseline, the type 1 diabetic patients in the RCT had a significant longer diabetes duration (18.7±12.3 vs.,13.8±12.7 yrs., p = .005), lower self-efficacy scores (21.9±4.7 vs.,23.7±6.1, p = .02) and a greater number of diabetes complications (0.8±1.3 vs.,0.4±0.9, p = .02).,After 6 months, PRIMAS achieved comparable effects under RCT and implementation trial conditions, as demonstrated by improvement in HbA1c (-0.36%±1.1 vs. -0.37±1.2; Δ -0.01, 95% CI -0.33 to 0.31) and hypoglycaemia unawareness (-0.5±1.4 vs. -0.3±1.4; Δ 0.18, 95% CI -0.21 to 0.57).,The likelihood of clinical improvement did not depend on the trial setting (RCT vs.,IT: OR 1.18, 95% CI 0.60 to 2.33).,The participants with worse glycaemic control (OR 1.40, 95% CI 1.02 to 1.92), hypoglycaemia problems (OR 2.13, 95% CI 1.53 to 2.97) or elevated diabetes distress (OR 1.40, 95% CI 1.03 to 1.89) had a better chance of clinical improvement.,The effectiveness of PRIMAS under routine care conditions was comparable to the efficacy demonstrated in the RCT.,Clinical improvement was independent of the setting in which PRIMAS was evaluated.,The PRIMAS education programme for type 1 diabetes can be delivered under conditions of routine care without a loss of effectiveness, compared to its original evaluation in an RCT.

Multiple Sclerosis (MuS) is a complex multifactorial neuropathology, resulting in heterogeneous clinical presentation.,A very active MuS research field concerns the discovery of biomarkers helpful to make an early and definite diagnosis.,The sphingomyelin pathway has emerged as a molecular mechanism involved in MuS, since high levels of ceramides in cerebrospinal fluid (CSF) were related to axonal damage and neuronal dysfunction.,Ceramides are the hydrolysis products of sphingomyelins through a reaction catalyzed by a family of enzymes named sphingomyelinases, which were recently related to myelin repair in MuS.,Here, using a lipidomic approach, we observed low levels of several sphingomyelins in CSF of MuS patients compared to other inflammatory and non-inflammatory, central or peripheral neurological diseases.,Starting by this result, we investigated the sphingomyelinase activity in CSF, showing a significantly higher enzyme activity in MuS.,In support of these results we found high number of total exosomes in CSF of MuS patients and a high number of acid sphingomyelinase-enriched exosomes correlated to enzymatic activity and to disease severity.,These data are of diagnostic relevance and show, for the first time, high number of acid sphingomyelinase-enriched exosomes in MuS, opening a new window for therapeutic approaches/targets in the treatment of MuS.

Inflammation is an immune response that works as a contained fire that is pre-emptively sparked as a defensive process during infections or upon any kind of tissue insult, and that is spontaneously extinguished after elimination or termination of the damage.,However, persistent and uncontrolled immune reactions act as a wildfire that promote chronic inflammation, unresolved tissue damage and, eventually, chronic diseases.,A wide network of soluble mediators, among which endogenous bioactive lipids, governs all immune processes.,They are secreted by basically all cells involved in inflammatory processes and constitute the crucial infrastructure that triggers, coordinates and confines inflammatory mechanisms.,However, these molecules are also deeply involved in the detrimental transition from acute to chronic inflammation, be it for persistent or excessive action of pro-inflammatory lipids or for the impairment of the functions carried out by resolving ones.,As a matter of fact, bioactive lipids have been linked, to date, to several chronic diseases, including rheumatoid arthritis, atherosclerosis, diabetes, cancer, inflammatory bowel disease, systemic lupus erythematosus, and multiple sclerosis.,This review summarizes current knowledge on the involvement of the main classes of endogenous bioactive lipids-namely classical eicosanoids, pro-resolving lipid mediators, lysoglycerophospholipids/sphingolipids, and endocannabinoids-in the cellular and molecular mechanisms that lead to the pathogenesis of chronic disorders.

Adult-onset Still’s disease (AOSD), a rare autoinflammatory disorder, resembles systemic juvenile idiopathic arthritis (SJIA).,The superimposable systemic clinical features of AOSD and SJIA suggest both clinical phenotypes represent the same disease continuum with different ages of onset.,To further characterize the similarity between AOSD and SJIA at the molecular level, 2 previously identified response gene sets in SJIA were used to investigate how genes that respond to interleukin (IL)-1β inhibition with canakinumab in SJIA patients behave in AOSD patients with active disease prior to IL-1β targeting therapy, relative to healthy subjects.,All genes downregulated in SJIA patients following canakinumab treatment were upregulated in most patients with active AOSD prior to canakinumab treatment, relative to healthy subjects.,A few patients with milder AOSD had expectedly gene-expression patterns that resembled those in healthy subjects.,Comparison of the gene-expression patterns with neutrophil counts showed a correlation between elevated neutrophil numbers and upregulation of canakinumab-responsive genes.,Correspondingly, most genes upregulated following canakinumab treatment in patients with SJIA patients were downregulated in the majority of AOSD patients.,These results further support the concept of a Still’s disease continuum that includes both a pediatric/juvenile onset (SJIA) and adult onset (AOSD) form.

Anakinra is the first interleukin-1 inhibitor to be used in clinical practice, and recent evidence showed that interleukin-1 plays a pivotal role in the pathogenesis of adult-onset Still disease (AoSD).,However, data concerning efficacy with anakinra use in different clinical trials has not been evaluated, and the overall remission of AoSD with anakinra treatment has not been well defined.,We conducted a search on Embase, PubMed, and the Cochrane Library for relevant trials.,Statistical analyses were conducted to calculate the overall remission rates, odds ratios (OR), and 95% confidence intervals (CI), by using either random effects or fixed effect models according to the heterogeneity.,Of the 273 articles that were identified, 265 were excluded.,Eight studies were eligible for inclusion.,The overall remission rate and complete remission rate of anakinra in AoSD patients were 81.66% (95% CI: 69.51%-89.69%) and 66.75% (95% CI: 59.94%-75.3%), respectively.,Compared with the controls, the use of anakinra was associated with a significant remission in AoSD, with an OR of 0.16 (95% CI: 0.06-0.44, P=0.0005).,There were also significant reductions of the dosage of corticosteroid (mean difference =21.19) (95% CI: 13.2-29.18, P<0.0001) from anakinra onset to the latest follow up time.,Clinical and laboratory parameters were all improved, and anakinra was well tolerated in patients with AoSD.,No evidence of publication bias was observed.,Our study has shown that anakinra is effective in remitting the manifestations of AoSD, with reduction of the dose of corticosteroid in patients with AoSD.,Further, anakinra therapy was not associated with increased risk of adverse events, and it was well tolerated in patients with AoSD.,Further research is still recommended to investigate these findings.

Vitamin D is a pleiotropic secosteroid yielding multiple actions in human physiology.,Besides the canonical regulatory activity on bone metabolism, several non-classical actions have been described and the ability of vitamin D to partake in the regulation of the immune system is particularly interesting, though far stronger and convincing evidence has been collected in in vitro as compared to in vivo studies.,Whether vitamin D is able to regulate at physiological concentrations the human immune system remains unproven to date.,Consequently, it is not established if vitamin D status is a factor involved in the pathogenesis of immune-mediated diseases and if cholecalciferol supplementation acts as an adjuvant for autoimmune diseases.,The development of autoimmunity is a heterogeneous process, which may involve different organs and systems with a wide range of clinical implications.,In the present paper, we reviewed the current evidences regarding vitamin D role in the pathogenesis and management of different autoimmune diseases.

The aim of this study was to evaluate differences in T helper cell sub-types and osteoclast (OCs) precursors in peripheral blood between patients affected by early rheumatoid arthritis (eRA) and healthy controls.,The effect of administration of cholecalcipherol on clinical and laboratory parameters was subsequently evaluated, by a parallel, randomized double blind, placebo controlled trial.,Thirty nine eRA patients and 31 age-matched controls were enrolled and compared for levels of 25OH vitamin D, T helper cell sub-types, OCs precursors including both classical and non-classical and pro-inflammatory cytokines at baseline.,Eligible patients were female ≥18 years of age with a diagnosis of RA, as defined by the American College of Rheumatology 2010 criteria for <6 months prior to inclusion in the study.,Patients with auto-immune or inflammatory diseases other than RA were excluded.,Patients treated with glucocorticoids (GCs), disease modifying activity drugs and biologic agents within the past 6 months were also excluded.,In the second phase of the study, eRA patients were randomly assigned to standard treatment with methotrexate (MTX) and GCs with (21) or without (18) cholecalcipherol (300,000 IU) and followed for 3 months; the randomization was done by computer generated tables to allocate treatments.,Three patients didn’t come back to the follow up visit for personal reasons.,None of the patients experienced adverse events.,The main outcome measures were T cells phenotypes, OCs precursors and inflammatory cytokines.,Secondary outcome measure were clinical parameters.,In eRA, 25OH vitamin D levels were significantly lower.,CD4+/IFNγ+,CD4+/IL4+, CD4+/IL17A+ and CD4+IL17A+IFNγ+, cells were increased in eRA as well as non-classical OCs precursors, whereas T regulatory cells were not altered.,TNFα, TGFβ1, RANKL, IL-23 and IL-6 were increased in eRA.,Non-classical OCs, IL-23 and IL-6 correlated with disease severity and activity.,Standard treatment with MTX and GC ameliorated clinical symptoms and reduced IL-23, whereas it did not affect CD4+ cells sub-sets nor OCs precursors.,After 3 months, the combined use of cholecalcipherol significantly ameliorated the effect of treatment on global health.,In eRA, a significant imbalance in T CD4+ sub-types accompanied by increased levels of non-classical OCs precursors and pro-inflammatory cytokines was observed.,A single dose of cholecalcipherol (300,000 IU) combined with standard treatment significantly ameliorates patients general health.

T cells control many immune functions, with Th17 cells critical in regulating inflammation.,Following activation, T cells undergo metabolic reprogramming and utilize glycolysis to increase the ATP availability.,Epigenetic mechanisms controlling metabolic functions in T cells are currently not well-defined.,Here, we establish an epigenetic link between the histone H3K27me3 demethylases KDM6A/B and the coordination of a metabolic response.,Inhibition of KDM6A/B leads to global increases in the repressive H3K27me3 histone mark, resulting in down-regulation of key transcription factors, followed by metabolic reprogramming and anergy.,This work suggests a critical role of H3K27 demethylase enzymes in maintaining Th17 functions by controlling metabolic switches.,Short-term treatment with KDM6 enzyme inhibitors may be useful in the therapy of chronic inflammatory diseases.,T helper (Th) cells are CD4+ effector T cells that play a critical role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations.,Using a combined chemico-genetic approach, we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets.,The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORγt during Th17 differentiation.,In mature Th17 cells, GSK-J4 induces an altered transcriptional program with a profound metabolic reprogramming and concomitant suppression of IL-17 cytokine levels and reduced proliferation.,Single-cell analysis reveals a specific shift from highly inflammatory cell subsets toward a resting state upon demethylase inhibition.,The root cause of the observed antiinflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1.,Overall, this leads to reduced mitochondrial biogenesis, resulting in a metabolic switch with concomitant antiinflammatory effects.,These data are consistent with an effect of GSK-J4 on Th17 T cell differentiation pathways directly related to proliferation and include regulation of effector cytokine profiles.,This suggests that inhibiting KDM6 demethylases may be an effective, even in the short term, therapeutic target for autoimmune diseases, including ankylosing spondylitis.

The objective of the study is to investigate potential citrullinated autoantigens as targets of anti-citrullinated protein antibodies (ACPAs) response in synovial fluids (SFs) of patients with rheumatoid arthritis (RA).,SFs from six RA patients and six osteoarthritis (OA) patients as controls were collected.,The citrullinated proteins in SFs were extracted by immunoprecipitation with rabbit anti-citrulline antibodies.,Matrix-assisted laser desorption/ionization time of flight mass spectrometry/time of flight mass spectrometry (MALDI-TOF/TOF) mass spectrometry was subsequently performed to discover a characteristic neutral loss to finally determine citrullinated autoantigens.,A total of 182 citrullinated peptides and 200 citrullinated sites were identified in RA SFs, while 3 citrullinated peptides and 4 citrullinated sites were identified in OA SFs.,The 182 citrullinated peptides from RA SFs and the 3 citrullinated peptides from OA SFs were derived from 83 and 3 autoantigens, respectively.,Eighty-three autoantigens except protein-arginine deiminase type-2 (PADI2) and protein-arginine deiminase type-2 (PADI4) were over-citrullinated compared with controls, and the citrullinated sites of PADI2 and PADI4 were different in two groups.,Interestingly, citrullinated histone H3.3 (H3F3A) was found in OA controls, but not in RA groups.,The differential citrullinated proteins identified in RA SFs suggested potential autoantigens were targeted for ACPAs response and might contribute to the induction and perpetuation of complement activation and joint inflammation in RA.,The online version of this article (doi:10.1007/s10067-016-3247-4) contains supplementary material, which is available to authorized users.

Rheumatoid arthritis (RA) is a systemic and heterogeneous autoimmune disease with symmetrical polyarthritis as its critical clinical manifestation.,The basic cause of autoimmune diseases is the loss of tolerance to self or harmless antigens.,The loss or functional deficiency of key immune cells, regulatory T (Treg) cells, has been confirmed in human autoimmune diseases.,The pathogenesis of RA is complex, and the dysfunction of Tregs is one of the proposed mechanisms underlying the breakdown of self-tolerance leading to the progression of RA.,Treg cells are a vital component of peripheral immune tolerance, and the transcription factor Foxp3 plays a major immunosuppressive role.,Clinical treatment for RA mainly utilizes drugs to alleviate the progression of disease and relieve disease activity, and the ideal treatment strategy should be to re-induce self-tolerance before obvious tissue injury.,Treg cells are one of the ideal options.,This review will introduce the classification, mechanism of action, and characteristics of Treg cells in RA, which provides insights into clinical RA treatment.

The present study aimed to investigate the anti-arthritic effects of curculigoside isolated from the rhizome of Curculigo orchioides Gaertn in vivo and in vitro, as well as to determine the potential underlying mechanisms.,A rat model of arthritis was induced with type II collagen.,Arthritic rats were treated with curculigoside (50 mg/kg) and blood samples were collected to determine serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-10, IL-12 and IL-17A.,Furthermore, indices of the thymus and spleen were determined.,The anti-proliferative effects of curculigoside were detected with Cell Counting kit-8 assays in rheumatoid arthritis-derived fibroblast-like synoviocyte MH7A cells.,In addition, expression levels of Janus kinase (JAK)1, JAK3, signal transducer and activator of transcription (STAT)3, nuclear factor (NF)-κB p65 and its inhibitor (IκB) were determined by western blotting.,The results revealed that curculigoside inhibited paw swelling and arthritis scores in type II collagen-induced arthritic (CIA) rats.,Additionally, curculigoside decreased serum levels of TNF-α, IL-1β, IL-6, IL-10, IL-12 and IL-17A in CIA rats.,Curculigoside also significantly inhibited MH7A cell proliferation in a time and concentration-dependent manner.,Furthermore, treatment downregulated the expression of JAK1, JAK3 and STAT3, and upregulated cytosolic nuclear factor (NF)-κB p65 and IκB.,In conclusion, the results of the present study indicated that curculigoside exhibited significant anti-arthritic effects in vivo and in vitro, and the molecular mechanism may be associated with the JAK/STAT/NF-κB signaling pathway.

Thrombospondin type I domain-containing 7A (THSD7A) is a known antigenic target of autoantibodies leading to primary membranous glomerulopathy and was reported to account for ~10% of phospholipase A2 receptor (PLA2R)-negative membranous glomerulopathy.,It has been proposed that PLA2R and THSD7A autoantibodies are mutually exclusive in membranous glomerulopathy.,We validated an immunohistochemical assay to investigate for THSD7A-associated membranous glomerulopathy and utilized it in 258 consecutive native kidney biopsies, which showed membranous glomerulopathy in our laboratory, with the exception of membranous lupus nephritis.,Membranous glomerulopathy stained positive for THSD7A-only in 7 (3%) cases, PLA2R-only in 141 (55%) cases, and showed dual positivity for THSD7A and PLA2R in 2 (1%) cases.,Serologic testing for antibodies to PLA2R and THSD7A was performed in a subset of these patients.,There was 100% correlation between positive THSD7A and/or PLA2R tissue staining and the presence of the corresponding autoantibodies in the serum including the two cases with dual positive THSD7A and PLA2R antibodies.,We describe and provide a protocol for detection of THSD7A-associated membranous glomerulopathy in clinical practice.,The cases with dual THSD7A and PLA2R positivity show that these autoantibodies are not mutually exclusive.,They also emphasize the importance of using a panel-based approach when subtyping membranous glomerulopathy as a patient could conceptually be identified and treated based on anti-PLA2R titers, but still have anti-THSD7A antibodies driving persistent disease.

Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults.,Anti-M-type phospholipase A2 receptor (anti-PLA2R) antibodies are found in most patients with idiopathic MN (iMN) worldwide, but the prevalence of anti-PLA2R antibodies among Japanese patients with MN is unknown.,In this study, we determined the prevalence of anti-PLA2R antibodies in Japanese patients with MN.,The study population of our retrospective cross-sectional consisted of 131 patients with biopsy-proven MN who had not received any immunosuppressive treatments at time of both renal biopsy and serum sample collection.,Of these, 100 had iMN and 31 had secondary MN (sMN).,The circulating anti-PLA2R antibodies were analyzed using a highly sensitive Western blot analysis.,Analysis was performed under non-reducing conditions with a human glomerular extract at serum dilutions of 1:25, 1:10, and 1 as the primary antibody.,Anti-PLA2R antibodies were detected in 53 (53 %) of 100 patients with iMN and 0 (0 %) of 31 patients with sMN.,The prevalence of anti-PLA2R antibodies was higher in patients with nephrotic syndrome (61 %) than in patients without nephrotic syndrome (43 %).,The number of patients with serum albumin ≤3.0 g/dL was significantly higher in those with anti-PLA2R antibodies (92 %) than that in those without them (68 %).,Anti-PLA2R antibodies were found in Japanese patients with iMN; however, the prevalence was lower than that of any other Asian country.,This may indicate that the presence of other pathogenic antigens plays a significant role in Japanese patients with iMN.

To characterize the accrual of long‐term disability in a cohort of actively treated multiple sclerosis (MS) patients and to assess whether clinical and magnetic resonance imaging (MRI) data used in clinical trials have long‐term prognostic value.,This is a prospective study of 517 actively managed MS patients enrolled at a single center.,More than 91% of patients were retained, with data ascertained up to 10 years after the baseline visit.,At this last assessment, neurologic disability as measured by the Expanded Disability Status Scale (EDSS) was stable or improved compared to baseline in 41% of patients.,Subjects with no evidence of disease activity (NEDA) by clinical and MRI criteria during the first 2 years had long‐term outcomes that were no different from those of the cohort as a whole.,25‐OH vitamin D serum levels were inversely associated with short‐term MS disease activity; however, these levels had no association with long‐term disability.,At a median time of 16.8 years after disease onset, 10.7% (95% confidence interval [CI] = 7.2-14%) of patients reached an EDSS ≥ 6, and 18.1% (95% CI = 13.5-22.5%) evolved from relapsing MS to secondary progressive MS (SPMS).,Rates of worsening and evolution to SPMS were substantially lower when compared to earlier natural history studies.,Notably, the NEDA 2‐year endpoint was not a predictor of long‐term stability.,Finally, the data call into question the utility of annual MRI assessments as a treat‐to‐target approach for MS care.,Ann Neurol 2016;80:499-510

Mesenchymal stem cells have emerged as a potential therapy for a range of neural insults.,In animal models of multiple sclerosis, an autoimmune disease that targets oligodendrocytes and myelin, treatment with human MSCs results in functional improvement that reflects both modulation of the immune response and myelin repair.,Here we demonstrate that conditioned medium (CM) from human MSCs reduces functional deficits in mouse MOG35-55-induced EAE and promotes the development of oligodendrocytes and neurons.,Functional assays identify a critical role for Hepatocyte Growth Factor (HGF) and its primary receptor cMet in MSCs stimulated recovery in EAE, neural cell development and remyelination.,Active MSC-CM contains HGF and exogenously supplied HGF promotes recovery in EAE while cMet and anti-HGF antibodies block the functional recovery mediated by HGF and MSC-CM.,Systemic treatment with HGF dramatically accelerated remyelination in lysolecithin-induced rat dorsal spinal cord lesions and in slice cultures.,Together these data strongly implicate HGF in mediating MSC-stimulated functional recovery in animal models of multiple sclerosis.

Recent years have brought notable progress in the field of IgA nephropathy.,Here, we highlight important new directions and latest developments, including successful discovery of several genetic susceptibility loci, formulation of the multi-hit pathogenesis model that integrates findings from studies of galactose-deficient IgA1, anti-glycan response and immune complex-induced kidney injury, introduction of the Oxford pathology scoring system, and formalization of the Kidney Disease Improving Global Outcomes (KDIGO) consensus treatment guidelines.,We focus on the latest genetic findings that confirm a strong contribution of inherited factors and explain some of the geo-ethnic disparities in disease susceptibility.,Most IgA nephropathy susceptibility loci discovered to date encode genes involved in the maintenance of the intestinal epithelial barrier and response to mucosal pathogens.,The concerted pattern of inter-population allelic differentiation across all Genome Wide Association Studies (GWAS) loci parallels the disease prevalence and correlates with variation in local pathogens, suggesting that multi-locus adaptation might have shaped the present-day landscape of IgA nephropathy.,Importantly, the “Intestinal Immune Network for IgA Production” emerged as one of the new targets for potential therapeutic intervention.,We place these findings in the context of the multi-hit pathogenesis model and existing knowledge of IgA immunobiology.,Lastly, we provide our perspective on the existing treatment options, discuss areas of clinical uncertainty, and outline ongoing clinical trials and translational studies.

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome.,Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain.,The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN.,Over a median follow-up of 4.7 years, 86% received renin-angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs.,M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival.,Their value was also assessed in patients not represented in the Oxford cohort.,In individuals with eGFR less than 30 ml/min per 1.73 m2, the M and T lesions independently predicted a poor survival.,In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more.,The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%).,The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease.,The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy.

The complement system, composed of the three activation pathways, has both protective and pathogenic roles in the development of systemic lupus erythematosus (or lupus), a prototypic autoimmune disease.,The classical pathway contributes to the clearance of immune complexes (ICs) and apoptotic cells, whereas the alternative pathway (AP) exacerbates renal inflammation.,The role of the lectin pathway (LP) in lupus has remained largely unknown.,Mannose-binding lectin (MBL)-associated serine proteases (MASPs), which are associated with humoral pattern recognition molecules (MBL or ficolins), are the enzymatic constituents of the LP and AP.,MASP-1 encoded by the Masp1 gene significantly contributes to the activation of the LP.,After the binding of MBL/ficolins to pathogens or self-altered cells, MASP-1 autoactivates first, then activates MASP-2, and both participate in the formation of the LP C3 convertase C4b2a, whereas, MASP-3, the splice variant of the Masp1 gene, is required for the activation of the zymogen of factor D (FD), and finally participates in the formation of the AP C3 convertase C3bBb.,To investigate the roles of MASP-1 and MASP-3 in lupus, we generated Masp1 gene knockout lupus-prone MRL/lpr mice (Masp1/3−/− MRL/lpr mice), lacking both MASP-1 and MASP-3, and analyzed their renal disease.,As expected, sera from Masp1/3−/− MRL/lpr mice had no or markedly reduced activation of the LP and AP with zymogen forms of complement FD.,Compared to their wild-type littermates, the Masp1/3−/− MRL/lpr mice had maintained serum C3 levels, little-to-no albuminuria, as well as significantly reduced glomerular C3 deposition levels and glomerular pathological score.,On the other hand, there were no significant differences in the levels of serum anti-dsDNA antibody, circulating ICs, glomerular IgG and MBL/ficolins deposition, renal interstitial pathological score, urea nitrogen, and mortality between the wild-type and Masp1/3−/− MRL/lpr mice.,Our data indicate that MASP-1/3 plays essential roles in the development of lupus-like glomerulonephritis in MRL/lpr mice, most likely via activation of the LP and/or AP.

Ozanimod (RPC1063) is a specific and potent small molecule modulator of the sphingosine 1-phosphate receptor 1 (S1PR1) and receptor 5 (S1PR5), which has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis and ulcerative colitis.,Ozanimod and its active metabolite, RP-101075, exhibit a similar specificity profile at the S1P receptor family in vitro and pharmacodynamic profile in vivo.,The NZBWF1 mouse model was used in therapeutic dosing mode to assess the potential benefit of ozanimod and RP-101075 in an established animal model of systemic lupus erythematosus.,Compared with vehicle-treated animals, ozanimod and RP-101075 reduced proteinuria over the duration of the study and serum blood urea nitrogen at termination.,Additionally, ozanimod and RP-101075 reduced kidney disease in a dose-dependent manner, as measured by histological assessment of mesangial expansion, endo- and exo-capillary proliferation, interstitial infiltrates and fibrosis, glomerular deposits, and tubular atrophy.,Further exploration into gene expression changes in the kidney demonstrate that RP-101075 also significantly reduced expression of fibrotic and immune-related genes in the kidneys.,Of note, RP-101075 lowered the number of plasmacytoid dendritic cells, a major source of interferon alpha in lupus patients, and reduced all B and T cell subsets in the spleen.,Given the efficacy demonstrated by ozanimod and its metabolite RP-101075 in the NZBWF1 preclinical animal model, ozanimod may warrant clinical evaluation as a potential treatment for systemic lupus erythematosus.

Multiple Sclerosis (MS) is characterised by an immune system attack targeting myelin, which is produced by oligodendrocytes (OLs).,We performed single-cell transcriptomic analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics several aspects of MS.,We found unique OLs and OL precursor cells (OPCs) in EAE and uncovered several genes specifically alternatively spliced in these cells.,Surprisingly, EAE-specific OL-lineage populations expressed genes involved in antigen processing and presentation via major histocompatibility complex class I and II (MHC-I and -II), and in immunoprotection, suggesting alternative functions of these cells in a disease context.,Importantly, we found that disease-specific oligodendroglia are also present in human MS brains and that a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells, are expressed in the OL lineage cells.,Finally, we demonstrate that OPCs can phagocytose and that MHC-II expressing OPCs can activate memory and effector CD4+ T cells.,Our results suggest that OLs and OPCs are not passive targets but instead active immunomodulators in MS.,The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS.

Macrophages play a dual role in multiple sclerosis (MS) pathology.,They can exert neuroprotective and growth promoting effects but also contribute to tissue damage by production of inflammatory mediators.,The effector function of macrophages is determined by the way they are activated.,Stimulation of monocyte-derived macrophages in vitro with interferon-γ and lipopolysaccharide results in classically activated (CA/M1) macrophages, and activation with interleukin 4 induces alternatively activated (AA/M2) macrophages.,For this study, the expression of a panel of typical M1 and M2 markers on human monocyte derived M1 and M2 macrophages was analyzed using flow cytometry.,This revealed that CD40 and mannose receptor (MR) were the most distinctive markers for human M1 and M2 macrophages, respectively.,Using a panel of M1 and M2 markers we next examined the activation status of macrophages/microglia in MS lesions, normal appearing white matter and healthy control samples.,Our data show that M1 markers, including CD40, CD86, CD64 and CD32 were abundantly expressed by microglia in normal appearing white matter and by activated microglia and macrophages throughout active demyelinating MS lesions.,M2 markers, such as MR and CD163 were expressed by myelin-laden macrophages in active lesions and perivascular macrophages.,Double staining with anti-CD40 and anti-MR revealed that approximately 70% of the CD40-positive macrophages in MS lesions also expressed MR, indicating that the majority of infiltrating macrophages and activated microglial cells display an intermediate activation status.,Our findings show that, although macrophages in active MS lesions predominantly display M1 characteristics, a major subset of macrophages have an intermediate activation status.

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) have been proved to be T cell-mediated autoimmune diseases.,Recent researches indicate that humoral immunity is also involved in the pathogenesis of these disorders.,T follicular helper (Tfh) cells are critical for B cell differentiation and antibody production.,However, the role of Tfh cells in MS and EAE remains unclear.,Here, we found elevated frequencies of CD4+CXCR5+PD-1+ Tfh-like cells in both MS patients and EAE.,In EAE mice, Tfh-like cells, together with B cells, were found in the ectopic lymphoid structures in spinal cords.,Moreover, Tfh-like cells promoted the antibody production via IL-21/IL-21R and CD40 ligand/CD40 interaction and the synergy effect of STAT3 and non-canonical NF-κB signaling pathway inside B cells.,Moreover, adoptive transfer of Tfh-like cells could increase the severity and delay the remission of EAE.,In conclusion, our data indicate that Tfh-like cells contribute to the pathogenesis of EAE.

Homeostatic B Cell-Attracting chemokine 1 (BCA-1) otherwise known as CXCL13 is constitutively expressed in secondary lymphoid organs by follicular dendritic cells (FDC) and macrophages.,It is the only known ligand for the CXCR5 receptor, which is expressed on mature B cells, follicular helper T cells (Tfh), Th17 cells and regulatory T (Treg) cells.,Aberrant expression of CXCL13 within ectopic germinal centers has been linked to the development of autoimmune disorders (e.g.,Rheumatoid Arthritis, Multiple Sclerosis, Systemic Lupus Erythematosis).,We, therefore, hypothesized that antibody-mediated disruption of the CXCL13 signaling pathway would interfere with the formation of ectopic lymphoid follicles in the target organs and inhibit autoimmune disease progression.,This work describes pre-clinical development of human anti-CXCL13 antibody MAb 5261 and includes therapeutic efficacy data of its mouse counterpart in murine models of autoimmunity.,We developed a human IgG1 monoclonal antibody, MAb 5261 that specifically binds to human, rodent and primate CXCL13 with an affinity of approximately 5 nM and is capable of neutralizing the activity of CXCL13 from these various species in in vitro functional assays.,For in vivo studies we have engineered a chimeric antibody to contain the same human heavy and light chain variable genes along with mouse constant regions.,Treatment with this antibody led to a reduction in the number of germinal centers in mice immunized with 4-Hydroxy-3-nitrophenylacetyl hapten conjugated to Keyhole Limpet Hemocyanin (NP-KLH) and, in adoptive transfer studies, interfered with the trafficking of B cells to the B cell areas of mouse spleen.,Furthermore, this mouse anti-CXCL13 antibody demonstrated efficacy in a mouse model of Rheumatoid arthritis (Collagen-Induced Arthritis (CIA)) and Th17-mediated murine model of Multiple Sclerosis (passively-induced Experimental Autoimmune Encephalomyelitis (EAE)).,We developed a novel therapeutic antibody targeting CXCL13-mediated signaling pathway for the treatment of autoimmune disorders.

Supplemental Digital Content is available in the text,Rheumatoid arthritis (RA) and osteoarthritis (OA) comprise the most common forms of arthritis.,The aim of this study was to identify differentially expressed genes (DEGs) and associated biological processes between RA and OA using a bioinformatics approach to elucidate their potential pathogenesis.,The gene expression profiles of the GSE55457 datasets, originally produced through use of the high-throughput Affymetrix Human Genome U133A Array, were downloaded from the Gene Expression Omnibus (GEO) database.,The GSE55457 dataset contains information from 33 samples, including 10 normal control (NC) samples, 13 RA samples, and 10 OA samples.,Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed to identify functional categories and associated molecular and biochemical pathways, respectively, for the identified DEGs, and a protein-protein interaction (PPI) network of the DEGs was constructed using Cytoscape software.,GO and KEGG results suggested that several biological pathways (ie, “immune response,” “inflammation,” and “osteoclast differentiation”) are commonly involved in the development of both RA and OA, whereas several other pathways (eg, “MAPK signaling pathway,” and “ECM-receptor interaction”) presented significant differences between these disorders.,This study provides further insights into the underlying pathogenesis of RA and OA, which may facilitate the diagnosis and treatment of these diseases.

Rheumatoid arthritis is a chronic inflammatory disease characterized by synovial hyperplasia and progressive joint destruction.,The impaired apoptosis of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) is pivotal in this process.,However, the molecular mechanisms responsible for the reduced apoptosis are not fully understood.,Both nitric oxide and thioredoxin 1 as two important mediators are widely investigated in the pathogenesis of rheumatoid arthritis.,Interestingly, studies have showed that thioredoxin 1 may serve as a master regulator of S-nitrosylation of caspase-3 to fine-tune apoptosis in vivo.,Thus, it is anticipated that further investigations on the role of thioredoxin 1 in the S-nitrosylation and denitrosylation of caspase-3 in RA-FLS will likely provide a novel understanding of mechanisms implicated in the impaired apoptosis of RA-FLS.,In this paper, we will provide an overview on pathways involved in the reduced apoptosis of RA-FLS and then discuss specially the possible roles of nitric oxide and the thioredoxin 1 redox system associated with apoptosis of RA-FLS.

To determine the frequency of newly diagnosed diabetic children with first- and second-degree relatives affected by type 1 diabetes and to characterize the effects of this positive family history on clinical markers, signs of β-cell autoimmunity, and HLA genotype in the index case.,Children (n = 1,488) with type 1 diabetes diagnosed under 15 years of age were included in a cross-sectional study from the Finnish Pediatric Diabetes Register.,Data on family history of diabetes and metabolic decompensation at diagnosis were collected using a questionnaire.,Antibodies to β-cell autoantigens (islet cell antibodies, insulin autoantibodies, GAD antibodies, and antibodies to the islet antigen 2 molecule) and HLA genotypes were analyzed.,A total of 12.2% of the subjects had a first-degree relative with type 1 diabetes (father 6.2%, mother 3.2%, and sibling 4.8%) and 11.9% had an affected second-degree relative.,Children without affected relatives had lower pH (P < 0.001), higher plasma glucose (P < 0.001) and β-hydroxybutyrate concentrations (P < 0.001), a higher rate of impaired consciousness (P = 0.02), and greater weight loss (P < 0.001).,There were no differences in signs of β-cell autoimmunity.,The familial cases carried the HLA DR4-DQ8 haplotype more frequently than sporadic cases (74.0 vs.,67.0%, P = 0.02).,When the extended family history of type 1 diabetes is considered, the proportion of sporadic diabetes cases may be reduced to <80%.,A positive family history for type 1 diabetes associates with a less severe metabolic decompensation at diagnosis, even when only second-degree relatives are affected.,Autoantibody profiles are similar in familial and sporadic type 1 diabetes, suggesting similar pathogenetic mechanisms.

Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is one of the most common of the immune-mediated diseases.,To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip.,The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases.,After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls.,We found evidence for seven new AITD risk loci (P < 1.12 × 10−6; a permutation test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases.

In autoimmune diseases, a disturbance of the balance between T helper 17 (Th17) and regulatory T cells (Tregs) is often observed.,This disturbed balance is also the case in rheumatoid arthritis (RA).,Genetic predisposition to RA confers the presence of several polymorphisms mainly regulating activation of T lymphocytes.,However, the presence of susceptibility factors is neither necessary nor sufficient to explain the disease development, emphasizing the importance of environmental factors.,Multiple studies have shown that commensal gut microbiota is of great influence on immune homeostasis and can trigger the development of autoimmune diseases by favoring induction of Th17 cells over Tregs.,However the mechanism by which intestinal microbiota influences the Th cell balance is not completely understood.,Here we review the current evidence supporting the involvement of commensal intestinal microbiota in rheumatoid arthritis, along with a potential role of Toll-like receptors (TLRs) in modulating the relevant Th cell responses to trigger autoimmunity.,A better understanding of TLR triggering by intestinal microbiota and subsequent T cell activation might offer new perspectives for manipulating the T cell response in RA patients and may lead to the discovery of new therapeutic targets or even preventive measures.

Genetic studies in the last 5 years have greatly facilitated our understanding of how the dysregulation of diverse components of the innate immune system contributes to pathophysiology of SLE.,A role for macrophages in the pathogenesis of SLE was first proposed as early as the 1980s following the discovery that SLE macrophages were defective in their ability to clear apoptotic cell debris, thus prolonging exposure of potential autoantigens to the adaptive immune response.,More recently, there is an emerging appreciation of the contribution both monocytes and macrophages play in orchestrating immune responses with perturbations in their activation or regulation leading to immune dysregulation.,This paper will focus on understanding the relevance of genes identified as being associated with innate immune function of monocytes and macrophages and development of SLE, particularly with respect to their role in (1) immune complex (IC) recognition and clearance, (2) nucleic acid recognition via toll-like receptors (TLRs) and downstream signalling, and (3) interferon signalling.,Particular attention will be paid to the functional consequences these genetic associations have for disease susceptibility or pathogenesis.

Human fibroblast-like synoviocytes play a vital role in joint synovial inflammation in rheumatoid arthritis (RA).,Proinflammatory cytokines induce fibroblast-like synoviocyte activation and dysfunction.,The inflammatory mediator Krüppel-like factor 4 is upregulated during inflammation and plays an important role in endothelial and macrophage activation during inflammation.,However, the role of Krüppel-like factor 4 in fibroblast-like synoviocyte activation and RA inflammation remains to be defined.,In this study, we identify the notion that Krüppel-like factor 4 is higher expressed in synovial tissues and fibroblast-like synoviocytes from RA patients than those from osteoarthritis patients.,In vitro, the expression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes is induced by proinflammatory cytokine tumor necrosis factor-α.,Overexpression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes robustly induced interleukin-6 production in the presence or absence of tumor necrosis factor-α.,Conversely, knockdown of Krüppel-like factor 4 markedly attenuated interleukin-6 production in the presence or absence of tumor necrosis factor-α.,Krüppel-like factor 4 not only can bind to and activate the interleukin-6 promoter, but also may interact directly with nuclear factor-kappa B.,These results suggest that Krüppel-like factor 4 may act as a transcription factor mediating the activation of fibroblast-like synoviocytes in RA by inducing interleukin-6 expression in response to tumor necrosis factor-α.

Bone destruction is a frequent and clinically serious event in patients with rheumatoid arthritis (RA).,Local joint destruction can cause joint instability and often necessitates reconstructive or replacement surgery.,Moreover, inflammation-induced systemic bone loss is associated with an increased fracture risk.,Bone resorption is a well-controlled process that is dependent on the differentiation of monocytes to bone-resorbing osteoclasts.,Infiltrating as well as resident synovial cells, such as T cells, monocytes and synovial fibroblasts, have been identified as sources of osteoclast differentiation signals in RA patients.,Pro-inflammatory cytokines are amongst the most important mechanisms driving this process.,In particular, macrophage colony-stimulating factor, RANKL, TNF, IL-1 and IL-17 may play dominant roles in the pathogenesis of arthritis-associated bone loss.,These cytokines activate different intracellular pathways to initiate osteoclast differentiation.,Thus, over the past years several promising targets for the treatment of arthritic bone destruction have been defined.

To summarize findings from studies reporting the prevalence and incidence of diabetic retinopathy and diabetic maculopathy in African countries in light of the rising prevalence of diabetes mellitus.,Using a predefined search strategy, we systematically searched MEDLINE, EMBASE, Science Citation index and Conference Proceedings Citation index, African Index Medicus and the grey literature database ‘OpenSIGLE’ for studies published between January 1990 and February 2011.,Included studies reported prevalence or incidence of diabetic retinopathy or diabetic maculopathy of subjects with diabetes resident in African countries.,Sixty-two studies from 21 countries were included: three population-based surveys; two cohort studies; five case-control studies; 32 diabetes clinic-based, nine eye clinic-based and 11 other hospital-based surveys.,Included studies varied considerably in terms of patient selection, method of assessing the eye and retinopathy classification.,In population-based studies, the reported prevalence range in patients with diabetes for diabetic retinopathy was 30.2 to 31.6%, proliferative diabetic retinopathy 0.9 to 1.3%, and any maculopathy 1.2 to 4.5%.,In diabetes clinic-based surveys, the reported prevalence range for diabetic retinopathy was 7.0 to 62.4%, proliferative diabetic retinopathy 0 to 6.9%, and any maculopathy 1.2 to 31.1%.,No obvious association between prevalence and income level of the country was detected.,Large, community-based cross-sectional and cohort studies are needed to investigate rates and determinants of prevalence of diabetic retinopathy, incidence and progression in Africa.,Consensus is needed on the most appropriate methods of identification and classification of retinopathy for research and clinical practice.,Estimates of prevalence of diabetic retinopathy, proliferative diabetic retinopathy and maculopathy are comparable with recent European and American studies.

To examine trends in microvascular complications in adolescents with type 1 diabetes between 1990 and 2009 in Sydney, Australia.,We used analysis of complications in 1,604 adolescents (54% female, aged 12-20 years, median duration 8.6 years), stratified by four time periods using Generalized Estimation Equations as follows: T1 (1990-1994), T2 (1995-1999), T3 (2000-2004), and T4 (2005-2009).,Early retinopathy was detected using seven-field fundal photography, albumin excretion rate (AER) using timed overnight urine collections, and albumin-to-creatinine ratio (ACR) and peripheral nerve function using thermal and vibration threshold.,Retinopathy declined (53, 38, 23, and 12%; P < 0.001), as did borderline elevation of AER/ACR (45, 30, 26, and 30%; P < 0.001) and microalbuminuria (8, 4, 3, and 3%; P = 0.006).,Multiple daily injections (MDI)/continuous subcutaneous insulin infusion (CSII) use increased (17, 54, 75, and 88%; P < 0.001), median HbA1c decreased (9.1, 8.9, 8.5, and 8.5%; P < 0.001), and severe hypoglycemia was unchanged (6, 8, 10, and 7%; P = 0.272).,Retinopathy was associated with diabetes duration (odds ratio [OR] 1.12 [95% CI 1.08-1.17]), age (1.13 [1.06-1.20]), HbA1c (1.16 [1.08-1.25]), systolic blood pressure (BP) SDS (1.31 [1.16-1.48]), socioeconomic disadvantage (1.42 [1.04-1.95]), and 1 to 2 injections per day (vs.,MDI/CSII; 1.35 [1.05-1.73]); borderline AER/ACR with male sex (1.32 [1.02-1.70]), age (1.19 [1.12-1.26]), HbA1c (1.18 [1.08-1.29]), weight SDS (1.31 [1.21-1.53]), insulin dose per kilograms (1.64 [1.13-2.39]), 1 to 2 injections per day (1.41 [1.08-1.84]), and socioeconomic disadvantage (1.68 [1.23-2.31]); and microalbuminuria with age (1.14 [1.01-1.29]), HbA1c (1.20 [1.05-1.37]), diastolic BP SDS (1.76 [1.26-2.46]), and 1 to 2 injections per day (1.95 [1.11-3.41]).,The decline in retinopathy supports contemporary guidelines that recommend lower glycemic targets and use of MDI/CSII in children and adolescents with type 1 diabetes.

Dietary salt intake has been considered an important risk factor for autoimmune diseases like multiple sclerosis (MS).,Here we studied the effects of a high-salt diet (HSD) using a spontaneous autoimmune disease mouse model resembling MS.,We found that high-salt consumption protects mice from developing the neurological disease by promoting the tightening of the blood-brain barrier and preventing the migration of autoreactive T cells into the CNS.,Our results emphasize the multifarious effects of high-salt consumption in autoimmune disease susceptibility.,Sodium chloride, “salt,” is an essential component of daily food and vitally contributes to the body’s homeostasis.,However, excessive salt intake has often been held responsible for numerous health risks associated with the cardiovascular system and kidney.,Recent reports linked a high-salt diet (HSD) to the exacerbation of artificially induced central nervous system (CNS) autoimmune pathology through changes in microbiota and enhanced TH17 cell differentiation [M.,Kleinewietfeld et al., Nature 496, 518-522 (2013); C.,Wu et al., Nature 496, 513-517 (2013); N.,Wilck et al., Nature 551, 585-589 (2017)].,However, there is no evidence that dietary salt promotes or worsens a spontaneous autoimmune disease.,Here we show that HSD suppresses autoimmune disease development in a mouse model of spontaneous CNS autoimmunity.,We found that HSD consumption increased the circulating serum levels of the glucocorticoid hormone corticosterone.,Corticosterone enhanced the expression of tight junction molecules on the brain endothelial cells and promoted the tightening of the blood-brain barrier (BBB) thereby controlling the entry of inflammatory T cells into the CNS.,Our results demonstrate the multifaceted and potentially beneficial effects of moderately increased salt consumption in CNS autoimmunity.

Neurodegeneration, rather than inflammation, plays a key role in the progressive phase of multiple sclerosis (MS).,Current disease modifying treatment options for people with progressive MS (PMS) do not specifically target neurodegeneration.,Preliminary evidence suggests that exercise therapy might have neuroprotective effects.,However, neuroprotective effect studies of exercise interventions in PMS are scarce and the possible mode of action underlying neuroprotective effects of exercise are unknown and need to be elucidated.,The main aim of this phase II trial is to assess whether progressive resistance training (PRT) and high intensity interval training (HIIT), can slow down neurodegeneration in people with PMS.,In a single-blinded phase II clinical trial with an extended baseline period, 60 people with PMS will be randomly assigned to PRT or HIIT.,The participants should have had a relapse onset of MS with confirmed disease progression, however still ambulatory.,The duration of the study is 48 weeks, consisting of 16 weeks baseline period (no intervention), 16 weeks intervention and 16 weeks follow-up.,Patient-tailored training will be performed 3 times per week for one hour in groups, led by an experienced physiotherapist.,The primary outcome measure is neurodegeneration, measured as whole brain atrophy on magnetic resonance imaging (MRI).,Secondary outcome parameters will include other biomarkers associated with neurodegeneration (i.e. regional brain atrophy, lesion load, white matter integrity, resting state functional connectivity, blood biomarkers (brain derived neurotrophic factor (BDNF) and serum neurofilament light (sNFL)), patient functioning (physical and cognitive) and cardiovascular risk factors.,Besides the primary outcome measures, this study will examine a large variety of biomarkers associated with neurodegeneration after an exercise intervention.,Combining outcome parameters may help to elucidate the mode of action underlying neuroprotective effects of exercise.,This trial is prospectively registered at the Dutch Trial Registry (number NL8265, date 06-01-2020).

Recent studies indicate a causal relationship between the periodontal pathogen P. gingivalis and rheumatoid arthritis involving the production of autoantibodies against citrullinated peptides.,We therefore postulated that therapeutic eradication P. gingivalis may ameliorate rheumatoid arthritis development and here turned to a mouse model in order to challenge our hypothesis.,F1 (DBA/1 x B10.,Q) mice were orally inoculated with P. gingivalis before collagen-induced arthritis was provoked.,Chlorhexidine or metronidazole were orally administered either before or during the induction phase of arthritis and their effects on arthritis progression and alveolar bone loss were compared to intraperitoneally injected methotrexate.,Arthritis incidence and severity were macroscopically scored and alveolar bone loss was evaluated via microcomputed tomography.,Serum antibody titres against P. gingivalis were quantified by ELISA and microbial dysbiosis following oral inoculation was monitored in stool samples via microbiome analyses.,Both, oral chlorhexidine and metronidazole reduced the incidence and ameliorated the severity of collagen-induced arthritis comparable to methotrexate.,Likewise, all three therapies attenuated alveolar bone loss.,Relative abundance of Porphyromonadaceae was increased after oral inoculation with P. gingivalis and decreased after treatment.,This is the first study to describe beneficial effects of non-surgical periodontal treatment on collagen-induced arthritis in mice and suggests that mouthwash with chlorhexidine or metronidazole may also be beneficial for patients with rheumatoid arthritis and a coexisting periodontitis.,Methotrexate ameliorated periodontitis in mice, further raising the possibility that methotrexate may also positively impact on the tooth supporting tissues of patients with rheumatoid arthritis.

Objectives.,To evaluate whether genetic and environmental factors associated with RA in European and Asian ancestry populations are also associated with RA in African ancestry individuals.,Methods.,A case-control study was undertaken in 197 RA cases and 868 controls of African ancestry (Black African, Black Caribbean or Black British ethnicity) from South London.,Smoking and alcohol consumption data at RA diagnosis was captured.,Genotyping was undertaken (Multi-Ethnic Genotyping Array) and human leukocyte antigen (HLA) alleles imputed.,The following European/Asian RA susceptibility factors were tested: 99 genome-wide loci combined into a genetic risk score; HLA region [20 haplotypes; shared epitope (SE)]; smoking; and alcohol consumption.,The SE was tested for its association with radiological erosions.,Logistic regression models were used, including ancestry-informative principal components, to control for admixture.,Results.,European/Asian susceptibility loci were associated with RA in African ancestry individuals.,The genetic risk score provided an odds ratio (OR) for RA of 1.53 (95% CI: 1.31, 1.79; P = 1.3 × 10 −7).,HLA haplotype ORs in European and African ancestry individuals were highly correlated (r = 0.83, 95% CI: 0.56, 0.94; P = 1.1 × 10 −4).,Ever-smoking increased (OR = 2.36, 95% CI: 1.46, 3.82; P = 4.6 × 10 −4) and drinking alcohol reduced (OR = 0.34, 95% CI: 0.20, 0.56; P = 2.7 × 10 −5) RA risk in African ancestry individuals.,The SE was associated with erosions (OR = 2.61, 95% CI: 1.36, 5.01; P = 3.9 × 10 −3).,Conclusion.,Gene-environment RA risk factors identified in European/Asian ancestry populations are relevant in African ancestry individuals.,As modern statistical methods facilitate analysing ancestrally diverse populations, future genetic studies should incorporate African ancestry individuals to ensure their implications for precision medicine are universally applicable.

The Janus kinase/signal transduction and activator of transcription (JAK-STAT) signaling pathway is implicated in the pathogenesis of inflammatory and autoimmune diseases including rheumatoid arthritis, psoriasis, and inflammatory bowel disease.,Many cytokines involved in the pathogenesis of autoimmune and inflammatory diseases use JAKs and STATs to transduce intracellular signals.,Mutations in JAK and STAT genes cause a number of immunodeficiency syndromes, and polymorphisms in these genes are associated with autoimmune diseases.,The success of small-molecule JAK inhibitors (Jakinibs) in the treatment of rheumatologic disease demonstrates that intracellular signaling pathways can be targeted therapeutically to treat autoimmunity.,Tofacitinib, the first rheumatologic Jakinib, is US Food and Drug Administration (FDA) approved for rheumatoid arthritis and is currently under investigation for other autoimmune diseases.,Many other Jakinibs are in preclinical development or in various phases of clinical trials.,This review describes the JAK-STAT pathway, outlines its role in autoimmunity, and explains the rationale/pre-clinical evidence for targeting JAK-STAT signaling.,The safety and clinical efficacy of the Jakinibs are reviewed, starting with the FDA-approved Jakinib tofacitinib, and continuing on to next-generation Jakinibs.,Recent and ongoing studies are emphasized, with a focus on emerging indications for JAK inhibition and novel mechanisms of JAK-STAT signaling blockade.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis.,Here, tofacitinib safety and efficacy data from a long-term extension study in Japanese patients are presented.,Study A3921041 was a multi-centre, open-label, long-term extension study that included Japanese patients who had participated in a prior Phase 2 or Phase 3 study of tofacitinib as monotherapy or with background methotrexate.,Patients received tofacitinib 5 mg twice daily (BID) or tofacitinib 10 mg BID.,Dose adjustment of tofacitinib during treatment period, and concomitant usage of disease-modifying antirheumatic drugs including methotrexate after week 12 were permitted.,Primary endpoints were adverse events, laboratory parameters and vital signs.,Secondary efficacy endpoints included American College of Rheumatology (ACR)20/50/70 response rates, Disease Activity Score (DAS)28-4(erythrocyte sedimentation rate (ESR))<2.6 response rate (DAS-defined remission) and Health Assessment Questionnaire-Disability Index (HAQ-DI) score.,Safety and efficacy data were assessed throughout the study.,A total of 486 patients were recruited and treated (1439.9 patient-years of exposure). 308 patients completed the study.,Median (range) duration of treatment in this extension study was 1185 (5-2016) days. 476 patients (97.9 %) experienced adverse events; the majority of which (97.8 %) were of mild or moderate severity.,The two most common treatment-emergent adverse events were nasopharyngitis (n = 293, 60.3 %) and herpes zoster (n = 94, 19.3 %).,For all tofacitinib-treated patients, the incidence rate (patients with events per 100 patient-years) was 10.7 for serious adverse events, 3.3 for serious infections, 7.4 for herpes zoster (serious and non-serious) and 1.2 for malignancies (excluding non-melanoma skin cancer).,Mean changes from baseline (start of the index study) in laboratory parameters were consistent with those seen in previously reported studies of tofacitinib.,ACR20/50/70 response rates, DAS-defined remission rates and HAQ-DI scores were sustained through to study completion.,Tofacitinib (with or without background methotrexate) demonstrated a stable safety profile and sustained efficacy in Japanese patients with active rheumatoid arthritis.,The risk of herpes zoster appears to be higher in Japanese patients treated with tofacitinib than in the global population.,Clinicaltrials.gov NCT00661661.,Registered 7 February 2008.,The online version of this article (doi:10.1186/s13075-016-0932-2) contains supplementary material, which is available to authorized users.

Recent evidence has suggested that the 1,25(OH)2D3/Vitamin D receptor (VDR) acts to suppress the immune response associated with systemic lupus erythematosus (SLE), a serious multisystem autoimmune disease.,Hence, the aim of the current study was to investigate the mechanism by which 1,25-(OH)2D3/VDR influences SLE through regulating the Skp2/p27 signaling pathway.,Initially, the levels of 1,25(OH)2D3, VDR, Skp2, and p27 were measured in collected renal tissues and peripheral blood.,Meanwhile, the levels of inflammatory factors, biochemical indicators (BUN, Cr, anti-nRNP IgG, anti-dsDNA IgG) and urinary protein levels were assayed in in VDRinsert and VDR-knockout mice in response to 1,25(OH)2D3 supplement.,In addition, the distribution of splenic immune cells was observed in these mice.,Among the SLE patients, the levels of 1,25(OH)2D3, VDR and p27 were reduced, while the levels of Skp2 were elevated.,In addition, the levels of anti-nRNP IgG and anti-dsDNA IgG were increased, suggesting induction of inflammatory responses.,Notably, 1,25(OH)2D3/VDR mice had lower concentrations of BUN and Cr, urinary protein levels, precipitation intensity of the immune complex and complement, as well as the levels of anti-nRNP IgG and anti-dsDNA IgG in SLE mice.,Additionally, 1,25(OH)2D3 or VDR reduced the degree of the inflammatory response while acting to regulate the distribution of splenic immune cells.,This study indicated that 1,25-(OH)2D3/VDR facilitated the recovery of SLE by downregulating Skp2 and upregulating p27 expression, suggesting the potential of 1,25-(OH)2D3/VDR as a promising target for SLE treatment.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS).,While the etiology of MS is still largely unknown, scientists believe that the interaction of several endogenous and exogenous factors may be involved in this disease.,Epidemiologists have seen an increased prevalence of MS in countries at high latitudes, where the sunlight is limited and where the populations have vitamin D deficiency and high melatonin levels.,Although the functions and synthesis of vitamin D and melatonin are contrary to each other, both are involved in the immune system.,While melatonin synthesis is affected by light, vitamin D deficiency may be involved in melatonin secretion.,On the other hand, vitamin D deficiency reduces intestinal calcium absorption leading to gut stasis and subsequently increasing gut permeability.,The latter allows gut microbiota to transfer more endotoxins such as lipopolysaccharides (LPS) into the blood.,LPS stimulates the production of inflammatory cytokines within the CNS, especially the pineal gland.,This review summarizes the current findings on the correlation between latitude, sunlight and vitamin D, and details their effects on intestinal calcium absorption, gut microbiota and neuroinflammatory mediators in MS.,We also propose a new mechanistic pathway for the initiation of MS.

Short-chain fatty acids (SCFAs) produced by the gut microbiota have beneficial anti-inflammatory and gut homeostasis effects and prevent type 1 diabetes (T1D) in mice.,Reduced SCFA production indicates a loss of beneficial bacteria, commonly associated with chronic autoimmune and inflammatory diseases, including T1D and type 2 diabetes.,Here, we addressed whether a metabolite-based dietary supplement has an impact on humans with T1D.,We conducted a single-arm pilot-and-feasibility trial with high-amylose maize-resistant starch modified with acetate and butyrate (HAMSAB) to assess safety, while monitoring changes in the gut microbiota in alignment with modulation of the immune system status.,HAMSAB supplement was administered for 6 weeks with follow-up at 12 weeks in adults with long-standing T1D.,Increased concentrations of SCFA acetate, propionate, and butyrate in stools and plasma were in concert with a shift in the composition and function of the gut microbiota.,While glucose control and insulin requirements did not change, subjects with the highest SCFA concentrations exhibited the best glycemic control.,Bifidobacterium longum, Bifidobacterium adolescentis, and vitamin B7 production correlated with lower HbA1c and basal insulin requirements.,Circulating B and T cells developed a more regulatory phenotype post-intervention.,Changes in gut microbiota composition, function, and immune profile following 6 weeks of HAMSAB supplementation were associated with increased SCFAs in stools and plasma.,The persistence of these effects suggests that targeting dietary SCFAs may be a mechanism to alter immune profiles, promote immune tolerance, and improve glycemic control for the treatment of T1D.,ACTRN12618001391268.,Registered 20 August 2018,https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?,id=375792,Video Abstract,Video Abstract,The online version contains supplementary material available at 10.1186/s40168-021-01193-9.

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.

B-cell depletion has become a common treatment strategy in anti-TNF-refractory rheumatoid arthritis (RA).,Although the exact mechanism of how B-cell depletion leads to clinical amelioration in RA remains to be elucidated, repetitive treatment with B-cell-depleting agents leading to long-term B-cell depletion has been reported to be beneficial.,The latter has led to the hypothesis that the beneficial effects of B-cell depletion might act through their influence on pathogenic autoreactive plasma cells.,In this study, we investigated the effects of a fixed retreatment regimen with anti-CD20 mAbs on the humoral (auto)immune system in a cohort of therapy-refractory RA patients.,Fixed retreatment led to long-term B-cell depletion in peripheral blood, bone marrow and, to a lesser extent, synovium.,Also, pathologic autoantibody secretion (that is, anticitrullinated peptide antibodies (ACPAs)) was more profoundly affected by long-term depletion than by physiological protective antibody secretion (that is, against measles, mumps and rubella).,This was further illustrated by a significantly shorter estimated life span of ACPA-IgG secretion compared to total IgG secretion as well as protective antibody secretion.,By studying plasma cell function during an extensive 2-year period of B-cell depletion, autoantibody secretion was significantly shorter-lived than physiologically protective antibody secretion.,This suggests that the longevity of autoreactive plasma cells is different from protective long-lived plasma cells and might indicate a therapeutic window for therapies that target plasma cells.

Antibodies against citrullinated proteins (ACPAs) are highly specific for RA.,Since the discovery of these antibodies, several of studies that focused on the presence and identity of citrullinated proteins in the joints of RA patients have been carried out.,The best-known antigens that bind ACPAs are citrullinated filaggrin, Type II collagen (CII), α-enolase, fibrinogen and vimentin.,This review compares citrullinated filaggrin, CII, α-enolase and fibrinogen with vimentin in their contribution to ACPA triggering, and gives an overview of the literature in which the role of citrullinated and non-citrullinated vimentin in the onset of ACPA production and the pathogenesis of RA is discussed.

Anti-phospholipid syndrome (APS) and systemic lupus erythematosus (SLE) are autoimmune diseases characterized by autoantibody production and autoantibody-related pathology.,Anti-phospholipid antibodies (aPL) are found in all patients with APS and in 20-30% of individuals with SLE. aPL recognize a number of autoantigens, but the primary target in both APS and SLE is β2-glycoprotein I (β2GPI).,The production of IgG aPL in APS and SLE, as well as the association of aPL with certain MHC class II molecules, has led to investigation of the role of β2GPI-reactive T helper (Th). β2GPI-reactive CD4 Th cells have been associated with the presence of aPL and/or APS in both primary APS and secondary APS associated with SLE, as well as in SLE patients and healthy controls lacking aPL.,CD4 T cells reactive with β2GPI have also been associated with atherosclerosis and found within atherosclerotic plaques.,In most cases, the epitopes targeted by autoreactive β2GPI-reactive CD4 T cells in APS and SLE appear to arise as a consequence of antigenic processing of β2GPI that is structurally different from the soluble native form.,This may arise from molecular interactions (e.g., with phospholipids), post-translational modification (e.g., oxidation or glycation), genetic alteration (e.g., β2GPI variants), or molecular mimicry (e.g., microbiota).,A number of T cell epitopes have been characterized, particularly in Domain V, the lipid-binding domain of β2GPI.,Possible sources of negatively charged lipid that bind β2GPI include oxidized LDL, activated platelets, microbiota (e.g., gut commensals), and dying (e.g., apoptotic) cells.,Apoptotic cells not only bind β2GPI, but also express multiple other cellular autoantigens targeted in both APS and SLE.,Dying cells that have bound β2GPI thus provide a rich source of autoantigens that can be recognized by B cells across a wide range of autoantigen specificities. β2GPI-reactive T cells could potentially provide T cell help to autoantigen-specific B cells that have taken up and processed apoptotic (or other dying) cells, and subsequently present β2GPI on their surface in the context of major histocompatibility complex (MHC) class II molecules.,Here, we review the literature on β2GPI-reactive T cells, and highlight findings supporting the hypothesis that these T cells drive autoantibody production in both APS and SLE.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease resulting from abnormal interactions between T and B cells.,The acquisition of SLE is linked to genetic susceptibility, and diverse environmental agents can trigger disease onset in genetically susceptible individuals.,However, the strongest risk factor for developing SLE is being female (9:1 female to male ratio).,The female sex steroid, estradiol, working through its receptors, contributes to the gender bias in SLE although the mechanisms remain enigmatic.,In a small clinical trial, monthly administration of the estrogen receptor (ERα) antagonist, ICI182,780 (fulvestrant), significantly reduced disease indicators in SLE patients.,In order to identify changes that could account for improved disease status, the present study utilized fulvestrant (Faslodex) to block ERα action in cultured SLE T cells that were purified from blood samples collected from SLE patients (n = 18, median age 42 years) and healthy control females (n = 25, median age 46 years).,The effects of ERα antagonism on estradiol-dependent gene expression and canonical signaling pathways were analyzed.,Pathways that were significantly altered by addition of Faslodex included T helper (Th) cell differentiation, steroid receptor signaling [glucocorticoid receptor (GR), ESR1 (ERα)], ubiquitination, and sumoylation pathways.,ERα protein expression was significantly lower (p < 0.018) in freshly isolated, resting SLE T cells suggesting ERα turnover is inherently faster in SLE T cells.,In contrast, ERα/ERβ mRNA and ERβ protein levels were not significantly different between SLE and normal control T cell samples.,Plasma estradiol levels did not differ (p > 0.05) between SLE patients and controls.,A previously undetected interaction between GR and ERα signaling pathways suggests posttranslational modification of steroid receptors in SLE T cells may alter ERα/GR actions and contribute to the strong gender bias of this autoimmune disorder.

Rodent complex trait genetic studies involving a cross between two inbred strains are usually followed by congenic mapping to refine the loci responsible for the phenotype.,However, progressing from a chromosomal region to the actual causal gene remains challenging because multiple polymorphic genes are often closely linked.,The goal of this study was to develop a strategy that allows candidate gene testing by allele-specific expression without prior knowledge of the credible causal variant.,Tnfrsf9 (encoding CD137) is a candidate gene for the Idd9.3 type 1 diabetes (T1D) susceptibility locus in the nonobese diabetic (NOD) mouse model.,A C57BL/10Sn (B10)-derived diabetes resistance Idd9.3 congenic region has been shown to enhance accumulation of CD137+ regulatory T cells and serum soluble CD137 in NOD mice.,By combining the power of congenic mapping and nuclease-based gene targeting, we established a system where a pair of F1 hybrids expressed either the B10 or NOD Tnfrsf9 allele mimicking coisogenic strains.,Using this approach, we demonstrated that the allelic difference in B10 and NOD Tnfrsf9 alone was sufficient to cause differential accumulation of CD137+ regulatory T cells and serum soluble CD137 levels.,This strategy can be broadly applied to other rodent genetic mapping studies.

The kallikrein-kinin system (KKS) comprises a cascade of proteolytic enzymes and biogenic peptides that regulate several physiological processes.,Over-expression of tissue kallikrein-1 and modulation of the KKS shows beneficial effects on insulin sensitivity and other parameters relevant to type 2 diabetes mellitus.,However, much less is known about the role of kallikreins, in particular tissue kallikrein-1, in type 1 diabetes mellitus (T1D).,We report that chronic administration of recombinant human tissue kallikrein-1 protein (DM199) to non-obese diabetic mice delayed the onset of T1D, attenuated the degree of insulitis, and improved pancreatic beta cell mass in a dose- and treatment frequency-dependent manner.,Suppression of the autoimmune reaction against pancreatic beta cells was evidenced by a reduction in the relative numbers of infiltrating cytotoxic lymphocytes and an increase in the relative numbers of regulatory T cells in the pancreas and pancreatic lymph nodes.,These effects may be due in part to a DM199 treatment-dependent increase in active TGF-beta1.,Treatment with DM199 also resulted in elevated C-peptide levels, elevated glucagon like peptide-1 levels and a reduction in dipeptidyl peptidase-4 activity.,Overall, the data suggest that DM199 may have a beneficial effect on T1D by attenuating the autoimmune reaction and improving beta cell health.

Background: Rheumatoid arthritis (RA) has been associated with air pollution, possibly due to the augmentation of inflammatory effects.,In this study, we aimed to determine the roles of inflammatory pathways and microRNA involved in the pathogenesis of RA fibroblast-like synoviocytes (FLS) inflammation induced by particulate matter.,Methods: The inflammatory mediators, messenger RNAs, microRNAs and their interrelationships were investigated using western blotting, QPCR, ELISA and immunohistochemistry.,Results: Particulate matter (PMs) induced an increase in the expression of interleukin-6 (IL-6) and cyclooxygenase-II (COX-II) in RA-FLS and microRNA-137 was found definitely to mediate the inflammatory pathways.,PMs-induced generation of reactive oxygen species (ROS) in RA-FLS was attenuated by pretreatment with antioxidants.,Nox-dependent ROS generation led to phosphorylation of ERK1/2, p38 and JNK, followed by downregulation of microRNA-137.,In vivo studies, the joints of rats exposed to PMs revealed synovial fibroblast inflammation under pathologic examination and the expressions of IL-6 and COX-II were obviously increased.,PMs exposure results in activated ROS-mediated mitogen-activated protein kinase (MAPK) signaling pathways and cause increased IL-6 and COX-II through downregulation of hsa-miRNA-137, which lead to inflammation and RA exacerbation.,Conclusions: microRNA-137 plays an important role in PMs-induced RA acute exacerbation through MAPK signaling pathways and IL-6/COX-II activation.,Targeting these mechanisms can potentially be used to develop new therapeutic strategies and prevention of RA inflammation in the future.

Fibroblast-like synoviocytes (FLS) and CCR7− effector memory T (TEM) cells are two of the major cell types implicated in the progression of rheumatoid arthritis (RA).,In particular, FLS become highly invasive, whereas TEM cells proliferate and secrete proinflammatory cytokines, during RA.,FLS and T cells may also interact and influence each other’s phenotypes.,Inhibition of the pathogenic phenotypes of both FLS and TEM cells can be accomplished by selectively blocking the predominant potassium channels that they upregulate during RA: KCa1.1 (BK, Slo1, MaxiK, KCNMA1) upregulated by FLS and Kv1.3 (KCNA3) upregulated by activated TEM cells.,In this study, we investigated the roles of KCa1.1 and Kv1.3 in regulating the interactions between FLS and TEM cells and determined if combination therapies of KCa1.1- and Kv1.3-selective blockers are more efficacious than monotherapies in ameliorating disease in rat models of RA.,We used in vitro functional assays to assess the effects of selective KCa1.1 and Kv1.3 channel inhibitors on the interactions of FLS isolated from rats with collagen-induced arthritis (CIA) with syngeneic TEM cells.,We also used flow cytometric analyses to determine the effects of KCa1.1 blockers on the expression of proteins used for antigen presentation on CIA-FLS.,Finally, we used the CIA and pristane-induced arthritis models to determine the efficacy of combinatorial therapies of KCa1.1 and Kv1.3 blockers in reducing disease severity compared with monotherapies.,We show that the interactions of FLS from rats with CIA and of rat TEM cells are regulated by KCa1.1 and Kv1.3.,Inhibiting KCa1.1 on FLS reduces the ability of FLS to stimulate TEM cell proliferation and migration, and inhibiting Kv1.3 on TEM cells reduces TEM cells’ ability to enhance FLS expression of KCa1.1 and major histocompatibility complex class II protein, as well as stimulates their invasion.,Furthermore, we show that combination therapies of selective KCa1.1 and Kv1.3 blockers are more efficacious than monotherapies at reducing signs of disease in two rat models of RA.,Our results demonstrate the importance of KCa1.1 and Kv1.3 in regulating FLS and TEM cells during RA, as well as the value of combined therapies targeting both of these cell types to treat RA.,The online version of this article (10.1186/s13075-018-1783-9) contains supplementary material, which is available to authorized users.

Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role.,We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with Systemic Sclerosis (SSc), 536 with Multiple Sclerosis (MS), and 93 with Myasthenia Gravis (MG) and 282 unrelated controls.,We confirmed previously established associations of HLA-DRB1∗15 (OR = 2.17) and HLA-DRB1∗03 (OR = 1.81) alleles with MS, HLA-DRB1∗03 with SLE (OR = 2.49), HLA-DRB1∗01 (OR = 1.79) and HLA-DRB1∗04 (OR = 2.81) with RA, HLA-DRB1∗07 with Ps + PsA (OR = 1.79), HLA-DRB1∗01 (OR = 2.28) and HLA-DRB1∗08 (OR = 3.01) with SSc, and HLA-DRB1∗03 with MG (OR = 2.98).,We further observed a consistent negative association of HLA-DRB1∗13 allele with SLE, Ps + PsA, RA, and SSc (18.3%, 19.3%, 16.3%, and 11.9%, resp., versus 29.8% in controls).,HLA-DRB1∗13 frequency in the AIDs group was 20.0% (OR = 0.58).,Although different alleles were associated with particular AIDs, the same allele, HLA-DRB1∗13, was underrepresented in all of the six diseases analysed.,This observation suggests that this allele may confer protection for AIDs, particularly for systemic and rheumatic disease.,The protective effect of HLA-DRB1∗13 could be explained by a more proficient antigen presentation by these molecules, favouring efficient clonal deletion during thymic selection.

Neuromuscular transmission failure in myasthenia gravis (MG) is most commonly elicited by autoantibodies (ab) to the acetylcholine receptor or the muscle-specific kinase, constituting AChR-MG and MuSK-MG.,It is controversial whether these MG subtypes arise through different T helper (Th) 1, Th2 or Th17 polarized immune reactions and how these reactions are blunted by immunosuppression.,To address these questions, plasma levels of cytokines related to various Th subtypes were determined in patients with AChR-MG, MuSK-MG and healthy controls (CON).,Peripheral blood mononuclear cells (PBMC) were activated in vitro by anti-CD3, and cytokines were quantified in supernatants.,In purified blood CD4+ T cells, RNA of various cytokines, Th subtype specific transcription factors and the co-stimulatory molecule, CD40L, were quantified by qRT-PCR.,Plasma levels of Th1, Th2 and Th17 related cytokines were overall not significantly different between MG subtypes and CON.,By contrast, in vitro stimulated PBMC from MuSK-MG but not AChR-MG patients showed significantly increased secretion of the Th1, Th17 and T follicular helper cell related cytokines, IFN-γ, IL-17A and IL-21.,Stimulated expression of IL-4, IL-6, IL-10 and IL-13 was not significantly different.,At the RNA level, expression of CD40L by CD4+ T cells was reduced in both AChR-MG and MuSK-MG patients while expression of Th subset related cytokines and transcription factors were normal.,Immunosuppression treatment had two effects: First, it reduced levels of IL12p40 in the plasma of AChR-MG and MuSK-MG patients, leaving other cytokine levels unchanged; second, it reduced spontaneous secretion of IFN-γ and increased secretion of IL-6 and IL-10 by cultured PBMC from AChR-MG, but not MuSK-MG patients.,We conclude that Th1 and Th17 immune reactions play a role in MuSK-MG.,Immunosuppression attenuates the Th1 response in AChR-MG and MuSK-MG, but otherwise modulates immune responses in AChR-MG and MuSK-MG patients differentially.

Multiple sclerosis is an acquired demyelinating disease of the central nervous system.,It is the second most common cause of disability in adults in United States after head trauma.,The etiology of MS is probably multifactorial, related to genetic, environmental, and several other factors.,The pathogenesis is not fully understood but is believed to involve T-cell-mediated inflammation directed against myelin and other related proteins with a possible role for B cells.,The McDonald criteria have been proposed and revised over the years to guide the diagnosis of MS and are based on clinical presentation and magnetic resonance imaging (MRI) of the brain and spinal cord to establish dissemination in time and space.,The treatment of MS includes disease modification with immunomodulator drugs and symptom management to address the specific symptoms such as fatigue, spasticity, and pain.,An update on etiology, pathogenesis, diagnosis, and immunomodulatory treatment of MS is presented.

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.

Cognitive and motor performance measures are commonly employed in multiple sclerosis (MS) research, particularly when the purpose is to determine the efficacy of treatment.,The increasing focus of new therapies on slowing progression or reversing neurological disability makes the utilization of sensitive, reproducible, and valid measures essential.,Processing speed is a basic elemental cognitive function that likely influences downstream processes such as memory.,The Multiple Sclerosis Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organizations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS.,Among the MSOAC goals is acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS.,A critical step for these neuroperformance metrics is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are deemed clinically meaningful.,This topical review provides an overview of research on one particular cognitive measure, the Symbol Digit Modalities Test (SDMT), recognized as being particularly sensitive to slowed processing of information that is commonly seen in MS.,The research in MS clearly supports the reliability and validity of this test and recently has supported a responder definition of SDMT change approximating 4 points or 10% in magnitude.

Patients with multiple sclerosis (MS) may face barriers, such as treatment fatigue, memory problems, or side effects, that may influence their adherence to medication.,The objective of our study was to use an online community to develop a self-report questionnaire to quantify adherence and barriers to achieving adherence, that is specific to MS disease-modifying treatments (DMTs) and predictive of missed doses.,A review of the scientific literature and analysis of discussions between MS patients on PatientsLikeMe.com were used to generate survey items salient to patients.,Cognitive debriefing was used to refine the items.,The Multiple Sclerosis Treatment Adherence Questionnaire (MS-TAQ) contains 30 questions in three subscales: Barriers, Side Effects, and Coping Strategies.,MS patients completed an online survey (response rate: 431 of 1209 invited, 35.7%).,Between 16% (14/86) and 51% (51/100) of MS patients missed at least 1 dose of their DMT in the previous 28 days, with significant between-treatment differences.,The MS-TAQ Barriers scale was positively correlated with the proportion of doses missed (r = .5), demonstrating a stronger relationship between adherence and perceived barriers than was found with clinical or demographic variables (r ≈ .3).,The Coping Strategies subscale was negatively correlated with missed doses (r = -.3), suggesting that use of more coping strategies is associated with higher adherence.,Online communities can provide domains of interest and psychometric data to more rapidly develop and prototype patient-reported outcome instruments.,The MS-TAQ offers patients and clinicians a simple method for identifying barriers to adherence, which may then be targeted through interventions.

Type 1 diabetes is an autoimmune disease characterised by the destruction of insulin producing beta cells in the pancreas.,Whilst it remains unclear what the original triggering factors for this destruction are, observations from the natural history of human type 1 diabetes, including incidence rates in twins, suggest that the disease results from a combination of genetic and environmental factors.,Whilst many different immune cells have been implicated, including members of the innate and adaptive immune systems, a view has emerged over the past 10 years that beta cell damage is mediated by the combined actions of CD4+ and CD8+ T cells with specificity for islet autoantigens.,In health, these potentially pathogenic T cells are held in check by multiple regulatory mechanisms, known collectively as ‘immunological tolerance’.,This raises the question as to whether type 1 diabetes develops, at least in part, as a result of a defect in one or more of these control mechanisms.,Immunological tolerance includes both central mechanisms (purging of the T cell repertoire of high-affinity autoreactive T cells in the thymus) and peripheral mechanisms, a major component of which is the action of a specialised subpopulation of T cells, known as regulatory T cells (Tregs).,In this review, we highlight the evidence suggesting that a reduction in the functional capacity of different Treg populations contributes to disease development in type 1 diabetes.,We also address current controversies regarding the putative causes of this defect and discuss strategies to correct it as a means to reduce or prevent islet destruction in a clinical setting.,The online version of this article (doi:10.1007/s00125-017-4377-1) contains a slide of the figure for download, which is available to authorised users.

Type 1 diabetes can be overcome by regulatory T cells (Treg) in NOD mice yet an efficient method to generate and maintain antigen-specific Treg is difficult to come by.,Here, we devised a combination therapy of peptide/MHC tetramers and IL-2/anti-IL-2 monoclonal antibody complexes to generate antigen-specific Treg and maintain them over extended time periods.,We first optimized treatment protocols conceived to obtain an improved islet-specific Treg/effector T cell ratio that led to the in vivo expansion and activation of these Treg as well as to an improved suppressor function.,Optimized protocols were applied to treatment for testing diabetes prevention in NOD mice as well as in an accelerated T cell transfer model of T1D.,The combined treatment led to robust protection against diabetes, and in the NOD model, to a close to complete prevention of insulitis.,Treatment was accompanied with increased secretion of IL-10, detectable in total splenocytes and in Foxp3− CD4 T cells.,Our data suggest that a dual protection mechanism takes place by the collaboration of Foxp3+ and Foxp3− regulatory cells.,We conclude that antigen-specific Treg are an important target to improve current clinical interventions against this disease.

The advent of new medications and new treatment strategies for rheumatoid arthritis has made it possible to achieve remission in more patients than before.,Furthermore, recent clinical trials and register studies suggest that some patients who initially required aggressive therapy may achieve biologic-free remission or even the ultimate goal of therapy, drug-free remission, resembling recovery.,Here, we present a discursive review of the most important studies addressing these issues.,Based on the overall results, it remains unclear if achieving biologic-free and drug-free remissions are primarily due to the natural course of the disease or to the early therapeutic intervention according to the ‘window of opportunity’ hypothesis.,Although medication-free remission is only achievable in a small subset of patients, characterizing this patient cohort may provide important information about beneficial prognostic factors and the underlying mechanisms.,In summary, in a subset of patients biologic-free and even drug-free remission can be achieved; pursuing these possibilities in practice may decrease the risk for long-term side effects and attenuate the economic burden of the disease.

The heterogeneous nature of rheumatoid arthritis (RA) complicates early recognition and treatment.,In recent years, a growing body of evidence has demonstrated that intervention during the window of opportunity can improve the response to treatment and slow-or even stop-irreversible structural changes.,Advances in therapy, such as biologic agents, and changing approaches to the disease, such as the treat to target and tight control strategies, have led to better outcomes resulting from personalized treatment to patients with different prognostic markers.,The various biomarkers identified either facilitate early diagnosis or make it possible to adjust management to disease activity or poor outcomes.,However, no single biomarker can bridge the gap between disease onset and prescription of the first DMARD, and traditional biomarkers do not identify all patients requiring early aggressive treatment.,Furthermore, the outcomes of early arthritis cohorts are largely biased by the treatment prescribed to patients; therefore, new challenges arise in the search for prognostic biomarkers.,Herein, we discuss the value of traditional and new biomarkers and suggest the need for intensive treatment as a new surrogate marker of poor prognosis that can guide therapeutic decisions in the early stages of RA.

Intronic single-nucleotide polymorphisms (SNPs) in the ANKRD55 gene are associated with the risk for multiple sclerosis (MS) and rheumatoid arthritis by genome-wide association studies (GWAS).,The risk alleles have been linked to higher expression levels of ANKRD55 and the neighboring IL6ST (gp130) gene in CD4+ T lymphocytes of healthy controls.,The biological function of ANKRD55, its role in the immune system, and cellular sources of expression other than lymphocytes remain uncharacterized.,Here, we show that monocytes gain capacity to express ANKRD55 during differentiation in immature monocyte-derived dendritic cells (moDCs) in the presence of interleukin (IL)-4/granulocyte-macrophage colony-stimulating factor (GM-CSF).,ANKRD55 expression levels are further enhanced by retinoic acid agonist AM580 but downregulated following maturation with interferon (IFN)-γ and lipopolysaccharide (LPS).,ANKRD55 was detected in the nucleus of moDC in nuclear speckles.,We also analyzed the adjacent IL6ST, IL31RA, and SLC38A9 genes.,Of note, in healthy controls, MS risk SNP genotype influenced ANKRD55 and IL6ST expression in immature moDC in opposite directions to that in CD4+ T cells.,This effect was stronger for a partially correlated SNP, rs13186299, that is located, similar to the main MS risk SNPs, in an ANKRD55 intron.,Upon analysis in MS patients, the main GWAS MS risk SNP rs7731626 was associated with ANKRD55 expression levels in CD4+ T cells.,MoDC-specific ANKRD55 and IL6ST mRNA levels showed significant differences according to the clinical form of the disease, but, in contrast to healthy controls, were not influenced by genotype.,We also measured serum sgp130 levels, which were found to be higher in homozygotes of the protective allele of rs7731626.,Our study characterizes ANKRD55 expression in moDC and indicates monocyte-to-dendritic cell (Mo-DC) differentiation as a process potentially influenced by MS risk SNPs.

Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms already known gene loci.,We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls.,In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance.,Four of these loci are novel MS susceptibility loci.,They map to the genes L3MBTL3, MAZ, ERG, and SHMT1.,The lead variant at SHMT1 was replicated in an independent Sardinian cohort.,Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation.,SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle.,This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures.,Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

At least half of patients with systemic lupus erythematosus (SLE) develop organ damage as a consequence of autoimmune disease or long-term therapeutic steroid use.,This study synthesised evidence on the association between organ damage and mortality in patients with SLE.,Systematic review and meta-analysis.,Electronic searches were performed in PubMed, Embase, Cochrane Library and Latin American and Caribbean Health Sciences Literature for observational (cohort, case-control and cross-sectional) studies published between January 2000 and February 2017.,Included studies reported HRs or ORs on the association between organ damage (measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score) and mortality.,Study quality was assessed using the modified Newcastle-Ottawa assessment.,Pooled HRs were obtained using the DerSimonian and Laird random-effects model.,Heterogeneity was assessed using the Cochrane Q (Q) and I2 statistics.,The search yielded 10 420 articles, from which 21 longitudinal studies were selected.,Most studies (85%) were of high quality.,For 10 studies evaluating organ damage (SDI) as a continuous variable and reporting HR as a measure of association, a 1-unit increase in SDI was associated with increased mortality; pooled HR was 1.34 (95% CI: 1.24 to 1.44, p<0.001; Q p=0.027, I2=52.1%).,Exclusion of one potential outlying study reduced heterogeneity with minimal impact on pooled HR (1.33 (95% CI: 1.25 to 1.42), p<0.001, Q p=0.087, I2=42.0%).,The 11 remaining studies, although they could not be aggregated because of their varying patient populations and analyses, consistently demonstrated that greater SDI was associated with increased mortality.,Organ damage in SLE is consistently associated with increased mortality across studies from various countries.,Modifying the disease course with effective therapies and steroid-sparing regimens may reduce organ damage, improve outcomes and decrease mortality for patients with SLE.

Systemic lupus erythematosus (SLE) impacts multiple organ systems, although the causes of many individual SLE pathologies are poorly understood.,This study was designed to elucidate organ-specific inflammation by identifying proteins that correlate with SLE organ involvement and to evaluate established biomarkers of disease activity across a diverse patient cohort.,Plasma proteins and autoantibodies were measured across seven SLE manifestations.,Comparative analyses between pathologies and correlation with the SLE Disease Activity Index (SLEDAI) were used to identify proteins associated with organ-specific and composite disease activity.,Established biomarkers of composite disease activity, SLE-associated antibodies, type I interferon (IFN), and complement C3, correlated with composite SLEDAI, but did not significantly associate with many individual SLE pathologies.,Two clusters of proteins were associated with renal disease in lupus nephritis samples.,One cluster included markers of infiltrating leukocytes and the second cluster included markers of tissue remodelling.,In patients with discoid lupus, a distinct signature consisting of elevated immunoglobulin A autoantibodies and interleukin-23 was observed.,Our findings indicate that proteins from blood samples can be used to identify protein signatures that are distinct from established SLE biomarkers and SLEDAI and could be used to conveniently monitor multiple inflammatory pathways present in different organ systems.

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.

•4.8% of MS patients fulfilled defined criteria for COVID-19-suspect group.,•Two patients required hospitalization; no intubation or ICU admission was reported.,•Patients on B-cell depleting agents had higher risk of being in the COVID-19-suspect group.,4.8% of MS patients fulfilled defined criteria for COVID-19-suspect group.,Two patients required hospitalization; no intubation or ICU admission was reported.,Patients on B-cell depleting agents had higher risk of being in the COVID-19-suspect group.,To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease.,In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system.,Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19, and the disposition after the diagnosis.,We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography.,We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models.,Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group.,Only two patients required hospitalization.,No patient required intensive care.,In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030), and history of sick contact (p-values<0.001) were associated with the risk of being in the COVID-19-suspect group.,Being on B-cell depleting antibodies (as compared to non-cell depleting, non-cell trafficking inhibitor DMTs) was associated with a 2.6-fold increase in the risk of being in the COVID-19-suspect group.,(RR: 3.55, 95%CI: 1.45, 8.68, p-value=0.005).,The course of infection in patients with MS suspected of having COVID-19 was mild to moderate, and all patients had a full recovery.,B-cell depleting antibodies may increase the susceptibility to contracting COVID-19.

Patients with incomplete systemic lupus erythematosus (iSLE) have lupus features, but do not meet classification criteria for SLE.,Type I interferons (IFN) are important early mediators in SLE, and IFN upregulation in incomplete SLE may be associated with progression to SLE.,Since many patients present with skin symptoms, the aim of this study is to investigate IFN type I expression and IFN-related mediators in the blood and skin of iSLE patients.,Twenty-nine iSLE patients (ANA titer ≥ 1:80, symptoms < 5 years, ≥ 1 objectified clinical criterion), 39 SLE patients with quiescent disease (fulfilling ACR or SLICC criteria, SLEDAI ≤4), and 22 healthy controls were included.,IFN signature was measured in whole blood, based on 12 IFN-related genes, using RT-PCR, and IFN-score was calculated.,IFN-related mediators myxovirus-resistance protein A (MxA), IFN-γ-induced protein 10 (IP-10), and monocyte chemoattractant protein (MCP-1) were measured using ELISA.,IFN type I expression in the unaffected skin was analyzed by immunostaining with MxA.,IFN-score was increased in 50% of iSLE patients and 46% of SLE patients and correlated positively with the number of autoantibodies, anti-SSA titer, ESR, and IgG and negatively with C4 in iSLE.,Levels of MxA correlated strongly with IFN-score (r = 0.78, p < 0.0001).,Furthermore, MxA expression was found in 29% of unaffected skin biopsies of iSLE and 31% of SLE patients and also correlated with IFN-score (r = 0.54, p < 0.0001).,IFN-score was increased in half of the iSLE patients, and given the correlation with complement and autoantibody diversity, this suggests a higher risk for disease progression.,MxA in the blood and unaffected skin correlated strongly with the IFN-score and is possibly an easily applicable marker for IFN upregulation.

A hallmark of systemic lupus erythematosus (SLE), and several related autoimmune diseases, is the presence of autoantibodies against nucleic acids and nucleic acid-binding proteins, as well as elevated type I interferons (IFNs), which appear to be instrumental in disease pathogenesis.,Here we discuss the sources and proposed mechanisms by which a range of cellular RNA and DNA species can become pathogenic and trigger the nucleic acid sensors that drive type I interferon production.,Potentially SLE-promoting DNA may originate from pieces of chromatin, from mitochondria, or from reverse-transcribed cellular RNA, while pathogenic RNA may arise from mis-localized, mis-processed, ancient retroviral, or transposable element-derived transcripts.,These nucleic acids may leak out from dying cells to be internalized and reacted to by immune cells or they may be generated and remain to be sensed intracellularly in immune or non-immune cells.,The presence of aberrant DNA or RNA is normally counteracted by effective counter-mechanisms, the loss of which result in a serious type I IFN-driven disease called Aicardi-Goutières Syndrome.,However, in SLE it remains unclear which mechanisms are most critical in precipitating disease: aberrant RNA or DNA, overly sensitive sensor mechanisms, or faulty counter-acting defenses.,We propose that the clinical heterogeneity of SLE may be reflected, in part, by heterogeneity in which pathogenic nucleic acid molecules are present and which sensors and pathways they trigger in individual patients.,Elucidation of these events may result in the recognition of distinct “endotypes” of SLE, each with its distinct therapeutic choices.

Beta-cell replacement is the best therapeutic option for patients with type 1 diabetes.,Because of donor scarcity, more extended criteria donors are used for transplantation.,Donation after circulatory death donors (DCD) are not commonly used for pancreas transplantation, because of the supposed higher risk of complications.,This review gives an overview on the pathophysiology, risk factors, and outcome in DCD transplantation and discusses different preservation methods.,Studies on outcomes of DCD pancreata show similar results compared with those of donation after brain death (DBD), when accumulation of other risk factors is avoided.,Hypothermic machine perfusion is shown to be a safe method to improve graft viability in experimental settings.,DCD should not be the sole reason to decline a pancreas for transplantation.,Adequate donor selection and improved preservation techniques can lead to enhanced pancreas utilization and outcome.

Patients with type 1 diabetes (T1D) who are recipients of pancreas transplants are believed to rarely develop T1D recurrence in the allograft if effectively immunosuppressed.,We evaluated a cohort of 223 recipients of simultaneous pancreas-kidney allografts for T1D recurrence and its risk factors.,With long‐term follow‐up, recurrence was observed in approximately 7% of patients.,Comparing the therapeutic regimens employed in this cohort over time, lack of induction therapy was associated with recurrence, but this occurs even with the current regimen, which includes induction; there was no influence of maintenance regimens.,Longitudinal testing for T1D‐associated autoantibodies identified autoantibody positivity, number of autoantibodies, and autoantibody conversion after transplantation as critical risk factors.,Autoantibodies to the zinc transporter 8 had the strongest and closest temporal association with recurrence, which was not explained by genetically encoded amino acid sequence donor-recipient mismatches for this autoantigen.,Genetic risk factors included the presence of the T1D‐predisposing HLA‐DR3/DR4 genotype in the recipient and donor-recipient sharing of HLA‐DR alleles, especially HLA‐DR3.,Thus, T1D recurrence is not uncommon and is developing in patients treated with current immunosuppression.,The risk factors identified in this study can be assessed in the transplant clinic to identify recurrent T1D and may lead to therapeutic advances.,This study demonstrates that recurrence of islet autoimmunity and type 1 diabetes is a significant cause of immune‐mediated endocrine pancreas graft function in immunosuppressed recipients of simultaneous pancreas‐kidney transplants, and defines risk factors for this condition.

Systemic lupus erythematosus (SLE) is a multi-system, complex disease in which the environment interacts with inherited genes to produce broad phenotypes with inter-individual variability.,Of 46 single nucleotide polymorphisms (SNPs) shown to confer genetic risk for SLE in recent genome-wide association studies, 30 lie within noncoding regions of the human genome.,We therefore sought to identify and describe the functional elements (aside from genes) located within these regions of interest.,We used chromatin immunoprecipitation followed by sequencing to identify epigenetic marks associated with enhancer function in adult neutrophils to determine whether enhancer-associated histone marks were enriched within the linkage disequilibrium (LD) blocks encompassing the 46 SNPs of interest.,We also interrogated available data in Roadmap Epigenomics for CD4+ T cells and CD19+ B cells to identify these same elements in lymphoid cells.,All three cell types demonstrated enrichment of enhancer-associated histone marks compared with genomic background within LD blocks encoded by SLE-associated SNPs.,In addition, within the promoter regions of these LD blocks, all three cell types demonstrated enrichment for transcription factor binding sites above genomic background.,In CD19+ B cells, all but one of the LD blocks of interest were also enriched for enhancer-associated histone marks.,Much of the genetic risk for SLE lies within or near genomic regions of disease-relevant cells that are enriched for epigenetic marks associated with enhancer function.,Elucidating the specific roles of these noncoding elements within these cell-type-specific genomes will be crucial to our understanding of SLE pathogenesis.,The online version of this article (doi:10.1186/s13075-016-1169-9) contains supplementary material, which is available to authorized users.

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.

Cambier et al. show that the tyrosine phosphatase SHP-1 and the inositol phosphatase SHIP-1 are required to maintain B cell anergy.,Many autoreactive B cells persist in the periphery in a state of unresponsiveness called anergy.,This unresponsiveness is rapidly reversible, requiring continuous BCR interaction with self-antigen and resultant regulatory signaling for its maintenance.,Using adoptive transfer of anergic B cells with subsequent acute induction of gene deletion or expression, we demonstrate that the continuous activities of independent inhibitory signaling pathways involving the tyrosine phosphatase SHP-1 and the inositol phosphatase SHIP-1 are required to maintain anergy.,Acute breach of anergy by compromise of either of these pathways leads to rapid cell activation, proliferation, and generation of short-lived plasma cells that reside in extrafollicular foci.,Results are consistent with predicted/observed reduction in the Lyn-SHIP-1-PTEN-SHP-1 axis function in B cells from systemic lupus erythematosus patients.

Despite advances in systemic lupus erythematosus (SLE) treatment, many patients suffer from the disease and side effects.,Atacicept is a fusion protein that blocks B-lymphocyte stimulator and a proliferation-inducing ligand, which are increased in patients with SLE.,In this double-blind, placebo-controlled study, patients with moderate-to-severe SLE were randomised to atacicept 75 mg or atacicept 150 mg administered subcutaneously, or placebo twice-weekly for 4 weeks, then weekly for 48 weeks.,Primary and secondary efficacy measures were the proportion of patients experiencing at least one flare of British Isles Lupus Assessment Group A or B, and time to first flare, respectively.,Enrolment in the atacicept 150 mg arm was discontinued prematurely due to two deaths.,In the intention-to-treat population (n=461), there was no difference in flare rates or time to first flare between atacicept 75 mg and placebo.,Analysis of patients treated with atacicept 150 mg suggested beneficial effect versus placebo in flare rates (OR: 0.48, p=0.002) and time to first flare (HR: 0.56, p=0.009).,Both atacicept doses were associated with reductions in total Ig levels and anti-dsDNA antibodies, and increases in C3 and C4 levels.,Most treatment-emergent adverse events were mild or moderate.,There was no difference between atacicept 75 mg and placebo for flare rate or time to first flare.,Analysis of atacicept 150 mg suggested benefit.,EudraCT: 2007-003698-13; NCT00624338.