bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pregnancy and lactation interfere with the response of autoimmunity to modulation of gut microbiota
Authors: Mu Qinghui , Cabana-Puig Xavier , Swartwout Brianna , Abdelhamid Leila , Cecere Thomas E , Wang Haifeng , Reilly Christopher M , Luo Xin M 
Published: January 2023

Abstract
Dysbiosis of gut microbiota exists in the pathogenesis of many autoimmune diseases, including lupus. Currently, women with lupus are recommended to avoid pregnancy, as lupus patients who experienced pregnancy usually had more severe disease flares. However, the possible role of gut microbiota in the link between pregnancy and exacerbation of lupus remains to be explored. In the present study, in the classical lupus mouse model MRL/lpr, we compared the structures of gut microbiota in pregnant and lactating individuals vs. age-matched naïve mice. Consistent with studies on non-lupus mice, both pregnancy and lactation significantly changed the composition and diversity of gut microbiota. Strikingly, modulation of gut microbiota using the same strategy resulted in different disease outcomes in experienced (which had undergone pregnancy and lactation) vs. control (naïve) MRL/lpr females: while vancomycin treatment attenuated lupus in naïve mice, it even exacerbated lupus in experienced mice. L. animalis flourished in the gut upon vancomycin treatment, and direct administration of the bacteria recapitulated the differential effects of vancomycin in experienced vs. control mice. A pregnancy-related enzyme, DHNA, was significantly inhibited by L. animalis; however, this inhibition was only apparent in experienced mice, which explained, at least partially, the lack of beneficial response to vancomycin in these mice. The differential production of IL-10 and IFNγ in experienced vs. control mice further explained why the disease phenotypes varied between the two types of mice bearing the same treatment. These results suggest that pregnancy and lactation interfere with the response of autoimmunity to modulation of gut microbiota.
Microbial exposure and autoimmunity in the etiopathogenesis of Sarcoidosis
Authors: Allushi Bujana , Bagavant Harini , Papinska Joanna , Montgomery Courtney G , Deshmukh Umesh S 
Published: January 2023

Abstract
Sarcoidosis is an enigmatic inflammatory disease affecting multiple organs such as the lungs, lymph nodes, brain, heart, and skin. It is characterized by the occurrence of multiple non-caseating granulomas comprised of macrophages, giant cells, and CD4 T cells. Although genetic and environmental factors increase the risk for sarcoidosis, the etiology remains unknown. Recent studies have shown that HLA-DR3+ sarcoidosis patients harbor CD4+ T cells reactive with a vimentin peptide 424–443. However, whether autoimmunity is a cause or consequence of the disease is not known.
This study was undertaken to investigate the mechanisms responsible for activation of vimentin reactive T cells and determine their pathogenic role in sarcoidosis. For this purpose, we immunized the NOD-DR3 mice with the vimentin peptide 424–443 and induced a robust T cell response against the peptide. Fine epitope mapping using T cell hybridomas reactive with the peptide showed that both N-terminal and C-terminal amino acids were critical for T cell activation. Homology searches of microbial protein database identified a 100% homologous sequence in a protein from Klebsiella pneumoniae. Immunization of mice with this peptide, followed by intravenous transfer of peptide-coupled agarose beads induced granulomatous lesions in the lungs. Immunohistochemical analysis of these lesions showed the presence of CD4+ T cells, macrophages, and an upregulated MHC-II expression.
In summary, our data demonstrate for the first time that autoimmunity is involved in the pathogenesis of sarcoidosis. Furthermore, the demonstration of molecular mimicry between a lung infecting microbe and vimentin might explain the role of microbial exposures as a risk factor for sarcoidosis.
Interactions between the host genome and the gut microbiome determine susceptibility to CNS autoimmune disease
Authors: Montgomery Theresa L , Fang Qian , Künster Axel , Busch Hauke , Teuscher Cory , Krementsov Dimitry 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a chronic autoimmune central nervous system (CNS) disease and the leading cause of non-traumatic neurological disability in young adults. The etiology of MS is multifactorial and polygenic, with 30% of risk genetic and 70% environmental. Recent studies identified an imbalance in the human gut microbiome within MS patients, including depletion of the Lactobacillus genus. Animal models support a causal role of the gut microbiome in MS, though the mechanisms remain unclear.
Here, we leverage natural genetic variation in wild-derived PWD/PhJ (PWD) mice as compared to classic C57BL/6J (B6) mice, modeling human genetic diversity to identify host genome and gut microbiome interactions governing disease susceptibility. In a model of MS, experimental autoimmune encephalomyelitis (EAE), 27 consomic strains carrying PWD chromosomes on the B6 background demonstrated that PWD-derived loci exhibit bidirectional and sex-specific effects on disease severity. 16S rRNA gene sequencing of the gut microbiome in consomic and parental strains identified strain-specific profiles and metabolic functions associated with differential susceptibility to EAE. Functionally, manipulation of the gut microbiome by co-housing or transplantation, demonstrated direct host genotype-dependent effects of the microbiome on EAE susceptibility, with transfer of signature Lactobacillus species associated with changes in circulating indole metabolites and altered EAE severity. These studies reveal the presence of complex bidirectional interactions between the host genome and gut microbiome that modulate susceptibility to CNS autoimmunity, and identify specific microbiome constituents as potential therapeutic candidates.
Periodontal disease: from infection to autoimmunity
Authors: Garzon Hernan Santiago , Suarez Lina 
Published: January 2023

Abstract
Five decades of publications have been necessary to document the relationship between immune response and tissue injury in periodontitis. Multiple mechanisms have been implicated in the progression of tissue damage, including the controversial mechanisms of autoimmunity. The aim of this paper is the development of the theories that considered periodontal disease as an autoimmune entity with a historical narrative and descriptive view. Diverse theories have been referenced involving the innate and acquired immunity: generation of anti-neutrophil cytoplasmic antibodies (ANCA), Th17 cell function and IL-17, auto-antibodies to collagen and epithelial components of the periodontium, the role of NK cells T lymphocytes and T CD5, development of molecular mimicry, among others. In conclusion, it’s still difficult to classify periodontal disease as an stabilshed autoimmune disease, because its multifactorial nature makes it difficult to understand. However, the evidence is clear and comprehensive showing related autoimmune mechanisms, which could eventually explain the progression and its relation to systemic events such as cardiovascular disease and atherosclerosis.
Abnormal B cell development in an SLE patient suffering from immunothrombocytopenia
Authors: CHOI YOUN SOO , KIM JOOHYUNG 
Published: January 2023

Abstract
Follicular helper T (Tfh) cells are effector CD4 T cells which help B cells form germinal center reactions for memory B cells and long-lived plasma cells. Abnormal Tfh differentiation and function is highly associated with development and disease progression of SLE. B cell and CD4 T cell compartments were analyzed in the spleen, which was removed from one of outpatients in SNU hospital, who suffer from SLE with severe immunothrombocytopenia. PD1+CXCR5+ Tfh cells were hardly found in the spleen, where little germinal center (GC) B cells exist. B cell frequency in the peripheral blood of the patient was significantly low (~0.1%), which led us to speculate that B cell development is impaired in the patient. To reveal mutation(s) of genes responsible for B cell development defect, B cells and non-B cells isolated from splenocytes of the patient, and from peripheral blood mononuclear cells of the patient’s daughter, who does not exhibit clinical symptoms, were subject to whole exome sequencing (WES) analysis. Our initial screen failed to locate mutations in genes, including BTK and IKAROS, which are able to develop primary B cell deficient conditions, indicating that B cell development could be regulated by function of novel gene(s). We were able to find mutations in genes, whose products were reported to function in signaling pathways downstream of B cell surface receptors, during mitotic division, and so on. Our future study includes (i) to examine whether gene(s) of interest are expressed during B cell development in humans and mice, and (ii) to analyze whether shRNA mediated knockdown or CRISPR/Cas9-sgRNA mediated deletion of genes, which are expressed by developing B cells in both humans and mice, could give rise to B cell development defect in mice.
The Glycosylation and Glycoprotein Signature of Immunoglobulins in Patients with Autoimmune Liver Diseases
Authors: Zhang Weici , Zhou Xing , Muchena John , Shuai Zongwen , Sun Ying , Yang Guo-Xiang , Liu Chung Heng , Dhaliwal Sandeep , Invernizzi Pietro , Bowlus Christopher , Leung Patrick S.C. , Lebrilla Carlito , Gershwin M Eric 
Published: January 2023

Abstract
Glycosylation of antibodies, particularly in the Fc domain, critically modulate the ability of antibodies to bind to FcRs, maintaining immune quiescence and marshaling appropriate immune response to achieve a finely orchestrated immune response. Alterations in the glycosylation profile of immunoglobulin (Ig) have been implicated in various autoimmune conditions, which may arise prior to symptoms and have been considered diagnostic for autoimmune disease. We applied QqQ mass spectroscopy with subsequent multiple reaction monitoring (MRM) to elucidate the overall profile, composition and linkage of the sugar residues of plasma IgG, IgM and IgA glycans in 225 serum samples from healthy donors (HD; n=50), PBC (n=100) and PSC (n=75) with or without IBD, using an Agilent 6490 triple quadruple (QqQ) mass spectrometer. Our data demonstrate that most of IgA 1 and 2 glycopeptides significantly distinguish PBC from PSC, which are associated with lower level of Bi anterary glycoforms and elevated HexNac containing glycoforms in PBC samples as compared to both controls and PSC. HexNac terminated IgG1 glycoforms are enriched in both PBC and PSC. The levels of IgM glycopeptide, IgM_439_5200, IgM_439_6200 and J chain distinguish among three categories of samples. Most importantly, a distinct pattern of glycoforms exists in PSC patients with IBD. Neu5Ac terminated IgA and IgM are enriched, while the galactosylated forms are lower in PSC with IBD. Ig glycosylation pattern can be a novel serological marker to distinguish between PBC and PSC. This novel technology highlights the importance of glycan biology in the immune response and as a potential mechanism in the loss of tolerance and/or a disease specific chronic signal of inflammation.
Salivary IgA as biomarker of disease activity in Systemic Lupus Erythematosus
Authors: Romero Sandra , Sánchez-Salguero Erick Saúl , Torres-Ruiz Jiram José , Núñez-Álvarez Carlos , Santos-Argumedo Leopoldo , Chacón-Salinas Rommel , Gómez-Martín Diana , Maravillas-Montero José Luis 
Published: January 2023

Abstract
Immunoglobulin A (IgA) is the main antibody isotype present in the body fluids such as tears, intestinal mucous, colostrum and saliva. There are two subtypes of IgA in humans: IgA1 mainly present in blood and IgA2, the preferentially expressed mucosal antibody. In clinical practice, immunoglobulins are typically measured in venous or capillary blood; however, alternative samples including saliva are now being considered given its non-invasive and easy collection nature.
Since IgA deficiency could be frequently detected in patients with autoimmune diseases, we decided to evaluate the levels of both IgA subtypes in serum and saliva of systemic lupus erythematosus (SLE) patients. Specific IgA1 and IgA2 levels were measured by a light chain capture-based ELISA in a cohort of 32 patients with SLE that were compared with antibody levels of healthy volunteers.
Surprisingly, our results indicated that in saliva of SLE patients, both IgA subtypes were significantly elevated; however, serum IgA1 levels were decreased when compared with control subjects. Interestingly, we also found that salivary IgA levels, most specifically IgA1, positively correlate with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) values as well with the amount of serum anti-nucleosomes and anti-dsDNA IgG autoantibodies. Strikingly, we also were able to detect the presence of salivary anti-nucleosome IgA antibodies in SLE patients, a feature that was not previously reported elsewhere.
According to our results, IgA characterization in saliva could be used as a pre-diagnostic or follow-up clinical tool in SLE with easier, faster and safer to manipulate than blood samples.
Age-associated B cells in early drug-naive rheumatoid arthritis patients
Authors: VIDAL-PEDROLA GEMMA VIDAL , Cameron James , Pratt Arthur , Mellor Andrew , Scheel-Toellner Dagmar , Isaacs John , Anderson Amy 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterised by joint inflammation. Studies in mice and patients suffering from autoimmune diseases described a novel subset of B cells named age-associated B cells (ABCs). Moreover, a subset of synovial fluid B cells with a similar phenotype and FcRL4 expression contributes to RA pathogenesis.
Newly diagnosed patients were recruited from the Newcastle Early Arthritis Clinic. B cell subsets in blood were phenotyped using flow cytometry. NanoString Immunlogy Panel was used to asses gene expression from sorted ABCs, naïve, memory and CD5+ B cells from RA patients, age-matched healthy controls and disease controls.
Our work showed that there are no significant differences in the frequency of ABCs between RA patients, and disease and healthy controls. Our results also show that ABCs resemble the memory B cell phenotype regarding class-switch immunoglobulins expression. Interestingly, the FcRL4+, the Ki67+ and the T-bet expressing B cells were enriched in the ABC population. ABCs expressed high levels of HLA-DR and co-stimulatory molecules, as well as the activation marker, CD69. Gene expression analysis showed a specific gene signature for the ABCs when compared to the other B cells. KEGG analysis results showed that differentially expressed genes were enriched in the antigen presentation and the cytokine-cytokine receptor interaction pathways. Moreover, 13 genes were overexpressed in ABCs from the RA patients compared to the other control groups.
This data supports the idea that ABCs have a pathogenic role in RA, potentially via T cell stimulation and migration to sites of inflammation. However, further characterisation of this subset and functional studies are needed.
MIF and MIF2 have distinct but synergistic roles in CIA pathogenesis
Authors: Doherty Edward H , Tilstam Pathricia Veronica , Bucala Richard 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is a relapsing autoimmune disease with progressive joint destruction. High expression alleles of the cytokine macrophage migration inhibitory factor (MIF) are associated with severe erosive RA. MIF and MIF family member D-dopachrome tautomerase (MIF2) signal through the receptor CD74. Previously we reported on the presence of CD74 expressing effector memory T cells in the collagen-induced arthritis (CIA) mouse model and identified CD74+ T cells in human RA synovium fluid. We studied MIF and MIF2 signaling on CD74+ T cells and inflammatory CD74high MΦ in the CIA model. We observed infiltration of CD74+ T cells (1.7 fold increase, p&lt;0.001) and inflammatory CD74high MΦ (2 fold increase, p&lt;0.001) in the joints of WT mice on day 28 post CIA induction. CD74+ T cell infiltration into paws positively correlated with CIA disease score (r=0.731, p=0.003). CD74+ T cells and CD74high MΦ failed to expand or infiltrate in the paws of Mif−/− mice in CIA. Interestingly, CIA induction in Mif2−/− mice expand CD74+ T cells in lymph nodes (0.5 fold increase, p=0.024), but fail to expand in other secondary lymphoid organs or infiltrate joints. Macrophage precursor Gr1high CD74+ monocytes expand in the spleen (3 fold, p&lt;0.001) and blood (1 fold, p&lt;0.001) of Mif2−/− mice, no change in CD74high MΦ levels is observed. The MIF inhibitor MIF098 ameliorates joint inflammation but did not inhibit the expansion or joint infiltration of CD74+ T cells (2 fold, p&lt;0.001), Gr1high CD74+ monocytes, and CD74high MΦ (0.7 fold, p&lt;0.01). Our findings provide evidence for a pathogenic role of novel MIF responsive CD74+ T cell in RA and suggest separate but crucial roles for both MIF and MIF2 in the development and localization for CD74+ T cells and CD74high MΦ in CIA.
STING-mediated chronic activation of ER stress through disrupting calcium homeostasis primes T cells for cell death
Authors: Wu Jianjun , Yan Nan 
Published: January 2023

Abstract
STING is a central protein for innate immune response to a wide range of microbial pathogens. Gain-of-function STING mutations cause systemic inflammation, lung disease and T cell cytopenia in humans and in mice, although the mechanism of disease is not known. Here, we found that SAVI mutation N154S induces chronic activation of ER stress and unfolded protein response (UPR), leading to spontaneous T cell death by apoptosis in the StingN153S/+ mouse and in human T cells. Mechanistically, we found that N154S severely disrupts calcium homeostasis in T cells, thus intrinsically primes T cells to become hyper-responsive to T cell receptor (TCR) signaling-induced ER stress and the UPR, leading to cell death. This intrinsic priming effect is mediated through a novel region of STING protein that we name ‘the UPR motif’, which is distinct from known domains required for interferon signaling. Point mutations that disrupt the UPR motif rescue N154S-mediated calcium dysregulation and ER stress, and blocks T cell death. Pharmacological inhibition of ER stress also prevented T cell death in vitro and in vivo. Furthermore, restoring only the CD8+ T cells rescued splenomegaly, hypercytokinmia and perivascular lung inflammation in the StingN153S/+ mouse. Collectively, our data uncovers a critical IFN-independent function of STING that regulates calcium homeostasis, ER stress and T cell survival.
Antigen-presenting cells from naive mice constitutively present the T cell epitope of SERCA2a and induce inflammatory cytokine production in antigen-specific T cells
Authors: Reddy Jay , Arumugam Rajkumar , Yalaka Bharathi , Massilamany Chandirasegaran , Ali Shihabudeen , Riethoven Jean-Jack , Sun Xinghui 
Published: January 2023

Abstract
We recently reported that sarcoplasmic/endoplasmic reticulum (SR) calcium-ATPase2a (SERCA2a) 971–990 induces atrial myocarditis by generating autoreactive T cells in A/J mice. However, it was unknown as to how the antigen-sensitized T cells could recognize SERCA2a 971–990, since SERCA2a-expression is confined to SR. Here, we present evidence that antigen-presenting cells (APCs) from naïve animals constitutively present SERCA2a 971–990 and stimulate T cells antigen-specifically. By using major histocompatibility complex (MHC) class IIdextramers for SERCA2a 971–990, we created a panel of antigen-specific T cell hybridomas and demonstrated that splenocytes from naïve A/J mice stimulated the hybridoma cells without exogenous supplementation of SERCA2a 971–990, and such an effect was pronounced with unirradiated cells as compared to irradiated cells. We recapitulated this phenomenon by using SERCA2a 971–990-specific, primary T cells, and the T cell responses were verified to be MHC-restricted. While T cells exposed to mononuclear cells obtained from heart and liver responded similar to splenocytes, endothelial cells (ECs) generated from the corresponding organs displayed opposing effects in that the T cell responses were suppressed with the heart-ECs, but not from liver. Finally, SERCA2a 971–990-reactive T cells exposed to APCs were found to produce inflammatory cytokines namely, interferon-γ, granulocyte macrophage colony stimulating factor and interleukin-17. Our data suggest that the constitutive expression of SERCA2a 971–990 by APCs can trigger pathogenic responses under the conditions of autoimmunity that may have implications on endothelial dysfunction.
Intestinal Interleukin (IL)-22RA1 signaling regulates the reciprocal control of IL-22 and onset of high fat diet-induced metabolic disorders
Authors: Gaudino Stephen , Huang Huakang , Jean-Pierre Makheni , Beaupre Michael , Lin Xun , Kumar Pawan 
Published: January 2023

Abstract
Impaired signaling by IL-22 has been shown to accelerate high fat diet (HFD)-induced obesity. However, it is not known if IL-22 signaling in the intestine regulates HFD-induced metabolic disorders.
To test this, intestinal epithelial-specific IL-22RA1 knockout mice – Il22RA1fl/fl;Villin cre+ (IL-22RA1ΔIEC) and control Il22RA1fl/fl;Villin cre- (IL-22RA1fl/fl) mice – were generated. When placed on HFD for 16 weeks, IL- 22RA1ΔIEC and IL-22RA1fl/fl mice display commensal dysbiosis, reduced antimicrobial peptide expression, and dysregulated IL-22 responses. No difference in weight gain was observed between these mice over the 16-week period. Interestingly, IL-22RA1ΔIEC mice displayed decreased glucose tolerance when compared to controls. Upon antibiotic treatment, differences in glucose tolerance between these mice were not observed. Furthermore, this difference in glucose tolerance was not due to histopathology changes in white adipose tissue (WAT) or liver tissue. In IL-22RA1ΔIEC mice, we observed that expression of genes related to β-oxidation (Acox1) were increased in the WAT, and liver tissues displayed decreased expression of β-oxidation (Pparα) and glycolysis (G6PC) genes. These changes were not observed in Il22−/− mice or liver-specific IL-22RA1 knockout mice which suggests IL-22 may drive the expression of critical metabolic genes in the WAT and liver. We found exacerbated IL-22 response in HFD-fed IL-22RA1ΔIEC mice. Indeed, injection of IL-22RA1ΔIEC mice with anti-IL-22 decreased glucose tolerance when compared to IL-22RA1ΔIEC mice injected with an isotype control.
Collectively, our data suggest that IL-22 signaling in the intestinal epithelium is important for regulating HFD-induced metabolic disorder.