Journal of autoimmunity最新文献

{"title":"A novel subset of inflammation-related liver NK cells modulates immune responses in a murine model of primary biliary cholangitis","authors":"Tian-Tian Da ,&nbsp;Meng-Chu Liu ,&nbsp;Zhen-Hua Bian ,&nbsp;Pan-Yue Luo ,&nbsp;Rui-Tao Ye ,&nbsp;Kai Yan ,&nbsp;Liang Li ,&nbsp;Zhe-Xiong Lian ,&nbsp;Zhi-Bin Zhao","doi":"10.1016/j.jaut.2025.103454","DOIUrl":"10.1016/j.jaut.2025.103454","url":null,"abstract":"<div><div>Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease marked by bile duct inflammation, with immune dysregulation playing a central role in its pathogenesis. Here, we identify a novel subset of inflammation-related natural killer (irNK) cells, characterized by CD49a⁺CXCR6⁻, which accumulate in the livers of both PBC mouse models and patients. Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing reveal that irNK cells form a distinct cluster with a unique gene expression profile, clearly distinguishing them from conventional NK (cNK) cells and type 1 innate lymphoid cells (ILC1s). We show that irNK cells arise from cNK cells in response to IL-15 stimulation and acquire liver-resident characteristics, including reduced circulation, confirming their tissue-resident identity. Functionally, irNK cells promote CD4⁺ T cell proliferation through TNF-α secretion, which we identify as the key mediator of immune dysregulation in the PBC murine model (ARE-Del^+/− mice; ARE). These findings highlight the pivotal role of irNK cells in modulating immune responses in PBC and suggest that targeting these cells could offer new therapeutic opportunities for autoimmune liver diseases.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"155 ","pages":"Article 103454"},"PeriodicalIF":7.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144523847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STAT3 phosphorylation in the rheumatoid arthritis immunological synapse","authors":"Hila Novak-Kotzer ,&nbsp;Jesusa Capera ,&nbsp;Ashwin Jainarayanan ,&nbsp;Mirudula Elanchezhian ,&nbsp;Salvatore Valvo ,&nbsp;Viveka Mayya ,&nbsp;Alexandra Zanin-Zhorov ,&nbsp;Joanne Macdonald ,&nbsp;Peter C. Taylor ,&nbsp;Michael L. Dustin","doi":"10.1016/j.jaut.2025.103456","DOIUrl":"10.1016/j.jaut.2025.103456","url":null,"abstract":"<div><div>Targeting the JAK/STAT pathway has emerged as a key therapeutic strategy for managing Rheumatoid Arthritis (RA). JAK inhibitors suppress cytokine-mediated signaling, including the critical IL-6/STAT3 axis, thereby effectively targeting different aspects of the pathological process. However, despite their clinical efficacy, a subset of RA patients remains refractory to JAK inhibition, underscoring the need for alternative approaches. Here, we identify a novel JAK-independent mechanism of STAT3 activation, which is triggered by the formation of the immunological synapse (IS) in naive CD4⁺ T cells. Our data demonstrates that LCK mediates the TCR-dependent phosphorylation of STAT3 at the IS, highlighting this pathway as a previously unrecognized hallmark of early T cell activation. Furthermore, we show that the synaptic LCK/TCR-STAT3 pathway is compromised in RA. This discovery highlights a new therapeutic target for RA beyond JAK inhibitors, offering potential avenues for treating patients resistant to current therapies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"155 ","pages":"Article 103456"},"PeriodicalIF":7.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144523846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stratifying patients by TNFSF13B genotype revealed increased flare and renal flare risk, but a greater benefit from belimumab: a potential biomarker for personalized treatment in systemic lupus erythematosus","authors":"Marta Paola Pireddu ,&nbsp;Giulia Rizzo ,&nbsp;Fabio Congiu ,&nbsp;Elisabetta Chessa ,&nbsp;Maristella Pitzalis ,&nbsp;Elena Ragusa ,&nbsp;Alberto Floris ,&nbsp;Francesca Deidda ,&nbsp;Mattia Congia ,&nbsp;Micaela Rita Naitza ,&nbsp;Maria Maddalena Angioni ,&nbsp;Francesco Cucca ,&nbsp;Alberto Cauli ,&nbsp;Matteo Piga","doi":"10.1016/j.jaut.2025.103455","DOIUrl":"10.1016/j.jaut.2025.103455","url":null,"abstract":"<div><h3>Objective</h3><div>To examine whether SLE patients carrying the TNFSF13B variant (BAFF-var) differ in the risk of overall and renal flares and the benefits from belimumab.</div></div><div><h3>Methods</h3><div>This retrospective study analyzed data from a monocentric cohort of Sardinian SLE patients between January 2006 and December 2022. We recorded demographic, clinical, serological, and treatment variables. A flare was defined as a new SLE manifestation or worsening of an existing one that required a change in therapy. Renal flares, categorized as nephritic or nephrotic, were recorded. Soluble B-cell activating factor (sBAFF) levels were evaluated in patients naïve to any treatment. We used Kaplan-Meier curves, Cox regression, and Poisson regression to investigate the association between BAFF-var and flares.</div></div><div><h3>Results</h3><div>Among 233 screened patients, 194 (89.2 % female, 61.3 % BAFF-var carriers) were included. The mean age was 41.1 (±14.8) years, and the mean number of follow-up visits was 17 (±8). sBAFF levels increased according to BAFF-var genotype (p &lt; 0.001). BAFF-var was significantly associated with an increased risk of flares (HR 1.5 per copy variant; 95 %CI 1.2–2.0; p = 0.002), and the frequency of flares (IRR 1.3 per copy variant; 95 %CI 1.1–1.6; p = 0.009). In 38 biopsy-confirmed lupus nephritis patients, the BAFF-var was associated with a higher risk of renal flare (HR 9.3; 95 %CI 1.7–49.5; p = 0.008). In 35 relapsing-remitting patients, belimumab reduced both the risk and frequency of flares, with higher effectiveness in patients carrying the BAFF-var (HR 0.12; 95 %CI 0.02–0.58; p = 0.009).</div></div><div><h3>Conclusions</h3><div>Pending further validation, BAFF-var may serve as a predictive and prognostic biomarker for personalized treatment in SLE.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"155 ","pages":"Article 103455"},"PeriodicalIF":7.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144517071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Post-translationally modified proteins bind and activate complement with implications for cellular uptake and autoantibody formation","authors":"M.D. van den Beukel ,&nbsp;L. Zhang ,&nbsp;S. van der Meulen ,&nbsp;N.V. Borggreven ,&nbsp;S. Nugteren ,&nbsp;M.C. Brouwer ,&nbsp;R.B. Pouw ,&nbsp;K.A. Gelderman ,&nbsp;A.H. de Ru ,&nbsp;G.M.C. Janssen ,&nbsp;P.A. van Veelen ,&nbsp;R. Knevel ,&nbsp;P.W.H.I. Parren ,&nbsp;L.A. Trouw","doi":"10.1016/j.jaut.2025.103444","DOIUrl":"10.1016/j.jaut.2025.103444","url":null,"abstract":"<div><h3>Introduction</h3><div>Autoimmune diseases, such as rheumatoid arthritis (RA), are characterized by the presence of autoantibodies including those targeting self-proteins modified by post-translational modifications (PTMs). The complement system is known for its role in innate immune defense, but also in clearing debris and induction of antibody responses. We therefore hypothesized that complement could directly bind to PTMs and target PTM-modified proteins for clearance, or stimulate (chronic) inflammation and development of anti-PTM autoimmunity.</div></div><div><h3>Methods</h3><div>Six PTMs were investigated: nitration (Nt), citrullination (Cit), carbamylation (Ca), acetylation (Ac), malondialdehyde-acetaldehyde adducts (MAA) and advanced glycation end-products (AGE). We used mass spectrometry and plate-bound assays to analyze binding of serum proteins to PTM-modified proteins. The impact of complement activation on cellular uptake was studied in phagocytosis assays. The relationship between complement SNPs, and presence of anti-PTM autoantibodies was analyzed in 587 RA patients.</div></div><div><h3>Results</h3><div>Mass spectrometry analysis revealed a strong binding of complement to proteins modified with Ca, Ac, MAA and AGE but not to Nt and Cit. These observations were confirmed by plate-bound assays revealing that Ca-, MAA- and AGE-modified proteins activated the classical pathway, without involving antibodies. Ac activated the lectin pathway through ficolin-3. Complement activation on Ca-, Ac-, MAA- and AGE-coupled beads enhanced phagocytosis. SNPs in complement genes, associated with higher complement activity, were strongly associated with the presence of anti-PTM antibodies in RA patients.</div></div><div><h3>Conclusion</h3><div>Proteins containing the PTMs Ca, Ac, MAA or AGE activate complement. These complement opsonized PTMs increase phagocytosis and may lead to the development of anti-PTM antibodies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"155 ","pages":"Article 103444"},"PeriodicalIF":7.9,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144365099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between autoimmune diseases and glucagon-like peptide-1 receptor agonists: A real-world evidence study","authors":"Yun-Jui Lee ,&nbsp;Yu-Wei Fang ,&nbsp;Mon-Ting Chen ,&nbsp;Hung-Hsiang Liou ,&nbsp;Tzu-Hao Li ,&nbsp;Ming-Hsien Tsai","doi":"10.1016/j.jaut.2025.103453","DOIUrl":"10.1016/j.jaut.2025.103453","url":null,"abstract":"<div><h3>Introduction</h3><div>The therapeutic advantages of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in diabetes management have been demonstrated. However, their potential association with autoimmune diseases remains unknown. Using a comprehensive real-world dataset, this study compared GLP-1 RAs against dipeptidyl peptidase-4 inhibitors (DPP-4is) with respect to the incidence of autoimmune diseases.</div></div><div><h3>Methods</h3><div>This retrospective cohort study, with an active-comparator and new-user design, analyzed data from the TriNetX US Collaborative Network. We identified 4,841,560 patients aged over 18 years with type 2 diabetes from 1 January 2015 to 31 December 2022. Finally, 412,021 and 383,415 patients were included in the GLP-1 RAs and DPP-4is groups, respectively. Propensity score matching was used to balance baseline characteristics, and hazard ratios (HRs) were estimated with Cox regression models over an eight-year follow-up.</div></div><div><h3>Results</h3><div>After propensity score matching, each group included 290,770 patients. The analysis revealed that patients receiving GLP-1 RAs exhibited significantly higher risks of certain autoimmune conditions, including ulcerative colitis (HR, 1.11; 95 % CI, 1.04–1.19), rheumatoid arthritis (HR, 1.08; 95 % CI, 1.03–1.12), autoimmune thyroiditis (HR, 1.30; 95 % CI, 1.24–1.38), ankylosing spondylitis (HR, 1.30; 95 % CI, 1.13–1.51), and psoriasis (HR, 1.17; 95 % CI, 1.12–1.22), compared to those on DPP-4is. Moreover, sensitivity analyses consistently revealed a significant link between GLP-1 RAs use and autoimmune diseases.</div></div><div><h3>Conclusions</h3><div>This study suggests that compared with DPP-4is, the use of GLP-1 RAs is linked to increased risks of certain autoimmune diseases. Careful monitoring might be required among patients on GLP-1 RAs.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"155 ","pages":"Article 103453"},"PeriodicalIF":7.9,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autoimmune associated HLAs and T cell autoantigens exhibit common patterns across several autoimmune diseases","authors":"Astrid Brix Saksager ,&nbsp;Freja Dahl Hede ,&nbsp;Carolina Barra","doi":"10.1016/j.jaut.2025.103443","DOIUrl":"10.1016/j.jaut.2025.103443","url":null,"abstract":"<div><div>Approximately 80 autoimmune diseases have been identified, with only a few proteins targeted by the immune system in each disease. The rest of the human proteome remains unaffected, indicating that the selection of these specific proteins is not random. Most autoimmune diseases show strong genetic associations with HLA alleles, suggesting a critical role for antigen presentation in autoimmunity.</div><div>In this study, we analyzed validated T cell epitopes and their associated HLAs from 21 autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and type 1 diabetes mellitus, using experimental data from the IEDB. We compared autoantigens to proteins not implicated in autoimmunity, investigated HLA binding motifs, and contrasted autoimmunogenic T cell epitopes with non-autoimmune T cell epitopes.</div><div>Autoantigens, compared to other non-autoimmunogenic proteins, exhibited higher mRNA expression, greater abundance in disease-specific tissues, and were frequently found in exposed subcellular locations such as membranes and extracellular spaces. Disease-associated HLAs showed distinct binding motifs compared to other HLAs, but the autoimmunogenic epitopes themselves did not differ markedly from other T cell epitopes. Autoantigens were enriched on MHC class II presented peptides, and the self-peptides differed from those seen in non-autoimmune contexts.</div><div>Our findings suggest that the interplay between specific HLA class II alleles and specific antigen features play a pivotal role in initiating autoimmune responses, while subsequent T cell activation likely follows typical immune mechanisms.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"155 ","pages":"Article 103443"},"PeriodicalIF":7.9,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144279926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Common Toll-like receptor 7 variants define disease risk and phenotypes in juvenile-onset systemic lupus erythematosus","authors":"Yves Renaudineau ,&nbsp;Francesca Sposito ,&nbsp;Valentina Natoli ,&nbsp;Amandine Charras ,&nbsp;Jenny Hawkes ,&nbsp;Joni Roachdown ,&nbsp;Mathieu Fusaro ,&nbsp;Eve MD. Smith ,&nbsp;Michael W. Beresford ,&nbsp;Christian M. Hedrich","doi":"10.1016/j.jaut.2025.103451","DOIUrl":"10.1016/j.jaut.2025.103451","url":null,"abstract":"<div><div>Toll-like receptor <em>(TLR)7</em> contributes to type I interferon (IFN) expression in systemic lupus erythematosus (SLE). This study investigated genetic variability of <em>TLR7</em> in 319 juvenile-onset (j)SLE patients from the UK. New generation sequencing was used to associate “common” <em>TLR7</em> variants with demographic and clinical features. Three jSLE-associated variants with <em>in silico</em> predicted impact on gene function presented minor allele frequencies ≥5 %: rs2302267/n.-20T &gt; G (<em>TLR7</em> promoter); rs179008/p.Gln11Leu (missense variant with predicted loss-of-function); and rs3853839/c.∗881C &gt; G (<em>TLR7</em> 3′UTR). The risk to develop jSLE was increased in African/Caribbean girls carrying rs3853839 GC/GG (OR: 1.8; 95 %-CI: 1.2–2.9), while the risk associated with this variant was reduced in European girls (OR: 0.5; 95 %-CI: 0.4–0.7). At inclusion, rs3853839 minor G allele carrier status associated with activity in the mucocutaneous BILAG domain (p = 0.004), “older” age at diagnosis (p = 0.003, Asian), C3 consumption (p = 0.015, boys), and higher anti-dsDNA antibody levels (p = 0.015, African/Caribbean). The negative linkage disequilibrium between rs179008 (T-C/TT) and rs3853839 (CC) associated with increased global disease activity (pBILAG-2004), and activity in the constitutional and musculoskeletal pBILAG domains. Functionally, rs2302267/n.-20T &gt; G, may protect from leukopenia through reduced <em>TLR7</em> promoter activity, while rs3853839/c.∗881C &gt; G-3′UTR increases TLR7 mRNA stability contributing to increased gene expression. In conclusion, common <em>TLR7</em> variants may influence jSLE risk and organ involvement in an ancestry-specific manner. Observations argue for genetic risk stratification and future consideration of gene variants affecting <em>TLR7</em> to guide personalized treatment and care strategies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"155 ","pages":"Article 103451"},"PeriodicalIF":7.9,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144280021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The phenotypic and functional characteristics of intrahepatic CD69+CD103+ tissue-resident MAIT cells in primary biliary cholangitis","authors":"Qiyun Xia ,&nbsp;Zhuwan Lyu ,&nbsp;Yudong Zhao ,&nbsp;Xiting Pu ,&nbsp;Jian Wang ,&nbsp;Yuyang Liu ,&nbsp;Yujie Zhou ,&nbsp;Jun Qian ,&nbsp;M.E. Gershwin ,&nbsp;Min Lian ,&nbsp;Xiong Ma","doi":"10.1016/j.jaut.2025.103442","DOIUrl":"10.1016/j.jaut.2025.103442","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset that plays a significant role in the immunopathology of primary biliary cholangitis (PBC). However, our understanding of the subpopulations involved in hepatic residency have not been elucidated. Herein, our goal was to delineate the phenotypic and functional properties of intrahepatic tissue-resident MAIT cells in PBC.</div></div><div><h3>Methods</h3><div>Liver tissue and intrahepatic mononuclear cells were collected and analyzed by immunohistochemistry, immunofluorescence and flow cytometry. The transcriptome was determined using in vitro generated tissue-resident MAIT cells. FOXM1's immunoregulatory role was evaluated with inhibitor treatment and regulatory features of BHLHE40 were confirmed by CUT&amp;Tag-seq and luciferase assays.</div></div><div><h3>Results</h3><div>In PBC, the frequency of intrahepatic MAIT cell decreased, but tissue-resident (CD69⁺CD103⁺) MAIT cells significantly expanded and expressed a notably pro-inflammatory phenotype, with substantial elevated expression of CXCR3, CXCR6; IL-17A, IFN-γ and T-bet. FOXM1, a transcriptional factor governing cell proliferation cycle, exhibited notably higher expression in tissue-resident MAIT cells than in non-resident MAIT cells. Inhibition of FOXM1 compromised the in vitro expansion of MAIT cells, and impaired the expression of CXCR3, IL-17A, IFN-γ and GM-SCF by tissue-resident MAIT cells. CUT&amp;Tag-seq and luciferase assay revealed a direct regulation of FOXM1 of BHLHE40 expression.</div></div><div><h3>Conclusion</h3><div>Our data reveals a pro-inflammatory role of expanded tissue-resident MAIT cells in PBC mediated via higher expression of effector cytokines, chemokine receptors and a related transcriptional factor. FOXM1 critically regulates MAIT cell proliferation and tissue-resident pro-inflammatory function, via interaction with BHLHE40, and establishes a transcriptional axis linking proliferation to effector responses.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103442"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144195607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated analysis of polygenic and environmental risk scores for late-onset systemic lupus erythematosus","authors":"Mehmet Hocaoǧlu ,&nbsp;Amr H. Sawalha","doi":"10.1016/j.jaut.2025.103441","DOIUrl":"10.1016/j.jaut.2025.103441","url":null,"abstract":"<div><h3>Objective</h3><div>Polygenic risk scores (PRS) have been constructed to summarize genetic risk but there is limited research on environment-wide analysis of risk factors for systemic lupus erythematosus (SLE). In this study, we performed an environment-wide association study to construct an environmental risk score (ERS) for SLE and compare the risk conferred by ERS and PRS.</div></div><div><h3>Methods</h3><div>A total of 335 incident SLE cases were identified in the UK Biobank and matched 1:10 with age, sex, and ethnic background 3350 healthy controls. We examined the association between 37 environmental factors and SLE, using a univariate followed by a multivariate analysis. We summed the natural logarithm of the odds ratios (OR) of statistically significant environmental variables in the multivariable model to derive an ERS for SLE. Model discrimination was compared by De-Long′s test. PRS was calculated using the ORs of previously reported SLE genetic risk loci.</div></div><div><h3>Results</h3><div>The multivariate analysis revealed the association between daily sunlight exposure, depression, sleeplessness, sex hormone binding globulin levels, and air pollution with increased risk of SLE, while moderate physical activity was a protective factor. Increasing quartiles of the newly developed ERS were associated with similar degree of risk for SLE as the PRS. Integrating PRS with environmental factors significantly improved model performance.</div></div><div><h3>Conclusions</h3><div>We devised an ERS for SLE that summarizes the environmental component of the disease risk. We show that ERS confers a comparable degree of SLE risk as the PRS. Combining genetic and environmental factors could improve risk prediction models in SLE.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103441"},"PeriodicalIF":7.9,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144147273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing local antibody responses in the muscle of inclusion body myositis patients","authors":"Sahana Jayaraman ,&nbsp;Andrew Wilson ,&nbsp;Xuwen Alice Zheng ,&nbsp;Janelle M. Montagne ,&nbsp;Iago Pinal-Fernandez ,&nbsp;Andrew L. Mammen ,&nbsp;Thomas E. Lloyd ,&nbsp;H. Benjamin Larman","doi":"10.1016/j.jaut.2025.103437","DOIUrl":"10.1016/j.jaut.2025.103437","url":null,"abstract":"<div><h3>Objective</h3><div>Sporadic inclusion body myositis (IBM) is the most common adult idiopathic inflammatory myopathy. IBM etiology has been elusive, due to both degenerative and autoimmune disease features found on muscle biopsy, and significant disease heterogeneity. Investigating the role of antibodies in the muscle of IBM patients may improve our understanding of disease pathogenesis.</div></div><div><h3>Methods</h3><div>We used an IBM xenograft mouse model in which muscle biopsy tissue from IBM patients (n = 98) and controls (n = 131; including 54 from other types of myopathy) were implanted into immunodeficient mice (NOD-Rag1^null-IL2rγ^null). We quantified the amount of human IgG, IgA, and IgM in xenografted mouse sera using MesoScale Diagnostics (MSD) assay. We detected donor-derived antibody reactivities targeting autoantigens and infectious agents using Phage ImmunoPrecipitation Sequencing (PhIP-Seq). Finally, we used FR3 AmplifiKation Sequencing (FR3AK-Seq) to sequence the antibody mRNAs from a separate cohort of 146 patient biopsies (14 IBM, 22 healthy controls, 110 other myositis subtypes).</div></div><div><h3>Results</h3><div>With the MSD assay we found human IgG, IgA, and IgM in a larger percentage of IBM xenografted mice versus controls. Using PhIP-Seq, we found anti-microbial reactivities secreted from IBM muscle are prevalent amongst a healthy control population but autoantigen reactivities in IBM are more unique at the peptide and protein level. Additionally, NT5C1A (IgG/IgA and IgM) and TIF1γ (IgG/A) autoantibodies are secreted from muscle tissues of 4/18 and 10/18 IBM xenograft donors, respectively.</div></div><div><h3>Conclusion</h3><div>Our characterization of antibody responses within the muscle of IBM patients reveals that muscle-infiltrating B cells produce both disease-associated autoantibodies and a broad spectrum of antibodies targeting non-self antigens.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103437"},"PeriodicalIF":7.9,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144134595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}