Pub Date : 2025-09-01Epub Date: 2025-08-08DOI: 10.1016/j.jaut.2025.103473
Roopa Hebbandi Nanjundappa, Harish Babu Kolla, Alexander Edgar, Patrick S Leung, Deepak S Chauhan, William M Ridgway, M Eric Gershwin, Channakeshava Sokke Umeshappa
Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by intrahepatic bile duct destruction, progressive cholestasis, and fibrosis, accompanied by elevated anti-mitochondrial antibodies (AMAs) and IgM. While multiple mouse models have been developed to study PBC pathogenesis, no single model fully recapitulates all aspects of human disease. Among these, the NOD.c3c4 mouse model, generated by incorporating B10 and B6 insulin-dependent diabetes (Idd) loci into NOD mice, uniquely develops PBC-like features without progressing to type-1 diabetes. NOD.c3c4 exhibit PDC-E2-reactive AMAs, elevated autoantibodies, biliary leukocyte infiltration, and progressive liver dysfunction. However, key pathogenic mechanisms, particularly the role of fibrosis, remain poorly understood. Here, we provide a comprehensive characterization of PBC development and progression in NOD.c3c4 mice, focusing on adaptive and innate immune contributions to disease pathology. Our study confirms that both T and B cells are central drivers, as their depletion significantly mitigates PBC pathology. Additionally, our findings highlight a previously underappreciated role of innate immunity in disease progression. Notably, NOD.c3c4 mice develop fibrosis, which advances with age, making them a valuable model for studying fibrotic events in PBC. Given their resemblance to human disease, NOD.c3c4 mice represent a powerful platform for investigating PBC pathogenesis and evaluating new immunotherapeutics.
{"title":"Immunological and fibrotic profiling in the NOD.c3c4 murine model of autoimmune cholangitis.","authors":"Roopa Hebbandi Nanjundappa, Harish Babu Kolla, Alexander Edgar, Patrick S Leung, Deepak S Chauhan, William M Ridgway, M Eric Gershwin, Channakeshava Sokke Umeshappa","doi":"10.1016/j.jaut.2025.103473","DOIUrl":"10.1016/j.jaut.2025.103473","url":null,"abstract":"<p><p>Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disease characterized by intrahepatic bile duct destruction, progressive cholestasis, and fibrosis, accompanied by elevated anti-mitochondrial antibodies (AMAs) and IgM. While multiple mouse models have been developed to study PBC pathogenesis, no single model fully recapitulates all aspects of human disease. Among these, the NOD.c3c4 mouse model, generated by incorporating B10 and B6 insulin-dependent diabetes (Idd) loci into NOD mice, uniquely develops PBC-like features without progressing to type-1 diabetes. NOD.c3c4 exhibit PDC-E2-reactive AMAs, elevated autoantibodies, biliary leukocyte infiltration, and progressive liver dysfunction. However, key pathogenic mechanisms, particularly the role of fibrosis, remain poorly understood. Here, we provide a comprehensive characterization of PBC development and progression in NOD.c3c4 mice, focusing on adaptive and innate immune contributions to disease pathology. Our study confirms that both T and B cells are central drivers, as their depletion significantly mitigates PBC pathology. Additionally, our findings highlight a previously underappreciated role of innate immunity in disease progression. Notably, NOD.c3c4 mice develop fibrosis, which advances with age, making them a valuable model for studying fibrotic events in PBC. Given their resemblance to human disease, NOD.c3c4 mice represent a powerful platform for investigating PBC pathogenesis and evaluating new immunotherapeutics.</p>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"103473"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812074","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}
Pub Date : 2025-07-01Epub Date: 2025-06-21DOI: 10.1016/j.jaut.2025.103453
Yun-Jui Lee , Yu-Wei Fang , Mon-Ting Chen , Hung-Hsiang Liou , Tzu-Hao Li , Ming-Hsien Tsai
Introduction
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.
Methods
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.
Results
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.
Conclusions
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.
{"title":"Association between autoimmune diseases and glucagon-like peptide-1 receptor agonists: A real-world evidence study","authors":"Yun-Jui Lee , Yu-Wei Fang , Mon-Ting Chen , Hung-Hsiang Liou , Tzu-Hao Li , 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":"2025-07-01","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}
Pub Date : 2025-07-01Epub Date: 2025-06-23DOI: 10.1016/j.jaut.2025.103444
M.D. van den Beukel , L. Zhang , S. van der Meulen , N.V. Borggreven , S. Nugteren , M.C. Brouwer , R.B. Pouw , K.A. Gelderman , A.H. de Ru , G.M.C. Janssen , P.A. van Veelen , R. Knevel , P.W.H.I. Parren , L.A. Trouw
Introduction
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.
Methods
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.
Results
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.
Conclusion
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.
{"title":"Post-translationally modified proteins bind and activate complement with implications for cellular uptake and autoantibody formation","authors":"M.D. van den Beukel , L. Zhang , S. van der Meulen , N.V. Borggreven , S. Nugteren , M.C. Brouwer , R.B. Pouw , K.A. Gelderman , A.H. de Ru , G.M.C. Janssen , P.A. van Veelen , R. Knevel , P.W.H.I. Parren , 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":"2025-07-01","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}
Pub Date : 2025-07-01Epub Date: 2025-07-02DOI: 10.1016/j.jaut.2025.103454
Tian-Tian Da , Meng-Chu Liu , Zhen-Hua Bian , Pan-Yue Luo , Rui-Tao Ye , Kai Yan , Liang Li , Zhe-Xiong Lian , Zhi-Bin Zhao
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.
{"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 , Meng-Chu Liu , Zhen-Hua Bian , Pan-Yue Luo , Rui-Tao Ye , Kai Yan , Liang Li , Zhe-Xiong Lian , 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<sup>+</sup>CXCR6<sup>−</sup>, 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<sup>+</sup> T cell proliferation through TNF-α secretion, which we identify as the key mediator of immune dysregulation in the PBC murine model (ARE-Del<sup>+/−</sup> 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}
Pub Date : 2025-07-01Epub Date: 2025-06-13DOI: 10.1016/j.jaut.2025.103443
Astrid Brix Saksager , Freja Dahl Hede , Carolina Barra
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.
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.
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.
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.
{"title":"Autoimmune associated HLAs and T cell autoantigens exhibit common patterns across several autoimmune diseases","authors":"Astrid Brix Saksager , Freja Dahl Hede , 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":"2025-07-01","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}
Pub Date : 2025-07-01Epub Date: 2025-06-13DOI: 10.1016/j.jaut.2025.103451
Yves Renaudineau , Francesca Sposito , Valentina Natoli , Amandine Charras , Jenny Hawkes , Joni Roachdown , Mathieu Fusaro , Eve MD. Smith , Michael W. Beresford , Christian M. Hedrich
Toll-like receptor (TLR)7 contributes to type I interferon (IFN) expression in systemic lupus erythematosus (SLE). This study investigated genetic variability of TLR7 in 319 juvenile-onset (j)SLE patients from the UK. New generation sequencing was used to associate “common” TLR7 variants with demographic and clinical features. Three jSLE-associated variants with in silico predicted impact on gene function presented minor allele frequencies ≥5 %: rs2302267/n.-20T > G (TLR7 promoter); rs179008/p.Gln11Leu (missense variant with predicted loss-of-function); and rs3853839/c.∗881C > G (TLR7 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 > G, may protect from leukopenia through reduced TLR7 promoter activity, while rs3853839/c.∗881C > G-3′UTR increases TLR7 mRNA stability contributing to increased gene expression. In conclusion, common TLR7 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 TLR7 to guide personalized treatment and care strategies.
{"title":"Common Toll-like receptor 7 variants define disease risk and phenotypes in juvenile-onset systemic lupus erythematosus","authors":"Yves Renaudineau , Francesca Sposito , Valentina Natoli , Amandine Charras , Jenny Hawkes , Joni Roachdown , Mathieu Fusaro , Eve MD. Smith , Michael W. Beresford , 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 > G (<em>TLR7</em> promoter); rs179008/p.Gln11Leu (missense variant with predicted loss-of-function); and rs3853839/c.∗881C > 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 > G, may protect from leukopenia through reduced <em>TLR7</em> promoter activity, while rs3853839/c.∗881C > 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":"2025-07-01","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}
Pub Date : 2025-07-01Epub Date: 2025-06-29DOI: 10.1016/j.jaut.2025.103455
Marta Paola Pireddu , Giulia Rizzo , Fabio Congiu , Elisabetta Chessa , Maristella Pitzalis , Elena Ragusa , Alberto Floris , Francesca Deidda , Mattia Congia , Micaela Rita Naitza , Maria Maddalena Angioni , Francesco Cucca , Alberto Cauli , Matteo Piga
Objective
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.
Methods
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.
Results
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 < 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).
Conclusions
Pending further validation, BAFF-var may serve as a predictive and prognostic biomarker for personalized treatment in SLE.
目的研究携带TNFSF13B变异（BAFF-var）的SLE患者在总体和肾脏发作的风险以及贝利单抗的获益方面是否存在差异。方法本回顾性研究分析了2006年1月至2022年12月撒丁岛SLE患者的单中心队列数据。我们记录了人口统计学、临床、血清学和治疗变量。耀斑被定义为新的SLE表现或现有表现的恶化，需要改变治疗。记录肾脏耀斑，分类为肾病或肾病。评估可溶性b细胞活化因子（sBAFF）水平naïve患者的任何治疗。我们使用Kaplan-Meier曲线、Cox回归和泊松回归来研究BAFF-var与耀斑之间的关系。结果在233例筛查患者中，包括194例（女性89.2%，BAFF-var携带者61.3%）。平均年龄41.1（±14.8）岁，平均随访次数17（±8）次。根据BAFF-var基因型，saff水平升高(p <；0.001)。BAFF-var与耀斑风险增加显著相关(每个拷贝变异的HR为1.5；95% ci 1.2-2.0；p = 0.002)，以及耀斑发生的频率(每个拷贝变异的IRR为1.3；95% ci 1.1-1.6；p = 0.009)。在38例活检证实的狼疮性肾炎患者中，BAFF-var与肾脏耀斑的高风险相关(HR 9.3；95% ci 1.7-49.5；p = 0.008)。在35例复发缓解型患者中，贝利单抗降低了耀斑发生的风险和频率，对携带BAFF-var的患者更有效(HR 0.12；95% ci 0.02-0.58；p = 0.009)。结论BAFF-var可作为SLE个体化治疗的预测和预后生物标志物，有待进一步验证。
{"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 , Giulia Rizzo , Fabio Congiu , Elisabetta Chessa , Maristella Pitzalis , Elena Ragusa , Alberto Floris , Francesca Deidda , Mattia Congia , Micaela Rita Naitza , Maria Maddalena Angioni , Francesco Cucca , Alberto Cauli , 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 < 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}
Pub Date : 2025-07-01Epub Date: 2025-07-02DOI: 10.1016/j.jaut.2025.103456
Hila Novak-Kotzer , Jesusa Capera , Ashwin Jainarayanan , Mirudula Elanchezhian , Salvatore Valvo , Viveka Mayya , Alexandra Zanin-Zhorov , Joanne Macdonald , Peter C. Taylor , Michael L. Dustin
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.
{"title":"STAT3 phosphorylation in the rheumatoid arthritis immunological synapse","authors":"Hila Novak-Kotzer , Jesusa Capera , Ashwin Jainarayanan , Mirudula Elanchezhian , Salvatore Valvo , Viveka Mayya , Alexandra Zanin-Zhorov , Joanne Macdonald , Peter C. Taylor , 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<sup>+</sup> 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}
Pub Date : 2025-06-01Epub Date: 2025-05-25DOI: 10.1016/j.jaut.2025.103440
Seunghyun Lee , Ah-Reum Jo , Youjin Kim , Wanhyung Lee , Xiaoxue Ma
Background
Occupational and environmental dust exposure is often overlooked, presenting significant public health concerns. Recent studies suggest it may increase the risk of autoimmune diseases. However, previous research has primarily focused on specific diseases or dust types, leaving the broader relationship unclear. A comprehensive meta-analysis are needed to clarify this connection.
Methods
We systematically searched PubMed and Google Scholar up to October 2023, following PRISMA guidelines. Study quality was assessed using standard tools, and a random-effects model was used to estimate pooled odds ratio (OR) and 95 % confidence interval (CI), with subgroup analyses by dust type and disease category.
Results
From 90 initial records, 19 studies were included. Dust exposure was significantly associated with increased autoimmune disease risk (OR 1.36, 95 % CI 1.13–1.59). Both occupational (OR 1.18, 95 % CI 1.11–1.26) and environmental dust exposure (OR 1.12, 95 % CI 1.04–1.20) were linked to higher risk. Subgroup analysis showed a strong association between silica exposure and connective tissue diseases, particularly granulomatosis with polyangiitis (OR 5.75, 95 % CI 2.79–8.71). Sensitivity analysis confirmed the findings, though publication bias was noted.
Conclusion
Our findings highlight a significant association between dust exposure and autoimmune disease risk, underscoring the need for stricter occupational safety measures and environmental regulations. Targeted interventions, such as improved ventilation systems and personal protective equipment (PPE), should be prioritized. Future research should focus on elucidating underlying mechanisms to inform prevention and treatment strategies.
职业和环境粉尘暴露往往被忽视，引起重大的公共卫生问题。最近的研究表明，它可能会增加自身免疫性疾病的风险。然而，之前的研究主要集中在特定的疾病或灰尘类型上，没有明确更广泛的关系。需要一个全面的荟萃分析来澄清这种联系。方法根据PRISMA指南，系统检索PubMed和谷歌Scholar，截止到2023年10月。使用标准工具评估研究质量，并使用随机效应模型估计合并优势比（OR）和95%置信区间（CI），并按粉尘类型和疾病类别进行亚组分析。结果从90份初始记录中纳入19项研究。粉尘暴露与自身免疫性疾病风险增加显著相关（OR 1.36, 95% CI 1.13-1.59）。职业（OR 1.18, 95% CI 1.11-1.26）和环境粉尘暴露（OR 1.12, 95% CI 1.04-1.20）都与较高的风险相关。亚组分析显示二氧化硅暴露与结缔组织疾病，特别是肉芽肿病合并多血管炎之间有很强的相关性（OR 5.75, 95% CI 2.79-8.71）。敏感性分析证实了这一发现，尽管存在发表偏倚。结论：我们的研究结果强调了粉尘暴露与自身免疫性疾病风险之间的显著关联，强调了更严格的职业安全措施和环境法规的必要性。应优先考虑有针对性的干预措施，如改进通风系统和个人防护装备。未来的研究应侧重于阐明潜在的机制，为预防和治疗策略提供信息。
{"title":"Association between occupational and environmental dust exposure and autoimmune diseases: A systematic review and meta-analysis","authors":"Seunghyun Lee , Ah-Reum Jo , Youjin Kim , Wanhyung Lee , Xiaoxue Ma","doi":"10.1016/j.jaut.2025.103440","DOIUrl":"10.1016/j.jaut.2025.103440","url":null,"abstract":"<div><h3>Background</h3><div>Occupational and environmental dust exposure is often overlooked, presenting significant public health concerns. Recent studies suggest it may increase the risk of autoimmune diseases. However, previous research has primarily focused on specific diseases or dust types, leaving the broader relationship unclear. A comprehensive meta-analysis are needed to clarify this connection.</div></div><div><h3>Methods</h3><div>We systematically searched PubMed and Google Scholar up to October 2023, following PRISMA guidelines. Study quality was assessed using standard tools, and a random-effects model was used to estimate pooled odds ratio (OR) and 95 % confidence interval (CI), with subgroup analyses by dust type and disease category.</div></div><div><h3>Results</h3><div>From 90 initial records, 19 studies were included. Dust exposure was significantly associated with increased autoimmune disease risk (OR 1.36, 95 % CI 1.13–1.59). Both occupational (OR 1.18, 95 % CI 1.11–1.26) and environmental dust exposure (OR 1.12, 95 % CI 1.04–1.20) were linked to higher risk. Subgroup analysis showed a strong association between silica exposure and connective tissue diseases, particularly granulomatosis with polyangiitis (OR 5.75, 95 % CI 2.79–8.71). Sensitivity analysis confirmed the findings, though publication bias was noted.</div></div><div><h3>Conclusion</h3><div>Our findings highlight a significant association between dust exposure and autoimmune disease risk, underscoring the need for stricter occupational safety measures and environmental regulations. Targeted interventions, such as improved ventilation systems and personal protective equipment (PPE), should be prioritized. Future research should focus on elucidating underlying mechanisms to inform prevention and treatment strategies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"154 ","pages":"Article 103440"},"PeriodicalIF":7.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131073","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}
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