Journal of autoimmunity最新文献

{"title":"Epigenetic differences at immune and type 1 diabetes susceptibility genes in blood from young children after COVID-19 infection","authors":"Raffael Ott ,&nbsp;Tarini Singh ,&nbsp;Katharina Schütte-Borkovec ,&nbsp;Marlon Scholz ,&nbsp;Kristina Casteels ,&nbsp;Gita Gemulla ,&nbsp;Olga Kordonouri ,&nbsp;Helena Elding Larsson ,&nbsp;Agnieszka Szypowska ,&nbsp;John A. Todd ,&nbsp;Anette-G. Ziegler ,&nbsp;Ezio Bonifacio","doi":"10.1016/j.jaut.2025.103468","DOIUrl":"10.1016/j.jaut.2025.103468","url":null,"abstract":"<div><h3>Background</h3><div>Viral infections, including COVID-19, are associated with an increased risk for type 1 diabetes (T1D), but potential underlying mechanisms remain unexplored. We evaluated whether COVID-19 or influenza A infection is characterized by differential DNA methylation at immune and T1D susceptibility genes in young children at risk for T1D.</div></div><div><h3>Methods</h3><div>Epigenome-wide association analysis using the Illumina MethylationEPIC microarray was performed in blood taken at age 1.5 years (IQR, 1.49–1.52 y) from 740 prospectively followed children with increased risk of T1D. SARS-CoV-2 and influenza A H1N1 antibodies were monitored at 2–4-month intervals from age 6 months to identify infection.</div></div><div><h3>Results</h3><div>COVID-19 and influenza infection occurred prior to the DNA methylation sample in 81 and 74 children, respectively. Of these, infection occurred within 3 months of the DNA methylation sample (recent infection) in 43 and 22 children. Compared to children without COVID-19 or influenza A infection, children with recent COVID-19 infection showed differential methylation at key immune- and antiviral genes, including <em>ADAR</em>, <em>IFI44L</em>, <em>MX1</em> and <em>OASL</em>. In addition to <em>ADAR</em>, six further T1D susceptibility genes, including the SARS-CoV-2 cell entry receptor neuropilin-1, had differential methylation at nearby CpGs in children infected by SARS-CoV-2. A quantitatively less differential methylation was also observed in children with an earlier COVID-19 infection at some of these CpG sites. Infections with influenza showed no associations.</div></div><div><h3>Conclusion</h3><div>Children with SARS-CoV-2 infection showed sustained DNA methylation changes at genes critical for antiviral response and T1D susceptibility, potentially contributing to immune dysregulation and promotion of the autoimmune process underlying T1D.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"Article 103468"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737988","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":"Targeted protein degradation in autoimmune diseases: from mechanisms to therapeutic breakthroughs","authors":"Yuxin Song,&nbsp;Boyang Zhou,&nbsp;Jiangang Long,&nbsp;Yunhua Peng","doi":"10.1016/j.jaut.2025.103475","DOIUrl":"10.1016/j.jaut.2025.103475","url":null,"abstract":"<div><div>Autoimmune diseases pose significant challenges due to the high risks associated with abnormal immune responses to self-antigens and the limitations of broad-spectrum immunosuppressants. Current therapeutic approaches primarily rely on immunosuppressive drugs, yet their non-specificity and side effects urge researchers to explore novel targets and the advancement of precision medicine. Recent advances in targeted protein degradation (TPD) technologies, including PROTAC, MGD and LYTAC, offer therapeutic potential by precisely eliminating pathogenic proteins. By leveraging cellular degradation machinery such as ubiquitin-proteasome an endolysosomal systems to overcome the undruggable targets, these TPD technologies offer promising therapeutic strategies for precise immune regulation. Preclinical studies demonstrate PROTAC-mediated degradation of IRAK4 reduce inflammatory cytokines. RIPK2 degraders are expected to become a new approach for treating inflammatory diseases. While BTK degraders L18I surpass inhibitors in blocking autoantibodies. There are still challenges to overcome, such as delivery barriers, off-target effects and limited E3 ligase diversity. Emerging solutions such as AI-driven design and modular platforms may improve the specificity and efficacy. This review summarizes the underlying mechanisms, therapeutic breakthroughs, and translational hurdles of TPD technologies, and explores how integrating AI can optimize the technologies. TPD strategies have the potential to revolutionize the treatment of autoimmune diseases by providing more targeted and personalized therapies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"Article 103475"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932341","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":"FAPI PET/CT for tracking disease trajectory in myositis-related interstitial lung disease.","authors":"Kastriot Kastrati, Svitlana Pochepnia, Oana C Kulterer, Thomas S Nakuz, Daniel Mrak, Irina Gessl, Elisabeth Simader, Florian Prayer, Helmut Prosch, Lukas Nics, Stefan Schmitl, Daniel Aletaha, Helga Lechner-Radner, Marcus Hacker, Peter Mandl","doi":"10.1016/j.jaut.2025.103471","DOIUrl":"10.1016/j.jaut.2025.103471","url":null,"abstract":"<p><strong>Background: </strong>Interstitial lung disease (ILD) is associated with morbidity and mortality in idiopathic inflammatory myopathies (IIM). Predicting ILD progression remains a significant challenge, as conventional diagnostic tools such as pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) have limited prognostic accuracy. This study evaluated whether ⁶⁸Ga-labelled inhibitor of Fibroblast-Activation-Protein (FAPI) based PET/CT at baseline predicts ILD evolution over two years.</p><p><strong>Material and methods: </strong>In this prospective observational study, n = 19 individuals with IIM (n = 14 with ILD) underwent [⁶⁸Ga] Ga-FAPI PET/CT at baseline. ILD progression was defined by three criteria: (1) FVC decline ≥10 % or FVC 5-9 % plus DLCO decline ≥15 %, (2) INBUILD criteria, and (3) a composite endpoint including INBUILD plus therapy escalation, hospitalization, or mortality. Pulmonary tracer uptake was quantified by calculating the maximum and mean target-to-background ratios across the whole lung (wlTBR_max and wlTBR_mean, respectively), derived from standardized uptake values corrected for blood pool activity, and their predictive value was analysed.</p><p><strong>Results: </strong>Over two years, n = 4 (28.6 %) patients met PFT-based progression criteria, while n = 6 (42.9 %) fulfilled INBUILD criteria, and n = 8 (57.1 %) reached the composite endpoint. Baseline wlTBR_max was significantly higher in INBUILD progressors compared to non-progressors (2.68 ± 1.06 vs. 1.59 ± 0.80, p = 0.04), as was wlTBR_mean (0.58 ± 0.22 vs. 0.34 ± 0.10, p = 0.04). Similarly, patients meeting the composite endpoint had higher wlTBR_max (2.63 ± 1.04 vs. 1.30 ± 0.31; p < 0.01) and wlTBR_mean (0.55 ± 0.20 vs. 0.31 ± 0.09; p = 0.01). Logistic regression analysis showed that incorporating pulmonary wlTBR_max and wlTBR_mean enhanced the predictive accuracy over PFT and HRCT alone.</p><p><strong>Conclusion: </strong>FAPI PET/CT may serve as a non-invasive biomarker for early prediction of ILD progression in IIM, supporting personalized disease management. However, given the small, single-centre cohort, these findings should be considered as preliminary and require validation in larger, multi-centre studies.</p>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"103471"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144804190","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":"Corrigendum to “Anti-DNA antibody-targeted D-peptide nanoparticles ameliorate lupus nephritis in MRL/lpr mice” [J. Autoimmun. 145 (2024) 103205]","authors":"Yaqi Wang ,&nbsp;Shuang Wang ,&nbsp;Wei Liu ,&nbsp;Hanjiang Gu ,&nbsp;Mai Luo ,&nbsp;Tong Xiao ,&nbsp;Mingzhu Zhou ,&nbsp;Yutong Ran ,&nbsp;Shengxiang Xiao ,&nbsp;Yumin Xia ,&nbsp;Huixia Wang","doi":"10.1016/j.jaut.2025.103470","DOIUrl":"10.1016/j.jaut.2025.103470","url":null,"abstract":"","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"156 ","pages":"Article 103470"},"PeriodicalIF":7.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144775470","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":"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}

{"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":"2025-07-01","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}

{"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":"2025-07-01","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}

{"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":"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":"2025-07-01","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}

{"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":"2025-07-01","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}