Journal of autoimmunity最新文献

{"title":"Sex differences in biomarkers and biologic mechanisms in psoriatic diseases and spondyloarthritis","authors":"Steven Dang ,&nbsp;Joan Wither ,&nbsp;Igor Jurisica ,&nbsp;Vinod Chandran ,&nbsp;Lihi Eder","doi":"10.1016/j.jaut.2025.103394","DOIUrl":"10.1016/j.jaut.2025.103394","url":null,"abstract":"<div><div>Psoriasis and spondyloarthritis (SpA), including psoriatic arthritis (PsA), are immune-mediated inflammatory conditions that affect the skin and musculoskeletal system. Males and female patients with psoriatic disease and SpA exhibit differences in clinical presentation, disease progression, and treatment response. The underlying biological mechanisms driving these sex differences remain poorly understood. This review explores the current evidence on sex-related differences in biomarkers and biological pathways in psoriasis, PsA, and SpA. While no conclusive sex-specific biomarkers have been validated, this review highlights several sex-related differences in biomarkers and biological pathways, including differences in bone turnover markers, IL-23/IL-17 pathway activity, pro-inflammatory cytokines, and cardio-metabolic profiles that may partially contribute to the clinical differences observed between male and female patients. Sex hormones may contribute to the altered bone metabolism and immune regulation in females. To effectively identify and validate sex-specific biomarkers, there is a need to prioritize sex as a biological variable in future research. Adopting such an approach should enhance more personalized therapeutic strategies and improve management for male and female patients with psoriatic disease and SpA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"152 ","pages":"Article 103394"},"PeriodicalIF":7.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Total lung capacity is predictive of disease severity and survival in systemic sclerosis: A longitudinal analysis in 2347 patients from the French National Cohort Study","authors":"Benjamin Chaigne ,&nbsp;Alexandre Bense ,&nbsp;Frédérique Aubourg ,&nbsp;Christian Agard ,&nbsp;Yannick Allanore ,&nbsp;Alice Berezne ,&nbsp;Grégory Pugnet ,&nbsp;Eric Hachulla ,&nbsp;Vincent Cottin ,&nbsp;Arnaud Hot ,&nbsp;Bertrand Dunogue ,&nbsp;Anuxcy Kanagaratnam ,&nbsp;Sylvain Palat ,&nbsp;Alain Lescoat ,&nbsp;Sabine Berthier ,&nbsp;Emmanuel Chatelus ,&nbsp;Sébastien Rivière ,&nbsp;David Launay ,&nbsp;Marie-Elise Truchetet ,&nbsp;Anh Tuan Dinh-Xuan ,&nbsp;Perrine Smets","doi":"10.1016/j.jaut.2025.103391","DOIUrl":"10.1016/j.jaut.2025.103391","url":null,"abstract":"<div><h3>Background</h3><div>Total lung capacity (TLC) is seldom assessed in the prediction of systemic sclerosis (SSc) disease severity.</div></div><div><h3>Objective</h3><div>To describe and analyse TLC in SSc.</div></div><div><h3>Methods</h3><div>We performed a retrospective multicentre study of SSc patients enrolled in the French national SSc cohort with at least one TLC assessment, described patients based on baseline TLC measurements, modelized TLC trajectories in SSc, and associated TLC measures with disease prognosis.</div></div><div><h3>Results</h3><div>Two thousand three hundred and forty-seven patients were included in the study. Baseline TLC was associated with disease severity and survival, as well as with the occurrence of interstitial lung disease (ILD), lung fibrosis (LF), and pulmonary arterial hypertension (PAH). Individual TLC trajectories varied among patients. Different models of TLC trajectories were assessed using latent process mixed models. The best model showed that the vast majority of SSc patients had stable TLC trajectories and clustered patients into three groups predictive of SSc survival, ILD, LF, and PAH. Lastly, a 10 % decrease of TLC was found to be predictive of a 5 % decrease in forced vital capacity (FVC), a 10 % decrease in DLCO, and consequently an earlier predictive marker of ILD and LF than FVC.</div></div><div><h3>Limitations</h3><div>Retrospective study.</div></div><div><h3>Conclusion</h3><div>TLC is predictive of disease severity and survival in SSc and SSc-ILD. This work suggests TLC as an earlier risk factor for ILD and LF than FVC in SSc.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"152 ","pages":"Article 103391"},"PeriodicalIF":7.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143535013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differences in innate immune cell populations distinguish autoimmune from herpesvirus-associated encephalitis","authors":"Saskia Räuber ,&nbsp;Andreas Schulte-Mecklenbeck ,&nbsp;Kelvin Sarink ,&nbsp;Kristin S. Golombeck ,&nbsp;Christina B. Schroeter ,&nbsp;Alice Willison ,&nbsp;Christopher Nelke ,&nbsp;Christine Strippel ,&nbsp;Andre Dik ,&nbsp;Marco Gallus ,&nbsp;Stjepana Kovac ,&nbsp;Heinz Wiendl ,&nbsp;Gerd Meyer zu Hörste ,&nbsp;Tobias Ruck ,&nbsp;Oliver M. Grauer ,&nbsp;Udo Dannlowski ,&nbsp;Tim Hahn ,&nbsp;Catharina C. Gross ,&nbsp;Sven G. Meuth ,&nbsp;Nico Melzer","doi":"10.1016/j.jaut.2025.103396","DOIUrl":"10.1016/j.jaut.2025.103396","url":null,"abstract":"<div><h3>Background</h3><div>Autoimmune encephalitis (AIE) is a disabling inflammatory condition of the brain deemed to be due to a dysregulated immune response. Viral infections and malignancies together with certain genetic polymorphisms are thought to contribute to the pathogenesis of AIE, yet the exact mechanisms remain insufficiently understood. Diagnosis of AIE currently relies on clinical consensus criteria. However, diagnostic workup can be challenging in some cases, potentially delaying treatment initiation associated with poor clinical outcomes.</div><div>This study aims to investigate the systemic and intrathecal immune cell profiles of AIE in comparison to viral meningoencephalitis (VME) as a clinically relevant differential diagnosis and evaluate its diagnostic and therapeutic potential.</div></div><div><h3>Methods</h3><div>97 mainly treatment-naïve AIE patients, 47 patients with VME, and 109 somatic symptom disorder (SD) controls were included. Analysis of peripheral blood (PB) and cerebrospinal fluid (CSF) immune cell profiles was performed using multidimensional flow cytometry (mFC) in combination with novel computational approaches.</div></div><div><h3>Results</h3><div>We were able to identify alterations in the adaptive B and T cell-mediated immune response in AIE compared to SD controls which correspond to respective changes in the brain parenchyma. AIE and VME exhibit similar patterns of adaptive B and T cell responses and differ in pattern of innate immunity especially NK cells. MFC together with routine CSF parameters can differentiate AIE from VME and SD controls implying diagnostic potential.</div></div><div><h3>Conclusion</h3><div>AIE is characterized by a B and T cell-mediated systemic and intrathecal immune-cell signature which corresponds to changes reported in the brain parenchyma providing insights into immunopathogenesis. Differences between AIE and VME were most prominent for the innate immune response indicating a potential role of NK cells in the pathogenesis of autoimmunity. Our data provides evidence that mFC could be a novel complementary approach to the diagnosis of AIE with diagnostic, therapeutic, and prognostic implications.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"152 ","pages":"Article 103396"},"PeriodicalIF":7.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143535015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advanced pulmonary sarcoidosis","authors":"Florence Jeny ,&nbsp;Dominique Valeyre ,&nbsp;Elyse E. Lower ,&nbsp;Robert P. Baughman","doi":"10.1016/j.jaut.2025.103397","DOIUrl":"10.1016/j.jaut.2025.103397","url":null,"abstract":"<div><div>Sarcoidosis affects the lungs in most patients. Manifestations of pulmonary sarcoidosis range from asymptomatic to death. Approximately a quarter of sarcoidosis patients develop chronic pulmonary disease. Advanced pulmonary sarcoidosis patients are those who have progressive disease and are at risk for significant morbidity and mortality. There are several features associated with advanced pulmonary disease: pulmonary fibrosis, pulmonary hypertension, chronic pulmonary inflammation, and/or complications of disease or therapy. Large retrospective studies have identified pulmonary fibrosis and pulmonary hypertension as the major causes of respiratory failure and death in pulmonary sarcoidosis. The high-resolution computer tomography scan (HRCT) and echocardiogram are key methods in screening for pulmonary hypertension and pulmonary fibrosis. Therapy for chronic pulmonary inflammation has been the major focus in chronic disease. However, treatment for pulmonary hypertension has been studied in sarcoidosis. To date, treatment studies for sarcoidosis associated progressive pulmonary fibrosis have been underpowered to demonstrate clear cut benefit of anti-fibrotic agents.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"152 ","pages":"Article 103397"},"PeriodicalIF":7.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143621408","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":"Poorer survival for patients with inflammatory arthritis treated with immune checkpoint inhibitors for melanoma","authors":"H.B. Tenstad ,&nbsp;C.H. Ruhlmann ,&nbsp;S. Möller ,&nbsp;S. Kjaer ,&nbsp;L. Bastholt ,&nbsp;S.A. Just ,&nbsp;H. Lindegaard","doi":"10.1016/j.jaut.2025.103400","DOIUrl":"10.1016/j.jaut.2025.103400","url":null,"abstract":"<div><h3>Background</h3><div>Patients with inflammatory arthritis treated with immune checkpoint inhibitors (ICIs) for melanoma face unique challenges, including disease flares and reduced treatment efficacy. Evidence on the survival impact of pre-existing arthritis in this population remains limited.</div></div><div><h3>Methods</h3><div>We conducted an observational cohort study using data from two Danish national registries, DANBIO and DAMMED, including patients with melanoma and pre-existing inflammatory arthritis treated with ICIs. Cases were matched with controls without arthritis based on sex, age, melanoma subtype, disease stage, and treatment regimen. Outcomes included overall survival (OS), progression-free survival (PFS)/recurrence-free survival (RFS), changes in rheumatic disease activity, and healthcare utilization.</div></div><div><h3>Results</h3><div>Seventy-five patients with inflammatory arthritis were identified, initiating 91 ICI treatment courses. Patients with arthritis demonstrated poorer OS (HR 1.4, 95 % CI: 1.04–1.91) and PFS/RFS (HR 1.5, 95 % CI: 1.13–1.94) compared to controls. Subgroup analysis of immunosuppressed patients yielded similar results. Rheumatic disease activity increased post-ICI initiation (mean DAS28 Δ +0.48, p = 0.001), while rheumatologic healthcare utilization decreased.</div></div><div><h3>Conclusion</h3><div>Patients with inflammatory arthritis have poorer OS and PFS/RFS following ICI therapy for melanoma, partly attributable to baseline immunosuppressive treatment. These findings underscore the need for enhanced multidisciplinary management to optimize outcomes and address the survival gap in this population.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"152 ","pages":"Article 103400"},"PeriodicalIF":7.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aberrant expansion of CD177+ neutrophils promotes endothelial dysfunction in systemic lupus erythematosus via neutrophil extracellular traps","authors":"Honglin Xu ,&nbsp;Minghua Zhan ,&nbsp;Ziyan Wu ,&nbsp;Jianing Chen ,&nbsp;Yanling Zhao ,&nbsp;Futai Feng ,&nbsp;Fang Wang ,&nbsp;Yongzhe Li ,&nbsp;Shulan Zhang ,&nbsp;Yudong Liu","doi":"10.1016/j.jaut.2025.103399","DOIUrl":"10.1016/j.jaut.2025.103399","url":null,"abstract":"<div><h3>Objective</h3><div>Aberrant neutrophil activation is implicated in the pathogenesis of systemic lupus erythematosus (SLE) and its related comorbidities. We found that <em>CD177</em> was one of the most highly up-regulated genes at the transcriptional level in purified neutrophils from SLE patients. In this study, we aimed to explore the role of CD177⁺ neutrophils in the pathogenesis of SLE.</div></div><div><h3>Methods</h3><div>Expression of CD177 was analyzed by neutrophil transcriptome and flow cytometry. CD177⁺ neutrophils and CD177⁻neutrophils were isolated to determine the role of neutrophils-derived NETs in endothelium dysfunction. Wild type and CD177^−/− murine model of lupus were analyzed for organ involvement, endothelium-dependent vasorelaxation, serum autoantibodies, and innate and adaptive immune responses in an imiquimod (IMQ)-induced lupus model.</div></div><div><h3>Results</h3><div>CD177^MFI-hi neutrophils and CD177^MFI-hi low-density granulocytes (LDGs) were expanded in active SLE, which were weakly but significantly associated with disease activity. CD177⁺neutrophils displayed enhanced production of reactive oxygen species (ROS) and NETs, which impaired the murine aortic endothelium-dependent vasorelaxation and induced endothelial cell apoptosis. Moreover, CD177^−/− mice exposed to IMQ showed alleviated splenomegaly, endothelium-dependent vasorelaxation, and renal immune complex deposition.</div></div><div><h3>Conclusions</h3><div>Our findings indicated that CD177 ^MFI-hi may serve as a novel biomarker for monitoring disease activity in SLE. Further, CD177⁺ neutrophils may play a vasculopathic role in cardiovascular disease (CVD) via NETs formation, suggesting that specific targeting CD177⁺ neutrophil subset may have therapeutic effect in SLE but reducing the levels of NETs-prone neutrophils.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"152 ","pages":"Article 103399"},"PeriodicalIF":7.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143621407","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":"Optimizing the tapering scheme of corticosteroid treatment for acute onset of autoimmune hepatitis","authors":"Rui Wang ,&nbsp;Qiuxiang Lin ,&nbsp;Li Sheng ,&nbsp;Yan Zhang ,&nbsp;Haoyu Wen ,&nbsp;You Li ,&nbsp;Mingxia Shi ,&nbsp;Xiao Xiao ,&nbsp;Li Yan ,&nbsp;Canjie Guo ,&nbsp;Qi Miao ,&nbsp;Jing Hua ,&nbsp;Zuxiong Huang ,&nbsp;Hai Li ,&nbsp;M. Eric Gershwin ,&nbsp;Qixia Wang ,&nbsp;Xiong Ma ,&nbsp;Min Lian","doi":"10.1016/j.jaut.2025.103387","DOIUrl":"10.1016/j.jaut.2025.103387","url":null,"abstract":"<div><h3>Background</h3><div>Uncertainties persist regarding the optimal management of acute onset of autoimmune hepatitis, including the use of corticosteroids. This study aimed to compare the effectiveness and safety of rapid versus slow corticosteroid tapering in acute onset of AIH.</div></div><div><h3>Methods</h3><div>A multicenter study involving patients with acute AIH was conducted. We defined acute AIH as an acute presentation (&lt;30 days) with AIH and exhibiting no evidence of pre-existing liver diseases. Initially, corticosteroid treatment and overall outcomes were reported. Subsequently, the role of corticosteroid tapering rate in modifying outcomes across subgroups was investigated. For patients with an initial corticosteroid dose of 20 mg/day or higher, we further classified patients into rapid tapering group (duration until dose of prednisone &lt;20 mg/day &lt;3 weeks) and slow tapering group (duration until dose of prednisone &lt;20 mg/day ≥3 weeks). Adverse events were defined as any of the following events, progression (e.g., acute icteric AIH progression to AS-AIH or AIH-ALF, AS-AIH progression to AIH-ALF, non-cirrhotic progression to cirrhosis, compensated cirrhosis progression to decompensation), LT, and liver-related death.</div></div><div><h3>Results</h3><div>This retrospective cohort study enrolled 237 patients, with 109 presenting acute icteric AIH, 97 with acute-severe AIH (AS-AIH), and 31 with AIH-acute liver failure (ALF). Among patients with acute icteric AIH, slow tapering significantly improved adverse outcome-free survival compared to rapid tapering (99 % <em>vs.</em> 71 %, <em>P</em> &lt; 0.0001). Similarly, in AS-AIH patients, slow tapering resulted in notably higher adverse outcome-free survival rates compared to rapid tapering (92 % <em>vs.</em> 54 %, <em>P</em> &lt; 0.001). Slow tapering independently predicted fewer adverse events (OR 0.144; 95 % CI 0.037–0.562; <em>P</em> = 0.005). However, in AIH-acute liver failure (ALF) patients, tapering rate did not significantly affect adverse outcome-free survival (38 % <em>vs.</em> 50 %, <em>P</em> = 0.590). Overall, there were no significant differences in osteoporosis or infection occurrence between tapering groups in the entire acute AIH cohort.</div></div><div><h3>Conclusion</h3><div>A slow corticosteroid tapering reduced adverse outcomes in acute exacerbation of AIH patients, particularly in acute icteric AIH and AS-AIH.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"152 ","pages":"Article 103387"},"PeriodicalIF":7.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treg fitness signatures as a biomarker for disease activity in Juvenile Idiopathic Arthritis","authors":"Meryl H. Attrill ,&nbsp;Diana Shinko ,&nbsp;Telma Martins Viveiros ,&nbsp;Martina Milighetti ,&nbsp;Nina M. de Gruijter ,&nbsp;Bethany Jebson ,&nbsp;Melissa Kartawinata ,&nbsp;Elizabeth C. Rosser ,&nbsp;Lucy R. Wedderburn ,&nbsp;CHARMS Study ,&nbsp;JIAP Study ,&nbsp;Anne M. Pesenacker","doi":"10.1016/j.jaut.2025.103379","DOIUrl":"10.1016/j.jaut.2025.103379","url":null,"abstract":"<div><div>Juvenile Idiopathic Arthritis (JIA) is an autoimmune condition characterised by flares of joint inflammation. However, no reliable biomarker exists to predict the erratic disease course. Normally, regulatory T cells (Tregs) maintain tolerance, with altered Tregs associated with autoimmunity. Treg signatures have shown promise in monitoring other conditions, therefore a Treg gene/protein signature could offer novel biomarker potential for predicting disease activity in JIA.</div><div>Machine learning on our nanoString Treg 48-gene signature on peripheral blood (PB) Tregs generated a model to distinguish active JIA (active joint count, AJC≥1) Tregs from healthy controls (HC, AUC = 0.9875 on test data). Biomarker scores from this model successfully differentiated inactive (AJC = 0) from active JIA PB Tregs. Moreover, scores correlated with clinical activity scores (cJADAS), and discriminated subclinical disease (AJC = 0, cJADAS≥0.5) from remission (cJADAS&lt;0.5).</div><div>To investigate altered protein expression as a surrogate measure for Treg fitness in JIA, we utilised spectral flow cytometry and unbiased clustering analysis. Three Treg clusters were of interest in active JIA PB, including TIGIT_highCD226_highCD25_low Teff-like Tregs, CD39-TNFR2-Helios_high, and a 4-1BB_lowTIGIT_lowID2_intermediate Treg cluster predominated in inactive JIA PB (AJC = 0). The ratio of these Treg clusters correlated to cJADAS, and higher ratios could potentially predict inactive individuals that flared by 9-month follow-up.</div><div>Thus, we demonstrate altered Treg signatures and subsets as an important factor, and useful biomarker, for disease progression versus remission in JIA, revealing genes and proteins contributing to Treg fitness. Ultimately, PB Treg fitness measures could serve as routine biomarkers to guide disease and treatment management to sustain remission in JIA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"152 ","pages":"Article 103379"},"PeriodicalIF":7.9,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective disruption of Traf1/cIAP2 interaction attenuates inflammatory responses and rheumatoid arthritis","authors":"Yitian Tang ,&nbsp;Fatemah Aleithan ,&nbsp;Sahib Singh Madahar ,&nbsp;Ali Mirzaesmaeili ,&nbsp;Sunpreet Saran ,&nbsp;Jialing Tang ,&nbsp;Safoura Zangiabadi ,&nbsp;Robert Inman ,&nbsp;Gary Sweeney ,&nbsp;Ali A. Abdul-Sater","doi":"10.1016/j.jaut.2025.103377","DOIUrl":"10.1016/j.jaut.2025.103377","url":null,"abstract":"<div><h3>Objectives</h3><div>Tumor necrosis factor receptor-associated factor 1 (TRAF1) is an immune signaling adapter protein linked to increased susceptibility to rheumatoid arthritis (RA). TRAF1 has dual roles in regulating NF-κB and MAPK signaling: it promotes signaling through its association with cellular inhibitor of apoptosis 2 (cIAP2) downstream of certain tumor necrosis factor receptor (TNFR) family members but inhibits Toll-like receptor (TLR) signaling by limiting linear ubiquitination of key signaling proteins. In this study, we investigated whether selectively targeting TRAF1/cIAP2 interaction would lower inflammation and reduce severity of RA.</div></div><div><h3>Methods</h3><div>We employed CRISPR/Cas9-mediated mediated gene editing to modify TRAF1 and specifically abrogate its interaction with cIAP2 in human macrophage cell lines and in mice. Biochemical studies were then employed to assess inflammatory signaling and cytokine production in gene edited macrophages. The collagen antibody-induced arthritis (CAIA) model of RA was used to trigger joint inflammation in mice.</div></div><div><h3>Results</h3><div>We identify a critical mutation in TRAF1 (V203A in humans, V196A in mice) that disrupts its interaction with cIAP2, leading to a significant reduction in TLR signaling and downstream inflammation in human and murine macrophages. We demonstrate that TRAF1 is recruited to the TLR4 complex and is indispensable for the recruitment of cIAP2, facilitating TAK1 phosphorylation and the activation of NF-κB and MAPK signaling pathways. Remarkably, mice harboring the TRAF1 V196A mutation are protected from LPS-induced septic shock and exhibit markedly reduced joint inflammation and disease severity in the CAIA model of RA.</div></div><div><h3>Conclusion</h3><div>These findings reveal a previously unrecognized and crucial role for the TRAF1/cIAP2 axis in promoting inflammation and offer a promising foundation for the development of novel therapeutic strategies for inflammatory conditions, such as RA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"152 ","pages":"Article 103377"},"PeriodicalIF":7.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LAMP3-mediated epithelial-mesenchymal transition promotes the invasion and excessive proliferation of fibroblast-like synoviocytes in rheumatoid arthritis","authors":"Wenxian Zhou ,&nbsp;Hui Cheng ,&nbsp;Chenghu Fan ,&nbsp;Xin Zhou ,&nbsp;Wenyu Chen ,&nbsp;Chenglong Xie ,&nbsp;Yuezheng Hu ,&nbsp;Yue Chen ,&nbsp;Xiaobing Wang ,&nbsp;Jinyu Wu","doi":"10.1016/j.jaut.2025.103359","DOIUrl":"10.1016/j.jaut.2025.103359","url":null,"abstract":"<div><h3>Objective</h3><div>The aim of this study was to explore the functional role of LAMP3-mediated epithelial-mesenchymal transition (EMT) in fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) patients and to evaluate its potential as a therapeutic target.</div></div><div><h3>Methodology</h3><div>Changes in EMT and LAMP3 were investigated in the synovial tissue and FLSs of RA patients. In vitro experiments were performed using the EMT inhibitor C19, siRNA, and lentivirus to examine the impact of EMT and LAMP3 on RA-FLSs and the underlying mechanisms involved. Finally, C19 was administered to mice with collagen-induced arthritis (CIA) to validate the therapeutic efficacy of C19 in treating arthritis.</div></div><div><h3>Results</h3><div>Compared with patients with osteoarthritis (OA), RA patients exhibited increased EMT and increased expression of LAMP3 in the synovium. The results from the <em>in vitro</em> experiments demonstrated that inhibiting EMT effectively reduced the excessive proliferation, anti-senescent properties, migration, and invasive behavior of RA-FLSs, as well as the secretion of MMP1, MMP3, and MMP13. Additionally, regulating the expression of LAMP3 not only affected the EMT pathway but also impacted the excessive proliferation and invasive behavior of RA-FLSs. In the CIA model, administration of the EMT inhibitor C19 significantly alleviated the progression of arthritis.</div></div><div><h3>Conclusion</h3><div>These findings demonstrate the inhibitory impact of EMT on arthritis and suggest that inhibiting EMT or LAMP3 may be a promising novel therapeutic approach for treating RA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"151 ","pages":"Article 103359"},"PeriodicalIF":7.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970959","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}