Journal of autoimmunity最新文献

{"title":"Unraveling the immunomodulatory impact of hydroxychloroquine on peripheral T cells using single-cell RNA sequencing.","authors":"Huizhong Long, Luis Espinosa, Amr H Sawalha","doi":"10.1016/j.jaut.2024.103324","DOIUrl":"10.1016/j.jaut.2024.103324","url":null,"abstract":"<p><p>Hydroxychloroquine (HCQ) is widely used in the treatment of a variety of autoimmune diseases. However, the mechanisms responsible for the immunomodulatory properties of HCQ in T cells remain unclear. Here we used single-cell RNA-sequencing to examine the effect of HCQ on T cells following in vitro stimulation. HCQ treatment led to a reduction in effector CD4⁺ T cells and upregulation of inhibitory genes including CTLA4 and TNFAIP3 in effector and naive CD4⁺ T cells, respectively. HCQ induced a significant expansion of effector CD8⁺ T cells, and significantly upregulated key cytotoxicity genes including GZMA, GZMB, GZMH, KLRD1, NKG7, and PRF1, as well as IFNG expression. Furthermore, HCQ treatment led to a reduction in the CD38⁺ CD8⁺ T cell subset, which is characterized by defective cytotoxicity and thought to both play a pathogenic role and increase susceptibility to infections in autoimmunity. We analyzed single-cell RNA-sequencing data in effector CD8⁺ T cells from lupus patients with or without HCQ treatment and confirmed upregulation of key cytotoxicity genes in patients receiving HCQ. In conclusion, this work provides additional insights into the immunomodulatory effects of HCQ and indicates that HCQ improves T cell cytotoxicity, which could explain a previously suggested protective effect of HCQ against infections in patients with autoimmune diseases.</p>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"103324"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466404","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":"Sarcoidosis and its relation to other immune-mediated diseases: Epidemiological insights","authors":"Elizabeth V. Arkema ,&nbsp;Marios Rossides ,&nbsp;Yvette C. Cozier","doi":"10.1016/j.jaut.2023.103127","DOIUrl":"10.1016/j.jaut.2023.103127","url":null,"abstract":"<div><div>Several epidemiological studies show a co-occurrence of sarcoidosis with other immune-mediated diseases (IMD). There are many similarities between sarcoidosis and IMDs in their geographical distribution and risk factors. Understanding these similarities and identifying the differences can help us to better understand sarcoidosis and put it into context with other IMDs. In this review, we present the current knowledge about the overlap between sarcoidosis and other IMDs derived from epidemiological studies. Epidemiologic methods utilize study design and statistical analysis to describe the patterns in data and, ideally, identify causal relationships between an exposure and a health outcome. We discuss how study design and analysis may affect the interpretation of epidemiological studies on this topic and highlight some theories that attempt to explain the relation between sarcoidosis and other IMDs.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103127"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41202114","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":"Application of laboratory models for sarcoidosis research","authors":"Maneesh Bhargava ,&nbsp;Elliott D. Crouser","doi":"10.1016/j.jaut.2024.103184","DOIUrl":"10.1016/j.jaut.2024.103184","url":null,"abstract":"<div><div>This manuscript will review the implications and applications of sarcoidosis models towards advancing our understanding of sarcoidosis disease mechanisms, identification of biomarkers, and preclinical testing of novel therapies. Emerging disease models and innovative research tools will also be considered.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103184"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140039492","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":"Developmental drugs for sarcoidosis","authors":"Ogugua Ndili Obi ,&nbsp;Lesley Ann Saketkoo ,&nbsp;Lisa A. Maier ,&nbsp;Robert P. Baughman","doi":"10.1016/j.jaut.2024.103179","DOIUrl":"10.1016/j.jaut.2024.103179","url":null,"abstract":"<div><div><span>Sarcoidosis<span> is a multi-organ granulomatous </span></span>inflammatory disease<span> of unknown etiology. Over 50% of patients will require treatment at some point in their disease and 10%–30% will develop a chronic progressive disease with pulmonary fibrosis leading to significant morbidity and mortality.</span></div><div><span>Recently published guidelines recommend immunosuppressive therapy for sarcoidosis patients at risk of increased disease-related morbidity and mortality, and in whom disease has negatively impacted quality of life. </span>Prednisone the currently recommended first line therapy is associated with significant toxicity however none of the other guideline recommended steroid sparing therapy is approved by regulatory agencies for use in sarcoidosis, and data in support of their use is weak. For patients with severe refractory disease requiring prolonged therapy, treatment options are limited.</div><div>The need for expanding treatment options in sarcoidosis has been emphasized. Well conducted large, randomized trials evaluating currently available therapeutic options as well as novel pathways for targeting disease are necessary to better guide treatment decisions. These trials will not be without significant challenges. Sarcoidosis is a rare disease<span> with heterogenous presentation and variable progression and clinical outcome. There are no universally agreed upon biomarkers of disease activity and measurement of outcomes is confounded by the need to balance patient centric measures and objective measures of disease activity.</span></div><div>Our paper provides an update on developmental drugs in sarcoidosis and outlines several novel pathways that may be targeted for future drug development<span>. Currently available trials are highlighted and ongoing challenges to drug development and clinical trial design are briefly discussed.</span></div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103179"},"PeriodicalIF":7.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140318366","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":"PD-1 antibody interactions with Fc gamma receptors enable PD-1 agonism to inhibit T cell activation – therapeutic implications for autoimmunity","authors":"Yiqing Feng ,&nbsp;Gordafaried Deyanat-Yazdi ,&nbsp;Kristin Newburn ,&nbsp;Scott Potter ,&nbsp;Mark Wortinger ,&nbsp;Miriam Ramirez ,&nbsp;Stephanie M.E. Truhlar ,&nbsp;Pia P. Yachi","doi":"10.1016/j.jaut.2024.103339","DOIUrl":"10.1016/j.jaut.2024.103339","url":null,"abstract":"<div><div>PD-1 has emerged as a central inhibitory checkpoint receptor in maintaining immune homeostasis and as a target in cancer immunotherapies. However, targeting PD-1 for the treatment of autoimmune diseases has been more challenging. We recently showed in a phase 2a trial that PD-1 could be stimulated with the PD-1 agonist antibody peresolimab to treat rheumatoid arthritis. Here, we demonstrate that PD-1 antibodies can elicit agonism and inhibit T cell activation by co-localization of PD-1 with the T cell receptor via Fcγ receptor (FcγR) engagement. Three PD-1 agonist antibodies with different antigen binding domains, including the clinically validated PD-1 blocking antibody pembrolizumab, suppressed T cell activation to a similar degree; this finding suggests that a specific PD-1-binding epitope is not required for PD-1 agonism. We next explored whether antibody-mediated clustering was an important driver of inhibition of T cell activation; however, we found that a monovalent PD-1 antibody was not inferior to a conventional bivalent antibody in its ability to suppress T cell activation. Importantly, we found that affinity to PD-1 correlated positively with inhibition of T cell activation, with higher affinity antibodies exhibiting higher levels of inhibition. Using a series of human Fc mutants with altered affinities to various FcγRs, we dissected the contributions of FcγRs and found that multiple FcγRs rather than a single receptor contribute to agonist activity. Our work reveals an important role for FcγR binding in the activity of PD-1 antibodies, which has implications for optimizing both PD-1 agonist and antagonist antibodies.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103339"},"PeriodicalIF":7.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142721420","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":"Sunscreen use associated with elevated prevalence of anti-nuclear antibodies in U.S. adults","authors":"Christine G. Parks ,&nbsp;Todd A. Jusko ,&nbsp;Helen C.S. Meier ,&nbsp;Jesse Wilkerson ,&nbsp;Lisa G. Rider ,&nbsp;Frederick W. Miller ,&nbsp;Dale P. Sandler","doi":"10.1016/j.jaut.2024.103340","DOIUrl":"10.1016/j.jaut.2024.103340","url":null,"abstract":"<div><h3>Background</h3><div>Antinuclear antibody (ANA) prevalence in the U.S. population increased from 1988 to 2012, especially in white and more educated individuals. In adults ages 20–39 years from the National Health and Nutrition Examination Survey (NHANES) 2003–2004 and 2011–2012, ANA prevalence was previously associated with urinary concentrations of a common sunscreen ingredient, benzophenone 3, measured in winter. Spot urines may not capture relevant chronic exposures, thus we examined whether ANA was related to sunscreen use.</div></div><div><h3>Methods</h3><div>In a cross-sectional study of adults ages 20–59 (N = 416 ANA positive, 2656 ANA negative, by Hep-2 immunofluorescence, 1:80 dilution), we examined associations of ANA with reported sunscreen use when in the sun for 1 h or more. Logistic regression was used to calculate covariate-adjusted prevalence odds ratios (POR) and 95 % Confidence Intervals (CI), overall and stratified by demographic factors, season, and vitamin D. We explored associations and joint effects with other sun protective behaviors and sunburn in the past 12 months.</div></div><div><h3>Results</h3><div>The association of ANA with sunscreen differed by age (interaction p = 0.004): for ages 20–39, we saw an exposure response (POR 2.61, 95 % CI 1.50, 4.24 for using sunscreen always or most of the time, and POR 1.85; 1.12, 3.05 for less frequent versus never-use; trend p &lt; 0.001). These associations were more apparent in females (interaction p = 0.082), non-Hispanic white and black participants (vs. other race/ethnicity, interaction p = 0.023), and those with sufficient serum vitamin D (≥50 vs. &lt;50 nmol/L, interaction p = 0.001). ANA was not associated with other protective behaviors and not confounded or modified by these behaviors or recent sunburn.</div></div><div><h3>Conclusions</h3><div>These cross-sectional findings showed frequent sunscreen was associated with ANA in younger adults, supporting the need for replication, and longitudinal studies with detailed exposure histories.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103340"},"PeriodicalIF":7.9,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142697349","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":"EZH2 promotes B-cell autoimmunity in primary Sjogren's syndrome via METTL3-mediated m6A modification","authors":"Yiying Yang ,&nbsp;Muyuan Li ,&nbsp;Liqing Ding ,&nbsp;Ying Zhang ,&nbsp;Ke Liu ,&nbsp;Meidong Liu ,&nbsp;Yisha Li ,&nbsp;Hui Luo ,&nbsp;Xiaoxia Zuo ,&nbsp;Huali Zhang ,&nbsp;Muyao Guo","doi":"10.1016/j.jaut.2024.103341","DOIUrl":"10.1016/j.jaut.2024.103341","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Objective&lt;/h3&gt;&lt;div&gt;Enhancer of zeste homologue 2 (EZH2) plays an important role in promoting B-cell activation and differentiation. This study aimed to elucidate the role of EZH2 in the B-cell autoimmune response in primary Sjögren's syndrome (pSS) and to explore the therapeutic potential of inhibiting EZH2 in pSS.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;Single-cell RNA sequencing analysis of B cells in peripheral blood from pSS patients was conducted to identify abnormal expression of EZH2 and METTL3 in B-cell subsets. The levels of EZH2 were further validated across multiple B-cell subsets and the salivary glands (SGs) of pSS patients, as well as three different mouse models of Sjögren's syndrome (SS). Correlation analyses were performed to explore the relationship between the expression of EZH2 and clinical features of pSS patients. Following EZH2 inhibition, SS-like signs and antibody production were assessed in an experimental Sjögren syndrome (ESS) mouse model. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) data post-EZH2 inhibition were bioinformatically analyzed to identify the EZH2 targets in pSS. ChIP-qPCR was performed to validate the binding of H3K27me3 to the &lt;em&gt;CDKN1A&lt;/em&gt; promoter. Flow cytometric apoptosis analysis and Carboxy Fluorescein Succinimidyl Ester (CFSE) assay were used to assess the impact of an EZH2 inhibitor on B-cell apoptosis and proliferation. Additionally, METTL3 expression and its correlation with disease activity were analyzed in pSS patients. EZH2 expression was examined after METTL3 knockdown. METTL3-RNA immunoprecipitation (RIP) and actinomycin D assays were conducted to confirm the direct binding of METTL3 to EZH2 mRNA and its impact on mRNA stability. M6A-RIP-qPCR was performed to validate the presence of m6A modifications on &lt;em&gt;EZH2&lt;/em&gt; mRNA.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;EZH2 was found upregulated in multiple B-cell subsets from the peripheral blood and SGs of pSS patients, as well as in three different animal models of SS. The expression of EZH2 in B cells was positively correlated with the ESSDAI score, which is a measure of disease activity. With treatment of EZH2 inhibitor, SS-like signs alleviated and autoantibody production reduced in ESS mice. Similarly, in pSS patients, METTL3 expression was increased in the SGs and peripheral blood CD19&lt;sup&gt;+&lt;/sup&gt; B cells, also showing a positively correlated with the ESSDAI score. With knockdown of &lt;em&gt;METTL3&lt;/em&gt;, the expression of EZH2 reduced. Mechanistically, EZH2 inhibited B-cell apoptosis and promoted B-cell proliferation by catalyzing H3K27me3 modification at the &lt;em&gt;CDKN1A&lt;/em&gt; locus. Furthermore, METTL3 bound to &lt;em&gt;EZH2&lt;/em&gt; mRNA and increased m6A modification on &lt;em&gt;EZH2&lt;/em&gt; mRNA, enhancing its stability and promoting EZH2 expression.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;The upregulation of EZH2 mediated by METTL3 is implicated in the B-cell autoimmune response in pSS. Inhibition of EZH2 presents","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103341"},"PeriodicalIF":7.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692953","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":"Bulk T cell repertoire sequencing (TCR-Seq) is a powerful technology for understanding inflammation-mediated diseases","authors":"Aya K.H. Mahdy,&nbsp;Evgeniya Lokes,&nbsp;Valentina Schöpfel,&nbsp;Valeriia Kriukova,&nbsp;Olga V. Britanova,&nbsp;Tim A. Steiert,&nbsp;Andre Franke,&nbsp;Hesham ElAbd","doi":"10.1016/j.jaut.2024.103337","DOIUrl":"10.1016/j.jaut.2024.103337","url":null,"abstract":"<div><div>Multiple alterations in the T cell repertoire were identified in many chronic inflammatory diseases such as inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis, suggesting that T cells might, directly or indirectly, be implicated in these pathologies. This has sparked a deep interest in characterizing disease-associated T cell clonotypes as well as in identifying and quantifying their contribution to the pathophysiology of different autoimmune and inflammation-mediated diseases. Bulk T cell repertoire sequencing (TCR-Seq) has emerged as a powerful method to profile the T cell repertoire of a sample in a high throughput fashion. Given the increasing utilization of TCR-Seq, we aimed here to provide a comprehensive, up-to-date review of the method, its extensions, and its ability to investigate chronic and autoimmune diseases. Specifically, we started by introducing the immunological basis of TCR repertoire generation and features, followed by discussing different experimental approach to perform TCR-Seq, then we describe different methods and frameworks for analyzing the generated datasets. Subsequently, different experimental techniques for investigating the antigenicity of T cell clonotypes are described. Lastly, we discuss recent studies that utilized TCR-Seq to understand different inflammation-mediated diseases, discuss fallbacks of the technology and potential future directions to overcome current limitations.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103337"},"PeriodicalIF":7.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687217","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":"Autoantibodies against a subunit of mitochondrial respiratory chain complex I in inclusion body myositis","authors":"Antonella Notarnicola ,&nbsp;Ceke Hellstrom ,&nbsp;Begum Horuluoglu ,&nbsp;Elisa Pin ,&nbsp;Charlotta Preger ,&nbsp;Francesco Bonomi ,&nbsp;Boel De Paepe ,&nbsp;Jan L. De Bleecker ,&nbsp;Anneke J. Van der Kooi ,&nbsp;Marianne De Visser ,&nbsp;Sabrina Sacconi ,&nbsp;Pedro Machado ,&nbsp;Umesh A. Badrising ,&nbsp;Anke Rietveld ,&nbsp;Ger Pruijn ,&nbsp;Simon Rothwell ,&nbsp;James B. Lilleker ,&nbsp;Hector Chinoy ,&nbsp;Olivier Benveniste ,&nbsp;Elisabet Svenungsson ,&nbsp;Ingrid E. Lundberg","doi":"10.1016/j.jaut.2024.103332","DOIUrl":"10.1016/j.jaut.2024.103332","url":null,"abstract":"<div><h3>Background</h3><div>Autoantibodies are found in up to 80 % of patients with idiopathic inflammatory myopathies (IIM) and are associated with distinct clinical phenotypes. Autoantibodies targeting cytosolic 5′-nucleotidase 1A (anti-NT5C1A) are currently the only known serum biomarker for the subgroup inclusion body myositis (IBM), although detected even in other autoimmune diseases. The aim of the study was to identify new autoimmune targets in IIM.</div></div><div><h3>Methods</h3><div>In a first cross-sectional exploratory study, samples from 219 IIM (108 Polymyositis (PM), 80 Dermatomyositis (DM) and 31 IBM) patients, 349 Systemic Lupus Erythematosus (SLE) patients and 306 population controls were screened for IgG reactivity against a panel of 357 proteins using an antigen bead array. All samples were identified in the local biobank of the Rheumatology clinic, Karolinska University Hospital. Positive hits for the IBM subgroup were then validated in an independent larger cohort of 287 patients with IBM followed at nine European rheumatological or neurological centers. IBM serum samples were explored by antigen bead array and results validated by Western blot. As controls, sera from 29 patients with PM and 30 with DM, HLA-matched with the Swedish IBM cohort, were included. Demographics, laboratory, clinical, and muscle biopsy data of the IBM cohort was retrieved.</div></div><div><h3>Results</h3><div>In the exploratory study, IgG reactivity towards NADH dehydrogenase 1 α subcomplex 11 (NDUFA11), a subunit of the membrane-bound mitochondrial respiratory chain complex I, was discovered with higher frequency in the IBM (9.7 %) than PM (2.8 %) and DM samples (1.3 %), although the difference was not statistically significant. Anti-NDUFA11 IgG was also found in 1.4 % of SLE and 2.0 % of population control samples. In the validation study, anti-NDUFA11 autoantibodies were detected in 10/287 IBM patients (3.5 %), 0/29 p.m. and 0/30 DM patients. Reactivity against NDUFA11 could be confirmed by Western blot. No statistically significant differences were found between patients with and without anti-NDUFA11 antibodies when comparing clinical, laboratory and histological data. However, we observed a trend of higher frequency of distal lower extremity muscle weakness, ragged red fibers and higher CK levels at time of diagnosis in the anti-NDUFA11 positive group. Co-existence of anti-NDUFA11 and anti-NT5C1A antibodies was not observed in any IBM patient.</div></div><div><h3>Conclusion</h3><div>Our results reveal a new autoimmune target in the mitochondrial respiratory chain complex I that might be specifically associated with IBM. This is of particular interest as mitochondrial abnormalities are known histological findings in muscle biopsies of IBM patients.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103332"},"PeriodicalIF":7.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675894","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":"Wiskott–Aldrich syndrome protein maintains regulatory T cell tolerance by modulating their surface IL-2 receptor levels","authors":"Qin Zhao ,&nbsp;Wenhui Li ,&nbsp;Wenyan Li ,&nbsp;Yang Lu ,&nbsp;Ting zeng ,&nbsp;Wenjing Zhang ,&nbsp;Min Zhang ,&nbsp;Lina Zhou ,&nbsp;Yunfei An ,&nbsp;Wenxia Song ,&nbsp;Zhou Shu ,&nbsp;Xiaodong Zhao","doi":"10.1016/j.jaut.2024.103336","DOIUrl":"10.1016/j.jaut.2024.103336","url":null,"abstract":"<div><div>Wiskott–Aldrich syndrome (WAS) is an X-linked immunodeficiency condition caused by ablation of functional WAS protein (WASP) expression, and associated with susceptibility to infections, eczema, and autoimmunity. Regulatory T cell (Treg) defects are an important cause of autoimmunity in WAS. Currently, the mechanisms underlying cytoskeleton involvement in Treg-regulated autoimmunity remain unclear, and WAS is an excellent model for investigation of this question. Here, we examined patients with WAS and WASP knockout (WASp^−/−) mice to uncover a new mechanism involving the actin nucleation promoting factor, WASP, in regulating Treg tolerance by modulating their surface IL-2 receptor (IL-2R) levels. Surface expression levels of IL-2R and its downstream signaling molecules, phosphoinositide 3-kinase/pSTAT5, are decreased in WASp^−/− Tregs. Low dosage IL-2 combined with anti-IL-2 monoclonal antibody (IL2 complex) treatment can compensate for Treg deficiency in WAS in vitro and in vivo. Moreover, IL2 complex treatment relieved autoimmune colitis in WASp^−/− mice. Reduced surface IL-2R is primarily caused by elevated IL-2R internalization and degradation, and lysosomal and endosomal genes associated with these processes are upregulated in WASp^−/− Tregs. Finally, spatiotemporal analysis of dynamin and Neural Wiskott Aldrich Syndrome Protein (N-WASP) recruitment, by generating lipid bilayers and total internal reflection fluorescence microscopy, showed that WASP deficiency promoted IL-2R internalization and degradation by enhancing N-WASP activation. Consistently, N-WASP inhibition in Tregs using wiskostatin reduced IL-2R internalization. Together, our results reveal a novel intrinsic role of WASP in regulation of surface IL-2R dynamics in Tregs, highlighting a potential new therapeutic approach for autoimmune diseases.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103336"},"PeriodicalIF":7.9,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644342","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}