Objective: 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.
Methods: 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 CDKN1A 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 EZH2 mRNA.
Results: 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+ B cells, also showing a positively correlated with the ESSDAI score. With knockdown of METTL3, the expression of EZH2 reduced. Mechanistically, EZH2 inhibited B-cell apoptosis and promoted B-cell proliferation by catalyzing H3K27me3 modification at the CDKN1A locus. Furthermore, METTL3 bound to EZH2 mRNA and increased m6A modification on EZH2 mRNA, enhancing its stability and promoting EZH2 expression.
Conclusions: The upregulation of EZH2 mediated by METTL3 is implicated in the B-cell autoimmune response in pSS. Inhibition of EZH2 presents a promising therapeutic strategy for pSS treatment.
{"title":"EZH2 promotes B-cell autoimmunity in primary Sjogren's syndrome via METTL3-mediated m6A modification.","authors":"Yiying Yang, Muyuan Li, Liqing Ding, Ying Zhang, Ke Liu, Meidong Liu, Yisha Li, Hui Luo, Xiaoxia Zuo, Huali Zhang, Muyao Guo","doi":"10.1016/j.jaut.2024.103341","DOIUrl":"https://doi.org/10.1016/j.jaut.2024.103341","url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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 CDKN1A 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 EZH2 mRNA.</p><p><strong>Results: </strong>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<sup>+</sup> B cells, also showing a positively correlated with the ESSDAI score. With knockdown of METTL3, the expression of EZH2 reduced. Mechanistically, EZH2 inhibited B-cell apoptosis and promoted B-cell proliferation by catalyzing H3K27me3 modification at the CDKN1A locus. Furthermore, METTL3 bound to EZH2 mRNA and increased m6A modification on EZH2 mRNA, enhancing its stability and promoting EZH2 expression.</p><p><strong>Conclusions: </strong>The upregulation of EZH2 mediated by METTL3 is implicated in the B-cell autoimmune response in pSS. Inhibition of EZH2 presents a promising therapeutic strategy for pSS treatment.</p>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"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}
Pub Date : 2024-11-20DOI: 10.1016/j.jaut.2024.103337
Aya K H Mahdy, Evgeniya Lokes, Valentina Schöpfel, Valeriia Kriukova, Olga V Britanova, Tim A Steiert, Andre Franke, Hesham ElAbd
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.
在许多慢性炎症性疾病（如炎症性肠病、多发性硬化症和类风湿性关节炎）中发现了 T 细胞群的多种变化，这表明 T 细胞可能直接或间接地与这些病症有关。这引发了人们对疾病相关 T 细胞克隆型特征的深入研究，以及对确定和量化它们对不同自身免疫和炎症介导疾病的病理生理学的贡献的浓厚兴趣。批量 T 细胞谱系测序（TCR-Seq）已成为以高通量方式剖析样本 T 细胞谱系的有力方法。鉴于 TCR-Seq 的应用日益广泛，我们在此旨在对该方法、其扩展及其研究慢性病和自身免疫性疾病的能力进行全面、最新的综述。具体来说，我们首先介绍了 TCR 队列生成和特征的免疫学基础，然后讨论了进行 TCR-Seq 的不同实验方法，接着介绍了分析生成数据集的不同方法和框架。随后，我们介绍了研究 T 细胞克隆型抗原性的不同实验技术。最后，我们讨论了近期利用 TCR-Seq 了解不同炎症介导疾病的研究，讨论了该技术的不足之处以及克服当前局限性的潜在未来方向。
{"title":"Bulk T cell repertoire sequencing (TCR-Seq) is a powerful technology for understanding inflammation-mediated diseases.","authors":"Aya K H Mahdy, Evgeniya Lokes, Valentina Schöpfel, Valeriia Kriukova, Olga V Britanova, Tim A Steiert, Andre Franke, Hesham ElAbd","doi":"10.1016/j.jaut.2024.103337","DOIUrl":"https://doi.org/10.1016/j.jaut.2024.103337","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-18DOI: 10.1016/j.jaut.2024.103332
Antonella Notarnicola, Ceke Hellstrom, Begum Horuluoglu, Elisa Pin, Charlotta Preger, Francesco Bonomi, Boel De Paepe, Jan L De Bleecker, Anneke J Van der Kooi, Marianne De Visser, Sabrina Sacconi, Pedro Machado, Umesh A Badrising, Anke Rietveld, Ger Pruijn, Simon Rothwell, James B Lilleker, Hector Chinoy, Olivier Benveniste, Elisabet Svenungsson, Helena Idborg, Per-Johan Jakobsson, Peter Nilsson, Ingrid E Lundberg
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
背景：多达80%的特发性炎症性肌病（IIM）患者体内存在自身抗体，而且这些抗体与不同的临床表型有关。针对细胞膜5'-核苷酸酶1A（抗NT5C1A）的自身抗体是目前唯一已知的包涵体肌炎（IBM）亚组的血清生物标志物，尽管在其他自身免疫性疾病中也能检测到。本研究旨在确定包涵体肌炎的新自身免疫靶标：在首次横断面探索性研究中，使用抗原珠阵列对 219 名 IIM（108 名多发性肌炎 (PM)、80 名皮肌炎 (DM) 和 31 名 IBM）患者、349 名系统性红斑狼疮 (SLE) 患者和 306 名人群对照的样本进行了筛查，以检测针对 357 种蛋白质的 IgG 反应性。所有样本都在卡罗林斯卡大学医院风湿病诊所的本地生物库中进行了鉴定。随后，在九个欧洲风湿病学或神经学中心随访的 287 名 IBM 患者组成的独立大型队列中对 IBM 亚组的阳性结果进行了验证。通过抗原珠阵列检测了 IBM 血清样本，并通过 Western 印迹验证了结果。作为对照组，29 名 PM 患者和 30 名 DM 患者的血清与瑞典 IBM 患者的 HLA 相匹配。研究人员还检索了 IBM 队列的人口统计学、实验室、临床和肌肉活检数据：在探索性研究中发现，IBM样本（9.7%）对NADH脱氢酶1 α亚复合物11（NDUFA11）（一种膜结合线粒体呼吸链复合物I的亚基）的IgG反应频率高于PM样本（2.8%）和DM样本（1.3%），但差异无统计学意义。在 1.4% 的系统性红斑狼疮样本和 2.0% 的人群对照样本中也发现了抗 NDUFA11 IgG。在验证研究中，有10/287名IBM患者（3.5%）、0/29名p.m.患者和0/30名DM患者检测到抗NDUFA11自身抗体。对 NDUFA11 的反应性可通过 Western 印迹得到证实。在比较临床、实验室和组织学数据时，未发现有抗NDUFA11抗体和无抗NDUFA11抗体的患者之间存在明显的统计学差异。不过，我们观察到抗-NDUFA11抗体阳性组患者在确诊时出现下肢远端肌无力、红色纤维褴褛和CK水平升高的频率较高。在所有 IBM 患者中均未观察到抗 NDUFA11 和抗 NT5C1A 抗体同时存在：我们的研究结果揭示了线粒体呼吸链复合物 I 中的一个新的自身免疫靶点，该靶点可能与 IBM 特别相关。结论：我们的研究结果揭示了线粒体呼吸链复合物 I 中新的自身免疫靶点，它可能与 IBM 特别相关，因为线粒体异常是 IBM 患者肌肉活检的已知组织学发现。
{"title":"Autoantibodies against a subunit of mitochondrial respiratory chain complex I in inclusion body myositis.","authors":"Antonella Notarnicola, Ceke Hellstrom, Begum Horuluoglu, Elisa Pin, Charlotta Preger, Francesco Bonomi, Boel De Paepe, Jan L De Bleecker, Anneke J Van der Kooi, Marianne De Visser, Sabrina Sacconi, Pedro Machado, Umesh A Badrising, Anke Rietveld, Ger Pruijn, Simon Rothwell, James B Lilleker, Hector Chinoy, Olivier Benveniste, Elisabet Svenungsson, Helena Idborg, Per-Johan Jakobsson, Peter Nilsson, Ingrid E Lundberg","doi":"10.1016/j.jaut.2024.103332","DOIUrl":"https://doi.org/10.1016/j.jaut.2024.103332","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"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}
Pub Date : 2024-11-16DOI: 10.1016/j.jaut.2024.103336
Qin Zhao , Wenhui Li , Wenyan Li , Yang Lu , Ting zeng , Wenjing Zhang , Min Zhang , Lina Zhou , Yunfei An , Wenxia Song , Zhou Shu , Xiaodong Zhao
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.
威斯科特-阿尔德里奇综合征（WAS）是一种 X 连锁免疫缺陷病，由功能性 WAS 蛋白（WASP）表达消减引起，与易感染、湿疹和自身免疫有关。调节性 T 细胞（Treg）缺陷是导致 WAS 自身免疫的一个重要原因。目前，细胞骨架参与调节性 Treg 自身免疫的机制仍不清楚，而 WAS 是研究这一问题的绝佳模型。在此，我们研究了WAS患者和WASP基因敲除（WASp-/-）小鼠，以揭示肌动蛋白成核促进因子WASP通过调节Treg表面IL-2受体（IL-2R）水平来调节Treg耐受性的新机制。WASp-/-Tregs的IL-2R及其下游信号分子磷脂肌醇3-激酶/pSTAT5的表面表达水平降低。低剂量IL-2联合抗IL-2单克隆抗体（IL2复合物）治疗可在体外和体内弥补WAS中Treg的不足。此外，IL2复合物治疗可缓解WASp-/-小鼠的自身免疫性结肠炎。表面IL-2R的减少主要是由于IL-2R内化和降解的升高造成的，与这些过程相关的溶酶体和内体基因在WASp-/-Tregs中上调。最后，通过生成脂质双层膜和全内反射荧光显微镜对达因明和神经维斯科特-奥尔德里奇综合征蛋白（N-WASP）招募的时空分析表明，WASP 缺乏通过增强 N-WASP 的活化促进了 IL-2R 的内化和降解。同样，使用威司他丁抑制Tregs中的N-WASP也会减少IL-2R的内化。总之，我们的研究结果揭示了 WASP 在调节 Tregs 表面 IL-2R 动态过程中的一种新的内在作用，为自身免疫性疾病的治疗提供了一种潜在的新方法。
{"title":"Wiskott–Aldrich syndrome protein maintains regulatory T cell tolerance by modulating their surface IL-2 receptor levels","authors":"Qin Zhao , Wenhui Li , Wenyan Li , Yang Lu , Ting zeng , Wenjing Zhang , Min Zhang , Lina Zhou , Yunfei An , Wenxia Song , Zhou Shu , 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<sup>−/−</sup>) 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<sup>−/−</sup> 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<sup>−/−</sup> 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<sup>−/−</sup> 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}
Rheumatoid arthritis (RA) is a chronic systemic and autoimmune disease that primarily affects joints and causes pain, stiffness and swelling. The affected joints exhibit severe inflammation in the synovium and bone erosion, leading to joint deformity. Aging is an important factor facilitating the development of RA, as it is associated with an increase in the number of senescent cells and the production of the autoantibodies and proinflammatory cytokines in tissues. Given that CCN3 is highly expressed in RA joints and that its level is associated with the severity of the disease, we explored its molecular function in joints and therapeutic potential in RA. An analysis of public scRNA-seq data from the RA synovium revealed that CCN3 is expressed by an inflammatory fibroblast subset. Interestingly, stimulation with CCN3 resulted in the activation of the senescence pathway in synoviocytes and osteoclast differentiation in monocytes in vitro. Consistent with these results, the administration of CCN3 into the knee joint and onto the calvarial bone resulted in increased numbers of senescent synoviocytes in the joint and osteoclasts in the bone, respectively. Furthermore, the therapeutic potential of targeting CCN3 was evaluated in an experimental RA model. Administration of the CCN3 antibody significantly suppressed inflammation and osteoclast numbers in the joints of the RA model mice. Our findings suggest that CCN3 contributes to pathological processes in RA and represents a promising therapeutic target for the treatment of RA.
类风湿性关节炎（RA）是一种慢性全身性自身免疫性疾病，主要影响关节并导致疼痛、僵硬和肿胀。受影响的关节会出现严重的滑膜炎症和骨侵蚀，导致关节变形。衰老是诱发 RA 的一个重要因素，因为衰老与衰老细胞数量的增加以及组织中自身抗体和促炎细胞因子的产生有关。鉴于CCN3在RA关节中高表达，且其水平与疾病的严重程度相关，我们探讨了它在关节中的分子功能以及在RA中的治疗潜力。对来自 RA 滑膜的公开 scRNA-seq 数据的分析表明，CCN3 在炎性成纤维细胞亚群中表达。有趣的是，CCN3 的刺激会激活滑膜细胞的衰老途径和体外单核细胞的破骨细胞分化。与这些结果一致的是，将 CCN3 植入膝关节和腓骨后，关节中的衰老滑膜细胞和骨中的破骨细胞数量分别增加。此外，还在实验性 RA 模型中评估了靶向 CCN3 的治疗潜力。服用CCN3抗体能明显抑制关节炎模型小鼠关节中的炎症和破骨细胞数量。我们的研究结果表明，CCN3参与了RA的病理过程，是治疗RA的一个很有前景的靶点。
{"title":"Cellular communication network factor 3 contributes to the pathological process of rheumatoid arthritis through promoting cell senescence and osteoclastogenesis in the joint","authors":"Taiki Tokuhiro, Gen Matsumae, Tsutomu Endo, Yuki Ogawa, Takuya Ogawa, Chen Liyile, Yoshio Nishida, Hend Alhasan, Hideyuki Kobayashi, Taku Ebata, Tomohiro Shimizu, Daisuke Takahashi, Tomohiro Onodera, Ken Kadoya, M Alaa Terkawi, Norimasa Iwasaki","doi":"10.1016/j.jaut.2024.103334","DOIUrl":"10.1016/j.jaut.2024.103334","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is a chronic systemic and autoimmune disease that primarily affects joints and causes pain, stiffness and swelling. The affected joints exhibit severe inflammation in the synovium and bone erosion, leading to joint deformity. Aging is an important factor facilitating the development of RA, as it is associated with an increase in the number of senescent cells and the production of the autoantibodies and proinflammatory cytokines in tissues. Given that CCN3 is highly expressed in RA joints and that its level is associated with the severity of the disease, we explored its molecular function in joints and therapeutic potential in RA. An analysis of public scRNA-seq data from the RA synovium revealed that CCN3 is expressed by an inflammatory fibroblast subset. Interestingly, stimulation with CCN3 resulted in the activation of the senescence pathway in synoviocytes and osteoclast differentiation in monocytes in vitro. Consistent with these results, the administration of CCN3 into the knee joint and onto the calvarial bone resulted in increased numbers of senescent synoviocytes in the joint and osteoclasts in the bone, respectively. Furthermore, the therapeutic potential of targeting CCN3 was evaluated in an experimental RA model. Administration of the CCN3 antibody significantly suppressed inflammation and osteoclast numbers in the joints of the RA model mice. Our findings suggest that CCN3 contributes to pathological processes in RA and represents a promising therapeutic target for the treatment of RA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103334"},"PeriodicalIF":7.9,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644332","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 : 2024-11-16DOI: 10.1016/j.jaut.2024.103338
Boris Sorin , Matthias Papo , Renato A. Sinico , Vítor Silvestre Teixeira , Nils Venhoff , Maria-Letizia Urban , Michele Iudici , Juliane Mahrhold , Francesco Locatelli , Giulia Cassone , Franco Schiavon , Benjamin Seeliger , Thomas Neumann , Claudia Feder , Claus Kroegel , Matthieu Groh , Chiara Marvisi , Maxime Samson , Thomas Barba , David Jayne , Benjamin Terrier
Objectives
Current guidelines suggest treating poor-prognosis eosinophilic granulomatosis with polyangiitis (EGPA) with a combination of glucocorticoids (GCs) plus cyclophosphamide (CYC). However, there is little data to support the need for the addition of CYC. The objective of this study was to compare GCs plus CYC to GCs alone as induction therapy in poor-prognosis EGPA.
Methods
We emulated a target trial using observational data from a European multicenter retrospective database. We included patients with newly diagnosed EGPA with a 1996 Five Factor Score (FFS) of at least 1, treated with GCs or GCs plus CYC between June 1985 and November 2018. Propensity score analysis was used to adjust for potential confounders. Primary outcome was relapse at 12months. Secondary outcomes included major relapse at 12months and GC-dependent asthma and/or ear nose and throat (ENT) manifestations at 24months.
Results
A total of 209 patients were included: 47 % were male and the mean age at diagnosis was 52 (±16 years); 26 % were treated with GCs alone and 74 % with GCs plus CYC. After adjustment, the risk of relapse (hazard ratio [HR]: 0.24, 95%CI [0.08–0.67], p = 0.007), major relapse (HR: 0.24, 95%CI [0.07–0.85], p = 0.026) and the proportion of GC-dependent asthma and/or ENT manifestations (odds ratio:0.30, 95%CI [0.14–0.66], p = 0.003) were lower in the GCs plus CYC group compared to the GCs alone group.
Conclusion
This target trial emulation study shows that the addition of CYC to GCs reduces the risk of vasculitis relapse and the rate of GC-dependent asthma and/or ENT manifestations in patients with poor-prognosis EGPA.
{"title":"Glucocorticoids versus glucocorticoids plus cyclophosphamide in eosinophilic granulomatosis with polyangiitis with poor-prognosis factors","authors":"Boris Sorin , Matthias Papo , Renato A. Sinico , Vítor Silvestre Teixeira , Nils Venhoff , Maria-Letizia Urban , Michele Iudici , Juliane Mahrhold , Francesco Locatelli , Giulia Cassone , Franco Schiavon , Benjamin Seeliger , Thomas Neumann , Claudia Feder , Claus Kroegel , Matthieu Groh , Chiara Marvisi , Maxime Samson , Thomas Barba , David Jayne , Benjamin Terrier","doi":"10.1016/j.jaut.2024.103338","DOIUrl":"10.1016/j.jaut.2024.103338","url":null,"abstract":"<div><h3>Objectives</h3><div>Current guidelines suggest treating poor-prognosis eosinophilic granulomatosis with polyangiitis (EGPA) with a combination of glucocorticoids (GCs) plus cyclophosphamide (CYC). However, there is little data to support the need for the addition of CYC. The objective of this study was to compare GCs plus CYC to GCs alone as induction therapy in poor-prognosis EGPA.</div></div><div><h3>Methods</h3><div>We emulated a target trial using observational data from a European multicenter retrospective database. We included patients with newly diagnosed EGPA with a 1996 Five Factor Score (FFS) of at least 1, treated with GCs or GCs plus CYC between June 1985 and November 2018. Propensity score analysis was used to adjust for potential confounders. Primary outcome was relapse at 12months. Secondary outcomes included major relapse at 12months and GC-dependent asthma and/or ear nose and throat (ENT) manifestations at 24months.</div></div><div><h3>Results</h3><div>A total of 209 patients were included: 47 % were male and the mean age at diagnosis was 52 (±16 years); 26 % were treated with GCs alone and 74 % with GCs plus CYC. After adjustment, the risk of relapse (hazard ratio [HR]: 0.24, 95%CI [0.08–0.67], p = 0.007), major relapse (HR: 0.24, 95%CI [0.07–0.85], p = 0.026) and the proportion of GC-dependent asthma and/or ENT manifestations (odds ratio:0.30, 95%CI [0.14–0.66], p = 0.003) were lower in the GCs plus CYC group compared to the GCs alone group.</div></div><div><h3>Conclusion</h3><div>This target trial emulation study shows that the addition of CYC to GCs reduces the risk of vasculitis relapse and the rate of GC-dependent asthma and/or ENT manifestations in patients with poor-prognosis EGPA.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103338"},"PeriodicalIF":7.9,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644334","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 : 2024-11-15DOI: 10.1016/j.jaut.2024.103335
Cansu Yanginlar , Nils Rother , Tomas G.J.M. Post , Maaike Jacobs , Inge Jonkman , Montsy Brouns , Sybren Rinzema , Joost H.A. Martens , Michiel Vermeulen , Leo A.B. Joosten , Mihai G. Netea , Luuk B. Hilbrands , Zaheeb A. Choudhry , Johan van der Vlag , Raphaël Duivenvoorden
Systemic lupus erythematosus (SLE) is an autoimmune disease directed against nuclear antigens, including those derived from apoptotic microparticles (MPs) and neutrophil extracellular traps (NETs). Here we investigated whether nuclear autoantigens can induce trained immunity in SLE patients. Trained immunity is a de facto innate immune memory elicited by an initial stimulus that induces a more vigorous long-term inflammatory response to subsequent stimuli. Isolated monocytes were stimulated with SLE-typical nuclear antigens, neutrophil extracellular traps (NETs), and apoptotic microparticles (MPs) or plasma from SLE patients. After five days of rest, cells were restimulated with Toll-like receptor (TLR) agonists, and cytokine production was measured using ELISA. Functional, transcriptomic and epigenetic changes in monocytes from SLE patients were evaluated by ex vivo stimulations, flow cytometric analysis, RNA sequencing, and chromatin immunoprecipitation (ChIP) sequencing for histone 3 lysine 4 trimethylation. We found that in vitro, both MPs and NETs, as well as plasma from SLE patients, can induce trained immunity. Furthermore, circulating monocytes from SLE patients produce increased levels of pro-inflammatory cytokines after stimulation with TLR ligands, indicating trained immunity. This is accompanied by deregulation in histone 3 lysine 4 trimethylation and increased expression of metabolism and inflammation-related genes. Our findings demonstrate that trained immunity can develop against nuclear antigens and that trained immunity is involved in the immunological dysregulation in SLE patients.
{"title":"Trained innate immunity in response to nuclear antigens in systemic lupus erythematosus","authors":"Cansu Yanginlar , Nils Rother , Tomas G.J.M. Post , Maaike Jacobs , Inge Jonkman , Montsy Brouns , Sybren Rinzema , Joost H.A. Martens , Michiel Vermeulen , Leo A.B. Joosten , Mihai G. Netea , Luuk B. Hilbrands , Zaheeb A. Choudhry , Johan van der Vlag , Raphaël Duivenvoorden","doi":"10.1016/j.jaut.2024.103335","DOIUrl":"10.1016/j.jaut.2024.103335","url":null,"abstract":"<div><div>Systemic lupus erythematosus (SLE) is an autoimmune disease directed against nuclear antigens, including those derived from apoptotic microparticles (MPs) and neutrophil extracellular traps (NETs). Here we investigated whether nuclear autoantigens can induce trained immunity in SLE patients. Trained immunity is a <em>de facto</em> innate immune memory elicited by an initial stimulus that induces a more vigorous long-term inflammatory response to subsequent stimuli. Isolated monocytes were stimulated with SLE-typical nuclear antigens, neutrophil extracellular traps (NETs), and apoptotic microparticles (MPs) or plasma from SLE patients. After five days of rest, cells were restimulated with Toll-like receptor (TLR) agonists, and cytokine production was measured using ELISA. Functional, transcriptomic and epigenetic changes in monocytes from SLE patients were evaluated by <em>ex vivo</em> stimulations, flow cytometric analysis, RNA sequencing, and chromatin immunoprecipitation (ChIP) sequencing for histone 3 lysine 4 trimethylation. We found that <em>in vitro,</em> both MPs and NETs, as well as plasma from SLE patients, can induce trained immunity. Furthermore, circulating monocytes from SLE patients produce increased levels of pro-inflammatory cytokines after stimulation with TLR ligands, indicating trained immunity. This is accompanied by deregulation in histone 3 lysine 4 trimethylation and increased expression of metabolism and inflammation-related genes. Our findings demonstrate that trained immunity can develop against nuclear antigens and that trained immunity is involved in the immunological dysregulation in SLE patients.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103335"},"PeriodicalIF":7.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644339","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}
Pub Date : 2024-11-15DOI: 10.1016/j.jaut.2024.103330
Alvise Berti , Michele Tomasi , Isabella Pesce , Enrico Lista , Anna Guella , Roberto Bortolotti , Giuseppe Paolazzi , Sophie Hillion , Ulrich Specks , Guido Grandi , Divi Cornec
Major target antigens of ANCA-associated vasculitis (AAV) are myeloperoxidase (MPO) and proteinase 3 (PR3). High-affinity MPO- and PR3-ANCA immunoglobulins are produced by antigen-experienced, class-switched autoreactive B cells. To prevent autoreactivity, B cells are subjected to several self-tolerance checkpoints, from the early immature stages in the bone marrow (BM), collectively called “central tolerance”, to late mature stages, collectively called “peripheral tolerance”; the latter was recently elucidated for autoreactive PR3+ B cells.
Here we investigated central tolerance controlling immature PR3+B cells in the BM before their migration into the periphery as transitional B cells. We applied an established flow cytometry-based method using labeled recombinant PR3 (rPR3) to identify the PR3+B cells to compare the phenotype of PR3+B cells in paired samples of BM mononuclear cells (BMMC) and peripheral blood mononuclear cells (PBMC) of non-vasculitis controls (No-AAV), and PBMC of patients with PR3-ANCA-associated vasculitis (PR3-AAV).
We observed that the proportion of PR3+B cells within BMMC was higher (median [IQR]; 1.98 % [1.77–2.75]) than within PBMC of No-AAV (0.9 % [0.63–1.44], p < 0.01 by paired comparison) and similar to their proportion within PBMC of patients with PR3-AAV (1.82 % [1.66–3.21]; p > 0.05). Within CD24++CD38++ B cells, the subset of B cell migrating from BM to the periphery, BMMC contained a greater proportion of PR3+B cells as compared to PBMC in No-AAV (3.35 % [1.99–4.92] versus 1.23 % [0.62–1.55], p < 0.01), showing different surface markers of maturation (i.e. higher proportion of CD27−CD10+ and lower expression of CD21, IgD, IgM). Importantly, we observed a significant decline of the PR3+ fraction from the immature subset (IgD−IgM+; 2.80 % [1.23–4.02]) to the early transitional subset (IgD+IgM+; 1.76 % [0.96–2.68], p < 0.01) in BMMC, while no significant reduction was observed between the early transitional of BMMC and the transitional compartment of PBMC in No-AAV (1.26 % [0.62–1.56], p > 0.05).
In conclusion, to prevent PR3-related autoimmunity, autoreactive PR3+B cells pass a stringent selection in the BM, and their removal by central tolerance checkpoint activity occurs mainly between T1-like/immature to T2-like/early transitional B cells of BMMC.
{"title":"Identification of the central tolerance checkpoint for autoreactive proteinase 3+ B cells in human bone marrow","authors":"Alvise Berti , Michele Tomasi , Isabella Pesce , Enrico Lista , Anna Guella , Roberto Bortolotti , Giuseppe Paolazzi , Sophie Hillion , Ulrich Specks , Guido Grandi , Divi Cornec","doi":"10.1016/j.jaut.2024.103330","DOIUrl":"10.1016/j.jaut.2024.103330","url":null,"abstract":"<div><div>Major target antigens of ANCA-associated vasculitis (AAV) are myeloperoxidase (MPO) and proteinase 3 (PR3). High-affinity MPO- and PR3-ANCA immunoglobulins are produced by antigen-experienced, class-switched autoreactive B cells. To prevent autoreactivity, B cells are subjected to several self-tolerance checkpoints, from the early immature stages in the bone marrow (BM), collectively called “central tolerance”, to late mature stages, collectively called “peripheral tolerance”; the latter was recently elucidated for autoreactive PR3<sup>+</sup> B cells.</div><div>Here we investigated central tolerance controlling immature PR3<sup>+</sup>B cells in the BM before their migration into the periphery as transitional B cells. We applied an established flow cytometry-based method using labeled recombinant PR3 (rPR3) to identify the PR3<sup>+</sup>B cells to compare the phenotype of PR3<sup>+</sup>B cells in paired samples of BM mononuclear cells (BMMC) and peripheral blood mononuclear cells (PBMC) of non-vasculitis controls (No-AAV), and PBMC of patients with PR3-ANCA-associated vasculitis (PR3-AAV).</div><div>We observed that the proportion of PR3<sup>+</sup>B cells within BMMC was higher (median [IQR]; 1.98 % [1.77–2.75]) than within PBMC of No-AAV (0.9 % [0.63–1.44], p < 0.01 by paired comparison) and similar to their proportion within PBMC of patients with PR3-AAV (1.82 % [1.66–3.21]; p > 0.05). Within CD24<sup>++</sup>CD38<sup>++</sup> B cells, the subset of B cell migrating from BM to the periphery, BMMC contained a greater proportion of PR3<sup>+</sup>B cells as compared to PBMC in No-AAV (3.35 % [1.99–4.92] versus 1.23 % [0.62–1.55], p < 0.01), showing different surface markers of maturation (i.e. higher proportion of CD27<sup>−</sup>CD10<sup>+</sup> and lower expression of CD21, IgD, IgM). Importantly, we observed a significant decline of the PR3<sup>+</sup> fraction from the immature subset (IgD<sup>−</sup>IgM<sup>+</sup>; 2.80 % [1.23–4.02]) to the early transitional subset (IgD<sup>+</sup>IgM<sup>+</sup>; 1.76 % [0.96–2.68], p < 0.01) in BMMC, while no significant reduction was observed between the early transitional of BMMC and the transitional compartment of PBMC in No-AAV (1.26 % [0.62–1.56], p > 0.05).</div><div>In conclusion, to prevent PR3-related autoimmunity, autoreactive PR3<sup>+</sup>B cells pass a stringent selection in the BM, and their removal by central tolerance checkpoint activity occurs mainly between T1-like/immature to T2-like/early transitional B cells of BMMC.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103330"},"PeriodicalIF":7.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644336","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}
Pub Date : 2024-11-08DOI: 10.1016/j.jaut.2024.103326
Qin-Yi Su , Zhong-Qing Jiang , Xuan-Yi Song , Sheng-Xiao Zhang
Autoimmune diseases are characterized by the body's immune system attacking its own cells, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). In recent studies, regulatory B cells (Bregs), which play a vital role in maintaining peripheral tolerance and controlling persistent autoimmune diseases (ADs), have shown great potential in treating ADs. This review synthesizes the latest advancements in targeted therapies for ADs, with a particular emphasis on the subgroups, phenotypic markers, and signal pathways associated with Bregs. Following an examination of these elements, the discussion pivots to innovative Breg-based therapeutic approaches for the management of ADs.
自身免疫性疾病的特征是人体免疫系统攻击自身细胞，如系统性红斑狼疮（SLE）、类风湿性关节炎（RA）和多发性硬化症（MS）。最近的研究显示，调节性 B 细胞（Bregs）在维持外周耐受性和控制顽固性自身免疫性疾病（ADs）方面发挥着重要作用，在治疗 ADs 方面具有巨大潜力。这篇综述综述了ADs靶向疗法的最新进展，特别强调了与Bregs相关的亚群、表型标记和信号通路。在对这些要素进行研究之后，讨论将转向基于 Breg 的创新性治疗方法，以治疗多发性硬化症。
{"title":"Regulatory B cells in autoimmune diseases: Insights and therapeutic potential","authors":"Qin-Yi Su , Zhong-Qing Jiang , Xuan-Yi Song , Sheng-Xiao Zhang","doi":"10.1016/j.jaut.2024.103326","DOIUrl":"10.1016/j.jaut.2024.103326","url":null,"abstract":"<div><div>Autoimmune diseases are characterized by the body's immune system attacking its own cells, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). In recent studies, regulatory B cells (Bregs), which play a vital role in maintaining peripheral tolerance and controlling persistent autoimmune diseases (ADs), have shown great potential in treating ADs. This review synthesizes the latest advancements in targeted therapies for ADs, with a particular emphasis on the subgroups, phenotypic markers, and signal pathways associated with Bregs. Following an examination of these elements, the discussion pivots to innovative Breg-based therapeutic approaches for the management of ADs.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103326"},"PeriodicalIF":7.9,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621155","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}
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic polyarthritis. It is well-established that helper T cells play crucial roles in the development and deterioration of RA. Recent studies also revealed the significant roles of regulatory T (Treg) cells in this context. Although Treg cells distributed in peripheral tissues exhibit various functions, the characteristics of synovial Treg cells remain unknown. In this study, we demonstrate that synovial Treg cells exacerbate synovial inflammation by reducing the number of immunoregulatory eosinophils through competitive consumption of IL-33. Synovial Treg cells expressed ST2 in a murine arthritis model, and surprisingly, Treg-specific ST2 knockout (ST2ΔTreg) mice exhibited attenuated arthritis. In ST2ΔTreg mice, an increase in immunoregulatory synovial eosinophils was observed. Additionally, immunoregulatory eosinophils were found to express ST2, and ST2-expressing Treg cells controlled the abundance of immunoregulatory eosinophils, possibly by consuming IL-33. Our results highlight that a subset of synovial Treg cells possesses the machinery to worsen arthritis by suppressing eosinophils. In the future landscape where Treg cell-based therapies are employed for autoimmune diseases, it is important to comprehend the characteristics of disease-related Treg cells. Understanding these aspects is crucial for ensuring safer treatment modalities that do not inadvertently worsen the diseases.
{"title":"Synovial regulatory T cells expressing ST2 deteriorate joint inflammation through the suppression of immunoregulatory eosinophils","authors":"Koto Hattori , Shigeru Tanaka , Daisuke Hashiba , Jun Tamura , Keishi Etori , Takahiro Kageyama , Takashi Ito , Kazuyuki Meguro , Arifumi Iwata , Akira Suto , Kotaro Suzuki , Junichi Nakamura , Seiji Ohtori , Steven F. Ziegler , Hiroshi Nakajima","doi":"10.1016/j.jaut.2024.103333","DOIUrl":"10.1016/j.jaut.2024.103333","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic polyarthritis. It is well-established that helper T cells play crucial roles in the development and deterioration of RA. Recent studies also revealed the significant roles of regulatory T (Treg) cells in this context. Although Treg cells distributed in peripheral tissues exhibit various functions, the characteristics of synovial Treg cells remain unknown. In this study, we demonstrate that synovial Treg cells exacerbate synovial inflammation by reducing the number of immunoregulatory eosinophils through competitive consumption of IL-33. Synovial Treg cells expressed ST2 in a murine arthritis model, and surprisingly, Treg-specific ST2 knockout (ST2<sup>ΔTreg</sup>) mice exhibited attenuated arthritis. In ST2<sup>ΔTreg</sup> mice, an increase in immunoregulatory synovial eosinophils was observed. Additionally, immunoregulatory eosinophils were found to express ST2, and ST2-expressing Treg cells controlled the abundance of immunoregulatory eosinophils, possibly by consuming IL-33. Our results highlight that a subset of synovial Treg cells possesses the machinery to worsen arthritis by suppressing eosinophils. In the future landscape where Treg cell-based therapies are employed for autoimmune diseases, it is important to comprehend the characteristics of disease-related Treg cells. Understanding these aspects is crucial for ensuring safer treatment modalities that do not inadvertently worsen the diseases.</div></div>","PeriodicalId":15245,"journal":{"name":"Journal of autoimmunity","volume":"149 ","pages":"Article 103333"},"PeriodicalIF":7.9,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592541","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}
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