Pub Date : 2024-12-01Epub Date: 2024-10-13DOI: 10.1016/j.jaut.2024.103324
Huizhong Long, Luis Espinosa, Amr H Sawalha
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.
羟氯喹（HCQ）被广泛用于治疗各种自身免疫性疾病。然而，HCQ对T细胞免疫调节作用的机制仍不清楚。在这里，我们使用单细胞 RNA 序列分析法研究了 HCQ 在体外刺激后对 T 细胞的影响。HCQ 处理导致效应 CD4+ T 细胞减少，抑制基因（包括 CTLA4 和 TNFAIP3）分别在效应和幼稚 CD4+ T 细胞中上调。HCQ 可诱导效应 CD8+ T 细胞显著扩增，并显著上调关键细胞毒性基因（包括 GZMA、GZMB、GZMH、KLRD1、NKG7 和 PRF1）以及 IFNG 的表达。此外，HCQ 治疗导致 CD38+ CD8+ T 细胞亚群减少，该亚群的特点是细胞毒性缺陷，被认为在自身免疫中既起致病作用又增加感染易感性。我们分析了接受或未接受 HCQ 治疗的狼疮患者效应 CD8+ T 细胞的单细胞 RNA 序列数据，证实了接受 HCQ 治疗的患者关键细胞毒性基因的上调。总之，这项研究为了解 HCQ 的免疫调节作用提供了新的视角，并表明 HCQ 能提高 T 细胞的细胞毒性，这可以解释之前提出的 HCQ 对自身免疫性疾病患者感染的保护作用。
{"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<sup>+</sup> T cells and upregulation of inhibitory genes including CTLA4 and TNFAIP3 in effector and naive CD4<sup>+</sup> T cells, respectively. HCQ induced a significant expansion of effector CD8<sup>+</sup> 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<sup>+</sup> CD8<sup>+</sup> 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<sup>+</sup> 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}
Pub Date : 2024-12-01DOI: 10.1016/j.jaut.2023.103127
Elizabeth V. Arkema , Marios Rossides , Yvette C. Cozier
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.
{"title":"Sarcoidosis and its relation to other immune-mediated diseases: Epidemiological insights","authors":"Elizabeth V. Arkema , Marios Rossides , 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}
Pub Date : 2024-12-01DOI: 10.1016/j.jaut.2024.103184
Maneesh Bhargava , Elliott D. Crouser
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.
{"title":"Application of laboratory models for sarcoidosis research","authors":"Maneesh Bhargava , 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}
Pub Date : 2024-12-01DOI: 10.1016/j.jaut.2024.103179
Ogugua Ndili Obi , Lesley Ann Saketkoo , Lisa A. Maier , Robert P. Baughman
Sarcoidosis is a multi-organ granulomatous inflammatory disease 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.
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. 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.
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 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.
Our paper provides an update on developmental drugs in sarcoidosis and outlines several novel pathways that may be targeted for future drug development. Currently available trials are highlighted and ongoing challenges to drug development and clinical trial design are briefly discussed.
{"title":"Developmental drugs for sarcoidosis","authors":"Ogugua Ndili Obi , Lesley Ann Saketkoo , Lisa A. Maier , 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}
Pub Date : 2024-11-27DOI: 10.1016/j.jaut.2024.103339
Yiqing Feng , Gordafaried Deyanat-Yazdi , Kristin Newburn , Scott Potter , Mark Wortinger , Miriam Ramirez , Stephanie M.E. Truhlar , Pia P. Yachi
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.
PD-1 已成为维持免疫平衡的核心抑制性检查点受体和癌症免疫疗法的靶点。然而，以 PD-1 为靶点治疗自身免疫性疾病却更具挑战性。我们最近在一项 2a 期试验中表明，可以用 PD-1 激动剂抗体培瑞索单抗刺激 PD-1 来治疗类风湿性关节炎。在这里，我们证明了 PD-1 抗体可以通过 Fcγ 受体（FcγR）的参与使 PD-1 与 T 细胞受体共定位，从而引起激动作用并抑制 T 细胞的活化。三种具有不同抗原结合域的PD-1激动剂抗体，包括临床验证的PD-1阻断抗体pembrolizumab，对T细胞活化的抑制程度相似；这一发现表明，PD-1激动并不需要特定的PD-1结合表位。我们接下来探讨了抗体介导的聚类是否是抑制 T 细胞活化的重要驱动因素；然而，我们发现单价 PD-1 抗体抑制 T 细胞活化的能力并不亚于传统的二价抗体。重要的是，我们发现与 PD-1 的亲和力与 T 细胞活化抑制呈正相关，亲和力越高的抗体抑制水平越高。我们利用一系列与各种 FcγR 亲和力不同的人类 Fc 突变体，剖析了 FcγR 的贡献，发现多个 FcγR 而不是单一受体对激动剂活性有贡献。我们的研究揭示了 FcγR 结合在 PD-1 抗体活性中的重要作用，这对优化 PD-1 激动剂和拮抗剂抗体都有影响。
{"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 , Gordafaried Deyanat-Yazdi , Kristin Newburn , Scott Potter , Mark Wortinger , Miriam Ramirez , Stephanie M.E. Truhlar , 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}
Pub Date : 2024-11-24DOI: 10.1016/j.jaut.2024.103340
Christine G. Parks , Todd A. Jusko , Helen C.S. Meier , Jesse Wilkerson , Lisa G. Rider , Frederick W. Miller , Dale P. Sandler
Background
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.
Methods
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.
Results
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 < 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. <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.
Conclusions
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.
背景1988年至2012年间，美国人口中的核抗体（ANA）流行率有所上升，尤其是在白人和受教育程度较高的人群中。在2003-2004年和2011-2012年国家健康与营养调查（NHANES）中，年龄在20-39岁的成年人中的ANA流行率与冬季测量的尿液中常见防晒霜成分二苯甲酮3的浓度有关。方法在一项针对 20-59 岁成年人的横断面研究中（通过 Hep-2 免疫荧光，1:80 稀释，N = 416 ANA 阳性，2656 ANA 阴性），我们研究了 ANA 与在阳光下晒 1 小时或更长时间时使用防晒霜的相关性。我们采用逻辑回归法计算了经协方差调整的患病几率比（POR）和 95 % 置信区间（CI），包括总体患病几率比和按人口统计学因素、季节和维生素 D 分层的患病几率比。结果ANA与防晒霜的关系因年龄而异（交互作用 p = 0.004）：在 20-39 岁的人群中，我们发现了一种暴露反应（经常或大部分时间使用防晒霜的 POR 为 2.61，95 % CI 为 1.50-4.24 ；较少使用与从不使用的 POR 为 1.85; 1.12-3.05; 趋势 p < 0.001）。这些关联在女性（交互作用 p = 0.082）、非西班牙裔白人和黑人参与者（与其他种族/族裔相比，交互作用 p = 0.023）以及血清维生素 D 充足者（≥50 与 50 nmol/L，交互作用 p = 0.001）中更为明显。结论：这些横断面研究结果表明，经常使用防晒霜与年轻成人的 ANA 有关，因此有必要进行重复研究和具有详细暴露史的纵向研究。
{"title":"Sunscreen use associated with elevated prevalence of anti-nuclear antibodies in U.S. adults","authors":"Christine G. Parks , Todd A. Jusko , Helen C.S. Meier , Jesse Wilkerson , Lisa G. Rider , Frederick W. Miller , 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 < 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. <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}
Pub Date : 2024-11-21DOI: 10.1016/j.jaut.2024.103341
Yiying Yang , Muyuan Li , Liqing Ding , Ying Zhang , Ke Liu , Meidong Liu , Yisha Li , Hui Luo , Xiaoxia Zuo , Huali Zhang , Muyao Guo
<div><h3>Objective</h3><div>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.</div></div><div><h3>Methods</h3><div>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 <em>CDKN1A</em> 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 <em>EZH2</em> mRNA.</div></div><div><h3>Results</h3><div>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 <em>METTL3</em>, the expression of EZH2 reduced. Mechanistically, EZH2 inhibited B-cell apoptosis and promoted B-cell proliferation by catalyzing H3K27me3 modification at the <em>CDKN1A</em> locus. Furthermore, METTL3 bound to <em>EZH2</em> mRNA and increased m6A modification on <em>EZH2</em> mRNA, enhancing its stability and promoting EZH2 expression.</div></div><div><h3>Conclusions</h3><div>The upregulation of EZH2 mediated by METTL3 is implicated in the B-cell autoimmune response in pSS. Inhibition of EZH2 presents
{"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":"10.1016/j.jaut.2024.103341","url":null,"abstract":"<div><h3>Objective</h3><div>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.</div></div><div><h3>Methods</h3><div>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 <em>CDKN1A</em> 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 <em>EZH2</em> mRNA.</div></div><div><h3>Results</h3><div>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 <em>METTL3</em>, the expression of EZH2 reduced. Mechanistically, EZH2 inhibited B-cell apoptosis and promoted B-cell proliferation by catalyzing H3K27me3 modification at the <em>CDKN1A</em> locus. Furthermore, METTL3 bound to <em>EZH2</em> mRNA and increased m6A modification on <em>EZH2</em> mRNA, enhancing its stability and promoting EZH2 expression.</div></div><div><h3>Conclusions</h3><div>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}
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。
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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 , 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 , 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}
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。
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