Impact of regulatory T cells on human peripheral B cell tolerance

调节性 T 细胞对人外周 B 细胞耐受的影响

基本信息

批准号：
8302578
负责人：
Eric Meffre
金额：
$ 24.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8302578
关键词：
Antibodies Apoptosis Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Binding Biological Assay Blood Bone Marrow CD19 gene CD4 Positive T Lymphocytes Cell Death Cell physiology Cells Data Defect Development Emigrant Excision Failure Frequencies Genes Genetic Genetic Recombination Goals Homeostasis Human IRAK4 gene Immune Insulin-Dependent Diabetes Mellitus Investigation Lead Link MHC Class II Genes Maintenance Mediating Modeling Multiple Sclerosis Mutation Patients Peripheral Play Polyglandular Autoimmune Syndrome Type I Process Receptor Signaling Receptors, Antigen, B-Cell Recombinant Antibody Regulation Regulatory T-Lymphocyte Reporting Research Rheumatoid Arthritis Role Serum Signal Pathway Signal Transduction Syndrome Systemic Lupus Erythematosus TNFRSF5 gene TNFSF5 gene Testing Transgenic Mice Variant Work anti-IgM autoreactive B cell congenital immunodeficiency immune function in vitro Assay mouse model prevent

项目摘要

DESCRIPTION (provided by applicant): Impaired immune functions leading to primary immunodeficiencies often correlate with paradoxical autoimmune complications. Patients with primary immunodeficiencies provide rare opportunities to study the impact of specific defective genes on the regulation of B cell tolerance and the removal of developing autoreactive B cells in humans. Alterations in B cell receptor (BCR) signaling pathways in patients lacking functional BTK, CD19, or molecules mediating TLR signaling such as IRAK4, MyD88, and UNC93B result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells (1, 2). Indeed, the binding of self-antigens to autoreactive BCRs and TLRs fail to induce tolerance mechanisms due to increase receptor signaling thresholds in all these patients' B cells and autoreactive B cells leaks from the bone marrow into the periphery (1, 2). Our latest investigations revealed that central B cell tolerance defects are primary to many autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) and result from genetic factors segregating with autoimmunity and which encode variants interfering with BCR signaling (3-5). However, we recently found that patients with multiple sclerosis (MS) only displayed peripheral B cell tolerance defects whereas central B cell tolerance was often established normally. Similar observations were observed in CD40L- and MHC class II-deficient patients, who pointed to a potential role for regulatory T (Treg) cells and serum B-cell activating factor (BAFF) in the removal of developing autoreactive B cells in the periphery (6). Interestingly, Treg cell functions have been reported to be defective in MS patients. Hence, Treg cells as second axis controlling the establishment and the maintenance of B cell tolerance in the periphery is proposed to be analyzed in this R21 application by studying immune deficiency, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients, who display a defective Treg cell compartment and suffer from autoimmune condition and the secretion of many self-reactive antibodies. The long range goal of the proposed research is to determine the mechanisms that regulate peripheral B cell tolerance in healthy humans but may be defective in IPEX and APECED patients. The working hypothesis is that genetic defects impacting Treg cell functions not only interfere with the removal of autoreactive B cells in the periphery but may lead to their activation, thereby potentially favoring the development of autoimmunity. Similarly to CD40L-deficient patients, we expect to find that FOXP3- and AIRE-deficient patients with abnormal Treg cell functions will display normal central yet defective peripheral B cell tolerance checkpoints. We will also assess the mechanisms by which Treg cells may induce autoreactive B cell death and contribute to B cell homeostasis regulation. Altogether, the proposed study intends to demonstrate a role for Treg cells in the restraining autoreactive B cells in the periphery. PUBLIC HEALTH RELEVANCE: This proposal intends to demonstrate a role for Treg cells in the peripheral removal of autoreactive B cells by analyzing Foxp3- and AIRE-deficient patients with altered Treg cell frequencies and functions, and assessing mechanisms by which Treg cells may prevent autoreactive B cell expansion in the periphery.

描述（由申请人提供）：导致原发性免疫缺陷的免疫功能受损通常与矛盾的自身免疫并发症相关。患有原发性免疫缺陷的患者提供了难得的机会来研究特定缺陷基因对 B 细胞耐受调节和去除人类中正在发育的自身反应性 B 细胞的影响。缺乏功能性 BTK、CD19 或介导 TLR 信号转导分子（如 IRAK4、MyD88 和 UNC93B）的患者中，B 细胞受体 (BCR) 信号转导通路的改变会导致中央检查点缺陷和无法反选择正在发育的自身反应性 B 细胞 (1, 2 ）。事实上，自身抗原与自身反应性 BCR 和 TLR 的结合无法诱导耐受机制，因为所有这些患者的 B 细胞中的受体信号传导阈值均增加，并且自身反应性 B 细胞从骨髓渗漏到外周 (1, 2)。我们的最新研究表明，中枢 B 细胞耐受缺陷是许多自身免疫性疾病的主要原因，包括类风湿性关节炎 (RA)、系统性红斑狼疮 (SLE) 和 1 型糖尿病 (T1D)，是由与自身免疫分离的遗传因素造成的，这些遗传因素编码干扰自身免疫的变异体。 BCR 信号传导 (3-5)。然而，我们最近发现多发性硬化症（MS）患者仅表现出外周B细胞耐受缺陷，而中枢B细胞耐受通常建立正常。在 CD40L 和 MHC II 类缺陷的患者中也观察到了类似的结果，他们指出调节性 T (Treg) 细胞和血清 B 细胞激活因子 (BAFF) 在去除外周发育中的自身反应性 B 细胞方面具有潜在作用。 6).有趣的是，据报道多发性硬化症患者的 Treg 细胞功能存在缺陷。因此，在该 R21 应用中，建议通过研究免疫缺陷、多内分泌病、肠病、X 连锁综合征 (IPEX) 和自身免疫性多内分泌病-念珠菌病，对 Treg 细胞作为控制外周 B 细胞耐受的建立和维持的第二轴进行分析-外胚层营养不良 (APECED) 患者，其 Treg 细胞区室有缺陷，患有自身免疫性疾病并分泌许多自身反应性抗体。拟议研究的长期目标是确定健康人中调节外周 B 细胞耐受性但在 IPEX 和 APECED 患者中可能存在缺陷的机制。目前的假设是，影响 Treg 细胞功能的遗传缺陷不仅会干扰外周自身反应性 B 细胞的清除，还可能导致其激活，从而可能有利于自身免疫的发展。与 CD40L 缺陷患者类似，我们期望发现 FOXP3 和 AIRE 缺陷且 Treg 细胞功能异常的患者将表现出正常的中枢但有缺陷的外周 B 细胞耐受检查点。我们还将评估 Treg 细胞诱导自身反应性 B 细胞死亡并促进 B 细胞稳态调节的机制。总而言之，这项研究旨在证明 Treg 细胞在抑制外周自身反应性 B 细胞中的作用。公共健康相关性：本提案旨在通过分析具有改变的 Treg 细胞频率和功能的 Foxp3 和 AIRE 缺陷患者，并评估 Treg 细胞预防自身反应性 B 细胞的机制，证明 Treg 细胞在外周去除自身反应性 B 细胞中的作用。细胞在周围扩张。