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

• 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
• 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

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反常的自身免疫并发症相关。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调节B细胞耐受性和清除人类自身反应性B细胞的影响。在缺乏功能性BTK、CD 19或介导TLR信号传导的分子（如IRAK 4、MyD 88和UNC 93 B）的患者中，B细胞受体（BCR）信号传导途径的改变导致中心检查点缺陷和无法反选择发育中的自身反应性B细胞（1，2）。实际上，由于所有这些患者的B细胞中的受体信号传导阈值增加，自身抗原与自身反应性BCR和TLR的结合不能诱导耐受机制，并且自身反应性B细胞从骨髓泄漏到外周（1，2）。我们的最新研究表明，中枢B细胞耐受性缺陷是许多自身免疫性疾病（包括类风湿性关节炎（RA）、系统性红斑狼疮（SLE）和1型糖尿病（T1 D））的原发性，并且是由与自身免疫分离的遗传因素引起的，并且其编码干扰BCR信号传导的变体（3-5）。然而，我们最近发现，多发性硬化症（MS）患者仅显示外周B细胞耐受性缺陷，而中枢B细胞耐受性通常建立正常。在CD 40 L和MHC II类缺陷患者中观察到类似的观察结果，他们指出调节性T（Treg）细胞和血清B细胞活化因子（BAFF）在清除外周中正在形成的自身反应性B细胞中的潜在作用（6）。有趣的是，据报道，Treg细胞功能在MS患者中存在缺陷。因此，提出在该R21申请中通过研究免疫缺陷、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-外胚层营养不良（APECED）患者来分析Treg细胞作为控制外周中B细胞耐受性的建立和维持的第二轴，其显示缺陷性Treg细胞区室并患有自身免疫性病症和分泌许多自身反应性抗体。该研究的长期目标是确定调节健康人外周B细胞耐受性的机制，但在IPEX和APECED患者中可能存在缺陷。工作假设是影响Treg细胞功能的遗传缺陷不仅干扰外周中自身反应性B细胞的去除，而且可能导致其活化，从而潜在地有利于自身免疫的发展。与CD 40 L缺陷患者类似，我们期望发现具有异常Treg细胞功能的FOXP 3和AIRE缺陷患者将显示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细胞死亡和促进B细胞稳态调节的机制。总之，所提出的研究旨在证明Treg细胞在抑制外周中的自身反应性B细胞中的作用。 公共卫生相关性：该提案旨在通过分析Treg细胞频率和功能改变的Foxp 3和AIRE缺陷患者，并评估Treg细胞可能阻止外周自身反应性B细胞扩增的机制，来证明Treg细胞在外周清除自身反应性B细胞中的作用。