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: 8424216
• 负责人: Eric Meffre
• 金额: $ 20.79万
• 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/8424216
• 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.

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。原发性免疫缺陷的患者为研究特定缺陷基因对B细胞耐受性的调节的影响提供了罕见的机会，并去除了人类发展的自动反应性B细胞。缺乏功能性BTK，CD19或分子的B细胞受体（BCR）信号通路的改变，介导TLR信号（例如IRAK4，MYD88和UNC93B）的分子发生了变化，导致中央检查点有缺陷，并且未能抵消与发展自动反应性B细胞的选择（1，2）。实际上，自抗原与自动反应性BCR和TLR的结合无法诱导所有这些患者的受体信号传导阈值引起的耐受性机制，并且自动反应性B细胞从骨髓泄漏到外围渗漏到外围（1，2）。我们的最新研究表明，中央B细胞的耐受性缺陷是许多自身免疫性疾病的主要疾病，包括类风湿关节炎（RA），全身性红斑狼疮（SLE）和1型糖尿病（T1D）（T1D）（T1D），以及遗传因子因自身免疫性和哪些Encode variants variants的遗传因素而引起的（3-5）。但是，我们最近发现，多发性硬化症患者（MS）仅显示外周B细胞耐受性缺陷，而中央B细胞耐受性经常正常建立。在CD40L和II类缺陷型患者中观察到了相似的观察结果，他们指出了调节性T（Treg）细胞和血清B细胞激活因子（BAFF）在去除外围生物反应性B细胞中的潜在作用（6）。有趣的是，据报道，Treg细胞功能在MS患者中有缺陷。 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细胞室并患有自身免疫性状况和许多自反应抗体的分泌。拟议的研究的远距离目标是确定健康人类外周B细胞耐受性的机制，但可能在IPEX和APECECTED患者中有缺陷。有效的假设是，影响Treg细胞功能的遗传缺陷不仅会干扰外围中自动反应性B细胞的去除，而且可能导致其激活，从而有利于自身免疫性的发展。与CD40L缺陷型患者类似，我们希望发现FOXP3和缺陷异常Treg细胞功能的患者将显示正常但有缺陷的外周B细胞耐受性检查点。我们还将评估Treg细胞可以诱导自身反应性B细胞死亡并导致B细胞稳态调节的机制。总的来说，拟议的研究旨在证明Treg细胞在限制周围自动反应性B细胞中的作用。