Impact of regulatory T cells on human peripheral B cell tolerance

描述（由申请人提供）：免疫功能受损导致原发性免疫缺陷通常与矛盾的自身免疫并发症相关。原发性免疫缺陷患者提供了难得的机会来研究特异性缺陷基因对B细胞耐受性调控和人类自身反应性B细胞清除的影响。在缺乏功能性BTK、CD19或介导TLR信号的分子（如IRAK4、MyD88和UNC93B）的患者中，B细胞受体（BCR）信号通路的改变会导致中心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的结合不能诱导耐受性机制，因为所有这些患者的B细胞中受体信号阈值增加，并且自身反应性B细胞从骨髓渗漏到外周（1,2）。我们最新的研究表明，中枢B细胞耐受缺陷是许多自身免疫性疾病的主要原因，包括类风湿关节炎（RA）、系统性红斑狼疮（SLE）和1型糖尿病（T1D），是遗传因素与自身免疫分离的结果，这些遗传因素编码干扰BCR信号传导的变异（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细胞耐受通常正常建立。在CD40L-和MHC ii类缺陷患者中也观察到类似的结果，这表明调节性T （Treg）细胞和血清B细胞活化因子（BAFF）在清除外周自身反应性B细胞中的潜在作用(6)。有趣的是，据报道多发性硬化症患者的Treg细胞功能有缺陷。因此，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，我们提出Treg细胞作为控制外周B细胞耐受性建立和维持的第二轴，在R21应用中进行分析，这些患者表现出Treg细胞室缺陷，患有自身免疫性疾病和分泌许多自身反应性抗体。拟议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。目前的假设是，影响Treg细胞功能的遗传缺陷不仅干扰外周自身反应性B细胞的清除，而且可能导致它们的激活，从而潜在地促进自身免疫的发展。与cd40l缺陷患者类似，我们希望发现FOXP3-和aire缺陷的Treg细胞功能异常的患者将显示正常的中央但有缺陷的外周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，该研究旨在证明Treg细胞在抑制外周自身反应性B细胞中的作用。

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.