Autoreactive B Cell Development in Autoimmune Disease

自身免疫性疾病中自身反应性 B 细胞的发育

• 批准号: 7687682
• 负责人: Eric Meffre
• 金额: $ 20.22万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687682
• 关键词: Accounting; Affect; Agreement; Alleles; Antibodies; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Cell Development; B-Lymphocytes; Biopsy; Blood; Blood specimen; Bone Marrow; Cell Therapy; Cell physiology; Characteristics; Child; Clinical; Crohn' s disease; Defect; Development; Disease; Disease Progression; Emigrant; Excision; Exhibits; Future; Genes; Genetic Polymorphism; Goals; Human; Insulin-Dependent Diabetes Mellitus; LYN gene; Lasers; Light; Molecular; Monoclonal Antibody CD20; Multiple Sclerosis; PTPN22 gene; Pathogenesis; Patients; Peripheral; Population; Production; Recombinant Antibody; Relapse; Research; Reverse Transcriptase Polymerase Chain Reaction; Rheumatoid Arthritis; Risk; Role; Salivary Glands; Serum; Sjogren' s Syndrome; Specificity; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Ulcerative Colitis; Work; autoreactive B cell; base; disorder control; novel strategies; prevent; rituximab

Autoantibodies are a characteristic of most autoimmune diseases and appear in the serum many years before the onset of clinical disease, suggesting an early break in B cell tolerance. An important role for B cells in some autoimmune diseases has been supported by successful treatment of patients with anti-CD20 monoclonal antibodies that eliminate B cells. The underlying mechanisms that account for autoreactive B cell and autoantibody production in autoimmune diseases are poorly defined. We analyzed B cell tolerance in untreated active rheumatoid arthritis (RA) and type 1 diabetes (T1D) patients by testing the specificity of recombinant antibodies cloned from single new emigrant and mature naive B cells. RA and T1D patients exhibit defective central and peripheral B cell tolerance checkpoints that result in the accumulation of selfreactive mature naive B cells, likely contributing to pathogenesis. The long range goal of the proposed research is to determine the mechanisms that regulate B cell tolerance in healthy humans but may be defective in patients with autoimmune diseases. The working hypothesis is that developing autoreactive B cells in patients with autoimmune diseases surfer from intrinsic defects that impinge on their proper counterselection in the bone marrow. In addition, defects in regulatory T cell functions and elevated BAFF levels may alter peripheral B cell tolerance and result in the abnormal recruitment and activation of autoreactive B cell clones. The first aim of the project will consist of determining whether B cell tolerance defects in T1D persist after B cell depletion and may therefore predict patients' relapse. The second part of the project will analyze the development and involvement of autoreactive B cells in primary Sjogren's syndrome. The third part of the project will characterize the molecular basis for early defects in B cell tolerance checkpoints by analyzing the impact of known polymorphism that are protective or associated to the development of autoimmune diseases.

自身抗体是大多数自身免疫性疾病的特征，并且出现在血清中多年 在临床疾病发作之前，表明B细胞耐受性早期破裂。 B的重要作用 成功治疗抗CD20患者，一些自身免疫性疾病中的细胞得到了支持 消除B细胞的单克隆抗体。解释自动反应性B细胞的基本机制 自身免疫性疾病中的自身抗体产生的定义很差。我们分析了B细胞的耐受性 未经治疗的活性类风湿关节炎（RA）和1型糖尿病（T1D）患者通过测试特异性 重组抗体从单个新移民和成熟的幼稚B细胞克隆。 RA和T1D患者 表现出有缺陷的中央和外围B细胞耐受性检查点，导致自我反应的积累 成熟的幼稚B细胞，可能导致发病机理。拟议的远距离目标 研究是确定调节健康人中B细胞耐受性的机制，但可能是 自身免疫性疾病患者中有缺陷。工作假设是开发自动反应性b 自身免疫性疾病患者的细胞因构成其适当的固有缺陷而冲浪 骨髓中的反选择。另外，调节性T细胞功能和BAFF升高的缺陷 水平可能会改变外周B细胞的耐受性，并导致异常募集和激活 自动反应性B细胞克隆。该项目的第一个目标将包括确定B细胞耐受性是否 B细胞耗竭后T1D的缺陷持续存在，因此可能预测患者的复发。第二部分 该项目将分析自动反应性B细胞在原发性Sjogren的开发和参与 综合征。该项目的第三部分将表征B细胞早期缺陷的分子基础 通过分析具有保护性或与之相关的已知多态性的影响来耐受性检查点 自身免疫性疾病的发展。