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，并且在血清中出现多年 在临床疾病发作之前，提示B细胞耐受性的早期破坏。B的重要角色 细胞在某些自身免疫性疾病中的作用得到了抗CD20抗体成功治疗患者的支持。 消除B细胞的单克隆抗体。自身反应性B细胞的潜在机制 自身免疫性疾病中自身抗体的产生还不清楚。我们分析了B细胞耐受性， 未治疗的活动性类风湿关节炎（RA）和1型糖尿病（T1D）患者，通过测试 从单个新的迁移和成熟幼稚B细胞克隆的重组抗体。RA和T1D患者 表现出有缺陷的中枢和外周B细胞耐受性检查点，导致自反应性 成熟的幼稚B细胞，可能有助于发病机制。拟议的长期目标 研究的目的是确定调节健康人B细胞耐受性的机制， 自身免疫性疾病患者的缺陷。工作假设是，发展自身反应性B 自身免疫性疾病患者的细胞从内在缺陷中冲浪， 骨髓中的反选择此外，调节性T细胞功能的缺陷和BAFF的升高也可能导致免疫缺陷。 水平可能改变外周B细胞耐受性，并导致异常募集和激活 自身反应性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 T1D缺陷在B细胞耗竭后持续存在，因此可以预测患者的复发。的第二部分 该项目将分析原发性干燥综合征中自身反应性B细胞的发展和参与 综合征该项目的第三部分将描述B细胞早期缺陷的分子基础 通过分析已知多态性的影响， 自身免疫性疾病的发展。