Loss of B cell tolerance in rheumatoid arthritis

类风湿性关节炎 B 细胞耐受性丧失

• 批准号: 7446808
• 负责人: Eric Meffre
• 金额: $ 41.67万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7446808
• 关键词: Accounting; Amino Acids; Antibodies; Autoantibodies; Autoantigens; Autoimmune Diseases; B-Cell Development; B-Lymphocytes; Bone Marrow; Characteristics; Clinical; Complementarity Determining Region III; Defect; Development; Disease; Emigrant; Ensure; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic Recombination; Goals; Human; Immunoglobulin G; Immunoglobulin Somatic Hypermutation; Individual; Joints; Mediating; Molecular; Molecular Profiling; Monoclonal Antibody CD20; Mus; Mutate; Onset of illness; Pathogenesis; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Physiology; Process; Production; RNA; Range; Receptor Signaling; Receptors, Antigen, B-Cell; Recombinant Antibody; Recruitment Activity; Reporting; Research; Research Personnel; Rheumatism; Rheumatoid Arthritis; Rheumatoid Factor; Risk; Role; Serum; Shapes; Specificity; Subgroup; Synovial Membrane; Systemic Lupus Erythematosus; Testing; V(D)J Recombination; Work; anergy; autoreactive B cell; base; complementarity-determining region 3; cyclic citrullinated peptide; kappa-Chain Immunoglobulins; programs; receptor

DESCRIPTION (provided by applicant): Autoantibodies are a characteristic of most autoimmune diseases including rheumatoid arthritis (RA) and appear in the serum many years before the onset of clinical disease, suggesting an early break in B cell tolerance in RA. An important role for B cells in RA has been supported by successful treatment of RA patients with anti-CD20 monoclonal antibodies that eliminate B cells. The underlying mechanisms that account for autoreactive B cell and autoantibody production in RA are poorly defined. We recently analyzed B cell tolerance in untreated active RA patients by testing the specificity of recombinant antibodies cloned from single new emigrant and mature naive B cells. RA patients exhibit defective central and peripheral B cell tolerance checkpoints that result in the accumulation of serf-reactive mature naive B cells, likely contributing to RA pathogenesis. In addition, about half of RA patients showed new emigrant B cells with defective receptor editing, one of the 3 mechanisms that normally ensure B cell tolerance. The other half of the patients displayed new emigrant B cells with unusually long (11 or more amino acids) complementarity determining region 3 (CDRSs) associated to self-reactivity and found enriched in the RA synovium. The long range goal of the proposed research is to determine the mechanisms that regulate B cell tolerance in healthy humans but are defective in RA patients. The working hypothesis is that RA B cells suffer from intrinsic BCR signaling defects that impinge on the proper counterselection of developing autoreactive B cells, and result in the abnormal recruitment and activation of peripheral self-reactive B cells into the synovium. The first aim of the project will consist of characterizing the molecular basis for early defects in B cell tolerance checkpoints in RA by comparing microarray gene expression profiles from control and RA B cell subpopulations (whether or not triggered by their BCR) that may reveal specific BCR signaling defects for the different subgroups of RA patients. The second part of the project will identify alternative B cell tolerance mechanisms such as anergy that can substitute for defective receptor editing in humans. The third part of the project will analyze how B cell tolerance is broken in the synovium of RA patients. These studies have significant implications for understanding how people with autoimmune diseases produce antibodies that attack their body and may provide clues for development of new medications.

描述（由申请人提供）：自身抗体是包括类风湿性关节炎（RA）在内的大多数自身免疫性疾病的特征，并在临床疾病发作前多年出现在血清中，表明RA中B细胞耐受性的早期破坏。B细胞在RA中的重要作用已得到抗CD20单克隆抗体消除B细胞的RA患者的成功治疗的支持。RA中自身反应性B细胞和自身抗体产生的潜在机制尚不清楚。我们最近分析了B细胞的耐受性在未经治疗的活动性RA患者通过测试的特异性重组抗体克隆从单一的新的移民和成熟的幼稚B细胞。RA患者表现出有缺陷的中枢和外周B细胞耐受检查点，导致自身反应性成熟幼稚B细胞的积累，可能有助于RA发病机制。此外，大约一半的RA患者显示新的迁移B细胞具有缺陷的受体编辑，这是通常确保B细胞耐受性的3种机制之一。另一半患者显示新的迁移B细胞，其具有与自身反应相关的异常长（11个或更多个氨基酸）的互补决定区3（CDR），并在RA滑膜中富集。这项研究的长期目标是确定在健康人中调节B细胞耐受性但在RA患者中有缺陷的机制。工作假设是RA B细胞存在固有的BCR信号传导缺陷，这会影响发育中的自身反应性B细胞的适当反选择，并导致外周自身反应性B细胞异常募集和激活进入滑膜。该项目的第一个目标将包括通过比较对照和RA B细胞亚群（无论是否由其BCR触发）的微阵列基因表达谱来表征RA中B细胞耐受性检查点早期缺陷的分子基础，这可能揭示RA患者不同亚群的特定BCR信号缺陷。该项目的第二部分将确定替代性B细胞耐受机制，例如可以替代人类有缺陷的受体编辑的无反应性。项目的第三部分将分析RA患者滑膜中B细胞耐受性是如何被打破的。这些研究对于了解自身免疫性疾病患者如何产生攻击其身体的抗体具有重要意义，并可能为新药的开发提供线索。