Loss of B cell tolerance in rheumatoid arthritis

描述(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的B细胞耐受性提前打破。B细胞在类风湿关节炎中的重要作用已经被成功地用抗CD20单抗治疗的类风湿关节炎患者所支持。解释类风湿关节炎自身反应性B细胞和自身抗体产生的潜在机制尚不清楚。我们最近通过检测从单个新移民和成熟的幼稚B细胞克隆的重组抗体的特异性，分析了未经治疗的活动期RA患者的B细胞耐受性。RA患者表现出中枢和外周B细胞耐受检查点缺陷，导致自身反应性成熟幼稚B细胞积聚，可能参与RA的发病。此外，大约一半的RA患者表现出受体编辑缺陷的新移民B细胞，这是通常确保B细胞耐受的三种机制之一。另一半患者表现为新移居的B细胞，其互补决定区3(CDRSs)异常长(11个或更多氨基酸)与自身反应性有关，并在RA滑膜中发现丰富。这项拟议研究的长期目标是确定在健康人中调节B细胞耐受性的机制，但在RA患者中存在缺陷。工作假说是RA B细胞存在固有的BCR信号缺陷，这种缺陷影响了对发育中的自身反应性B细胞的正确选择，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患者B细胞耐受检查点早期缺陷的分子基础，这些基因表达谱可能揭示不同RA患者亚群的特定BCR信号缺陷。该项目的第二部分将确定替代的B细胞耐受机制，如无能，可以替代人类有缺陷的受体编辑。该项目的第三部分将分析类风湿关节炎患者滑膜中的B细胞耐受性是如何被打破的。这些研究对于了解患有自身免疫性疾病的人是如何产生攻击自己身体的抗体具有重要意义，并可能为开发新药提供线索。

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.