Loss of B Cell Tolerance in Rheumatoid Arthritis

然而，B细胞促进自身免疫性疾病发展的潜在机制仍然知之甚少。我们先前证明，未经治疗的活动期RA患者、系统性红斑狼疮患者和1型糖尿病患者表现出异常的早期B细胞耐受检查点，导致其血液中大量自身反应性NAOVE B细胞积聚。因此，RA患者NAOVE自身反应性B细胞数量的增加可能有利于疾病的发展，但什么途径和机制打破B细胞耐受性仍有待确定。这项拟议研究的长期目标是继续表征在健康人中调节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细胞存在由相关风险等位基因引起的固有缺陷，这些缺陷影响感知自身抗原，并导致中枢B细胞耐受机制的诱导/调节发生改变。此外，了解防止或解释自身反应性B细胞产生的机制可能会为控制疾病和设计更特异和更持久的治疗方法提供新的方法。 公共卫生相关性：这项提案旨在展示遗传易感性如何改变类风湿性关节炎B细胞耐受机制的诱导和调节。此外，我们还将研究自身反应性B细胞的激活，这些细胞渗透到RA患者的滑膜中，并可能促进疾病的发病。

DESCRIPTION (provided by applicant): A role for B cells in autoimmune diseases is now clearly established both with mouse models as well as in humans by successful treatment of rheumatoid arthritis (RA) and other autoimmune diseases with anti-CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells may promote the development of autoimmune diseases remain poorly understood. We previously demonstrated that untreated active RA patients, patients with systemic lupus erythematosus, and patients with type 1 diabetes display abnormal early B cell tolerance checkpoints resulting in the accumulation of large numbers of autoreactive naove B cells in their blood. We recently established that these early B cell tolerance defects were primary to these autoimmune diseases and can be induced in asymptomatic donors by risk alleles such as PTPN22, which interfere with B cell receptor (BCR) signaling and the establishment of central B cell tolerance. In addition, anergy, one of the central B cell tolerance mechanisms, seems to be favored in some RA patients as illustrated by the increased frequency of peripheral unresponsive autoreactive B cells, which do not express the complement receptor 2/CD21 and are refractory to BCR and CD40 triggering. Hence, increased numbers of naove autoreactive B cells in patients with RA may favor disease development but it remains to be determined what pathways and mechanisms break B cell tolerance. The long range goal of the proposed research is to continue to characterize 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 defects caused by associated risk alleles, which impinge on sensing self-antigens and result in an altered induction/regulation of central B cell tolerance mechanisms. Hence, receptor editing and deletion fail to be properly regulated in RA patients whereas anergy also contributes to the increased numbers of autoreactive B cells reaching the periphery where inflammatory conditions such as in the synovium may lead the activation of these autoreactive B cells and promote disease development. In addition, understanding the mechanisms that prevent or account for the production of autoreactive B cells may suggest new approaches to control disease and design more specific and sustained therapies. PUBLIC HEALTH RELEVANCE: This proposal intends to demonstrate how genetic predispositions alter the induction and the regulation of B cell tolerance mechanisms in rheumatoid arthritis. In addition, we will study the activation of autoreactive B cells that infiltrate the synovium of RA patients and potentially promote disease pathogenesis.