Loss of B Cell Tolerance in Rheumatoid Arthritis

描述(申请人提供)：通过成功地用消除B细胞的抗CD20单抗治疗类风湿性关节炎(RA)和其他自身免疫性疾病，B细胞在自身免疫疾病中的作用现在在小鼠模型和人类中都得到了明确的证实。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。我们最近证实，这些早期的B细胞耐受缺陷是这些自身免疫性疾病的主要原因，并且可以由PTPN22等风险等位基因诱导，这些风险等位基因干扰B细胞受体(BCR)信号转导和中枢B细胞耐受的建立。此外，作为中枢B细胞耐受机制之一的无能，似乎在一些RA患者中受到青睐，如外周无反应性自身反应性B细胞的频率增加，这些B细胞不表达补体受体2/CD21，并且对BCR和CD40的触发无效。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。因此，在RA患者中，受体的编辑和缺失无法得到适当的调节，而无能也导致到达周围的自体反应性B细胞的数量增加，在那里，炎症条件，如滑膜，可能导致这些自体反应性B细胞的激活，促进疾病的发展。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。

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.