Loss of B Cell Tolerance in Rheumatoid Arthritis

描述（由申请人提供）：B细胞在自身免疫性疾病中的作用现在已经通过小鼠模型和人类模型明确确立，通过使用抗cd20单克隆抗体消除B细胞成功治疗类风湿关节炎（RA）和其他自身免疫性疾病。然而，B细胞可能促进自身免疫性疾病发展的潜在机制仍然知之甚少。我们之前的研究表明，未经治疗的活动性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nave B细胞的积累。我们最近发现，这些早期B细胞耐受缺陷是这些自身免疫性疾病的原发原因，可以在无症状供者中由PTPN22等风险等位基因诱导，这些等位基因干扰B细胞受体（BCR）信号传导和中央B细胞耐受的建立。此外，能量作为中枢B细胞耐受机制之一，似乎在一些RA患者中更受欢迎，外周无应答性自身反应性B细胞的频率增加说明了这一点，这些B细胞不表达补体受体2/CD21，并且对BCR和CD40的触发难以耐受。因此，RA患者自身反应性B细胞数量的增加可能有利于疾病的发展，但尚不清楚是什么途径和机制破坏了B细胞的耐受性。拟议研究的长期目标是继续表征在健康人中调节B细胞耐受性但在RA患者中存在缺陷的机制。工作假设是RA B细胞遭受由相关风险等位基因引起的内在缺陷，这些等位基因影响感知自身抗原并导致中枢B细胞耐受机制的诱导/调节改变。因此，受体编辑和缺失在RA患者中不能得到适当的调节，而能量也会导致自身反应性B细胞数量增加，到达周围，在那里滑膜等炎症条件可能导致这些自身反应性B细胞的激活并促进疾病的发展。此外，了解预防或解释自身反应性B细胞产生的机制可能为控制疾病和设计更具体和持续的治疗方法提供新方法。

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.