无能B细胞免疫耐受失衡参与系统性红斑狼疮发病机制的研究

Anergic B cells are natural to bind with self-antigen but unable to burst to immune response. The non-response to self-antigen is an important mechanism for the maintenance of immune tolerance. However, the possible role of anergic B cells in Systemic lupus erythematosus(SLE) remain unclear. Our early research found that the anergic state of anery B cells were reversed in patients of SLE. Hence,we hypothesized that the anergic B cells may restore their immune respond ability and then develop to autoreactive B cells in SLE. To verify this hypothesis, we try to assess the anergic state of anergy B cells in patients of SLE to explore the possible mechanisms involved from both intrinsic(cell signal transduction) and extrinsic(cell-cell contact) ways by FACS. In this study, we attempt to demonstrate the possible roles of anergic B cells in the pathogenesis of SLE from moleculars, cells and patients. These results may provide a new mechanism for the abnormal activation of B cells by aberrant immune regulation and envision new possibilities of targeted intervention in the disease pathogenesis.

无能B细胞（Anergic B cell）是一群能够与自身抗原相结合的自身反应性B 细胞，其免疫的无应答状态是维持免疫自身耐受的重要机制。迄今对无能B细胞在系统性红斑狼疮（SLE）患者中的研究仍知之甚少。我们的前期研究提示SLE中无能B细胞的免疫稳态失衡。为此我们提出假说：SLE中无能B细胞的"免疫无应答"状态被逆转，可能演变成为分泌致病抗体的自身反应性B细胞，作为促进SLE疾病发生发展的危险因素。为验证这一假说，我们拟采用流式细胞术检测无能B细胞在SLE患者中的免疫应答能力，从信号传导通路和细胞间相互作用两个不同角度，探索无能B细胞在SLE中免疫失耐受的机制。试图从分子、细胞及临床患者等多层次阐明无能B细胞免疫耐受失衡在SLE疾病发展中的作用。本研究将为SLE免疫调节紊乱导致无能B 细胞异常活化的机制提供新的思路，为寻求SLE新的治疗靶标作进一步的实践探索和理论铺垫。

无能B细胞（BND）的免疫无应答状态是维持免疫耐受的重要机制。其免疫耐受状态被激活可能发生自身免疫疾病的重要机制。在本项目的资助下，我们研究了系统性红斑狼疮(SLE)中BND在外周血中的比例与病情严重度和疾病活动性的关系。采用细胞表面活化分子检测和少量细胞RNA测序技术，评估了SLE患者中BND免疫耐受状态。利用狼疮小鼠动物模型，研究调节性T细胞对BND的调控作用。并初步探索了诱导B细胞无能的策略。该项目重要结果包括：证实了BND在系统性红斑狼疮(SLE)外周血中的比例显著降低，并与病情的严重度和活动性呈正相关；SLE中BND的免疫耐受状态被激活，调节性T细胞可通过CTLA-4/CD86通路影响B细胞的免疫无能状态；单克隆抗体Anti-CD79b可以通过下调BCR的表达诱导B细胞无能。这些研究结果提示：无能B细胞免疫耐受状态被激活参与SLE疾病的发生发展，无能B细胞在外周血中的比例与SLE的病情和活动度密切相关，是评估SLE病情的有效指标，利用单克隆抗体Anti-CD79b诱导B细胞无能有望作为调控SLE免疫耐受的新方法。