类风湿关节炎（RA）是一种高致残性自身免疫病，免疫稳态打破和自身免疫激活是其发病的关键和始动环节。研究提示调节性B细胞，尤其是B10细胞在维持免疫稳态中至关重要。本课题组前期研究发现，RA病人调节性B10细胞发生数量及功能缺陷，并与疾病发生发展密切相关，但具体机制不清。我们首次发现，在RA疾病状态下，B10细胞异常高表达致炎细胞因子、骨破坏因子以及幼稚B细胞标志物，展现致病性趋向。在此基础上，本项目拟利用RA患者和胶原诱导性关节炎小鼠，系统性探讨B10细胞致病性转变，包括致炎性转变（IFN-γ/IL-17-producing B10）、促破骨性转变（RANKL-producing B10）以及幼稚性转变（IgD+ B10）在RA发病中的作用、机制和信号通路，明确其相互关联，并进一步鉴定其表面标志物。据此揭示B10细胞数量/功能缺陷的机制，并筛选真正具有免疫调节功能的B10细胞用于RA治疗。

Rheumatoid arthritis (RA) is a kind of disease that causes highly progressive disability. It often results from the breakdown of immunological self-tolerance and activation of autoimmunity. Regulatory B cells, particularly B10 cells play crucial roles in the maintenance of the systemic immune homeostasis. Our previous studies showed that B10 cells were numerically decreased and functionally impaired in RA, playing crucial roles in the initiation and progression of the disease, yet the detailed mechanisms were largely unknown. In addition, we found for the first time that under RA circumstance, B10 cells ectopically expressed high levels of pro-inflammatory cytokines, osteoclast-priming factors, and naïve B cell marker, demonstrating pathogenic tendency. In this study, using RA patient specimens as well as collagen-induced arthritis (CIA) mice, we will systemically explore the role of B10 cell pathogenic conversion in RA. The pro-inflammatory conversion (IFN-γ/IL-17-producing B10), osteoclast-priming conversion (RANKL-producing B10), and naïve conversion (IgD+ B10) of B10 cells, as well as the intrinsic interactions and signaling pathways will be studied. Furthermore, the surface markers of these pathogenic B10 cells will be identified. This study will not only reveal the mechanisms of B10 cell numerical and functional impairment in RA, but also screen the veritable B10 cells with regulatory functions for RA treatment.