调节性B10细胞功能失调及异常调控在干燥综合征发病中的作用及机制研究

Sjogren's syndrome (SS) is characterized by infiltration of exocrine glands with T lymphocytes and activated B lymphocytes, leading to glandular dysfunction and multiorgan involvement. Loss of balance and activation of the innate immune system are therefore central to its pathophysiology. Regulatory B cells, particularly B10 cells play crucial roles in the maintenance of the systemic immune homeostasis. We have reported that in RA, regulatory B10 cells demonstrated the potential of converting into RANKL-producing cells, thus exacerbating disease progression. More importantly, our preliminary data showed that B10 cells were numerically decreased and functionally impaired in SS, and B10 cells ectopic expressed high level of pro-inflammatory cytokines, demonstrating pathogenic tendency. In this study, using SS patient specimens as well as mice models, we will systemically explore the numerical decrease, the functional impairment, the pathogenic conversion and the abnormal regulation of B10 cells and the mechanisms in SS. The pathogenic conversion (IFN-γ/IL-17-producing B10, antibody-secreting B10) as well as the intrinsic interactions and signaling pathways will be investigated. 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 SS, but also help screen the veritable B10 cells with regulatory functions for SS treatment.

干燥综合征（SS）是一种以淋巴细胞浸润外分泌腺和B淋巴细胞异常活化为特征的、可累及全身多器官多系统的慢性自身免疫性疾病。免疫稳态被打破和自身免疫激活是其发病的关键和始动环节。调节性B细胞，尤其是B10细胞在维持免疫稳态中至关重要。我们前期已发表的工作首次报道了调节性B10细胞功能缺陷，并发生致病性促破骨性转变，促进类风湿关节炎发病。本课题组前期研究发现，在SS患者中，调节性B10细胞发生数量及功能缺陷，且B10细胞异位高表达炎性细胞因子，展现致病性趋向，并初步鉴定了B10关键调控基因SHIP-1。在此基础上，本项目拟利用SS患者和小鼠模型标本，系统性探讨B10细胞数量/功能缺陷、致病性转变及异常调控在SS发病中的作用及分子机制，进而鉴定发生致病性转变的B10细胞的表面标志物。据此揭示B10细胞在SS发病中的作用及机制，并进一步筛选真正具有免疫负调控功能的B10细胞用于SS的治疗。

干燥综合征（Sjögren’s Syndrome, SS）是一种以淋巴细胞浸润外分泌腺引起口、眼干燥为特征，并可累及全身多系统和器官的慢性自身免疫性疾病。调节性B细胞，尤其是B10细胞在维持免疫稳态中至关重要。目前尚缺乏调节性B10细胞在pSS中的研究报道。本课题进行了系列探索，以揭示B10在pSS发病中发挥的重要作用。本研究发现：(1)B10细胞在pSS中发生了数量及功能缺陷，与疾病发生发展密切相关。B10细胞数量在pSS患者中明显降低，并与病程、血清IgA、IgG、类风湿因子、anti-SSA等pSS相关指标成负相关。pSS患者B10细胞抑制单核细胞分泌炎性细胞因子(如IL-6和TNF-α)的功能明显受损，提示B10细胞在pSS中发生功能缺陷。(2)B10细胞在pSS患者中发生了促炎性转变，转变为一群致炎性细胞(IFN-γ-pruducing B10 cells)，即CD19+CD24hiCD27+IFN-γ+细胞，其在pSS患者中的比例明显升高，提示B10细胞在pSS中发挥作用的可能机制。 (3)B10细胞在pSS患者中发生了促抗体性转变。B10细胞表达IgM及IgG的水平明显升高，表达IgD的水平明显降低，与pSS患者的抗体产生机制有关。(4)另一群新型调节性B细胞即CD24+CD38hi B细胞在pSS患者中显著升高，且与CD24hiCD27+ B10细胞呈负相关性，提示该群调节性B细胞可能共同参与了pSS的发病机制。 .通过该课题的研究，使我们对调节性B细胞免疫失衡在pSS发病中的作用及其机制有了进一步的认识，并为 pSS的免疫干预提供了新的思路。