脂联素调节B细胞功能的分子机制及其在类风湿关节炎致病中的作用研究

The adipocytes have originally been considered as none-bioactive cells mainly devoted to energy storage. During the last decade or so, we have shown that adiponectin (AD), one of adipokines produced by adipocytes, is highly expressed in the inflammated joint of rheumatoid arthritis (RA) patients and correlats closely with progressive bone erosion, but the mechanism remained largely unclear. The most important pathologic changes at chronic inflammatory stage of RA include synovitisis and tissue lesion, which involves in B cells. Several lines of evidence have pointed to B cell function as a critical factor in the development of RA. And we have found that not only AD receptor was highly expressed on B-cell surface,but also AD could promote B-cell proliferation and differentiation, which involves in synovitisis in CIA. Base on our previous studies and current findings, we hypothesize that AD may mediate synovial inflammation and tissue lesion of RA through modulating B-cell function directly. Taken together, our proposed studies will determine a critical role of AD during the pathogenesis of autoimmune arthritis, which may contribute to the identification of AD as a new therapeutic target for RA treatment.

现代医学发展已经意识到脂肪细胞在炎症发生中有重要作用。我们近十年来的工作也证实类风湿关节炎炎性关节中脂肪细胞分泌的脂联素高表达后，滑膜炎症和骨侵蚀明显加重，表明脂联素的确与类风湿关节炎的局部炎症和组织损伤有关，但作用机制尚不清楚。B细胞在类风湿关节炎的局部病理变化也非常重要。而我们已发现B细胞表面高表达脂联素受体，用脂联素刺激B细胞能使其发生增殖与活化，并参与胶原诱导关节炎（collagen induced arthritis，CIA）小鼠的滑膜炎症发生。据此，本研究拟在已有研究基础上，以CIA小鼠为模型，系统研究脂联素介导的B细胞通路在类风湿关节炎发病中作用和调控机制，为阐明脂联素参与炎症、介导组织损伤提供实验理论与实验依据，也为脂肪因子参与炎症提供新的依据，为进一步发展类风湿关节炎临床治疗提供新的靶点。

现代医学发展已经意识到脂肪细胞在炎症发生中有重要作用。我们近十年来的工作也证实类风湿关节炎炎性关节中脂肪细胞分泌的脂联素高表达后，滑膜炎症和骨侵蚀明显加重，表明脂联素的确与类风湿关节炎的局部炎症和组织损伤有关，但作用机制尚不清楚。B细胞在类风湿关节炎发病中发挥着重要的病理作用，而我们已发现B细胞表面高表达脂联素受体。据此本研究在已有工作基础上，以胶原诱导关节炎（CIA）小鼠为模型，发现小鼠关节局部高表达脂联素后可显著促进CIA小鼠发病时间的提前并加重病情，而且通过流式细胞术检测到CIA小鼠关节局部CD138+浆细胞的比例显著增加。继而在体外实验中观察到脂联素可以明显促进B细胞的增殖和分化，并与脂联素的剂量存在依赖性。在这一过程中与B细胞分化成熟密切相关的转录因子Blimp-1的表达明显增高，另一转录因子PAX-5的表达显著下降。而在CIA小鼠关节局部注射脂联素受体1的shRNA从而抑制脂联素受体1的表达后，关节局部浆细胞比例显著减少，而CIA小鼠发病更迟且疾病严重程度明显减轻。本研究阐述了脂联素对B细胞增殖和分化具有的直接促进作用，而这可能是加重类风湿关节炎关节炎症和组织损伤的重要机制之一，为进一步发展类风湿关节炎的临床治疗提供了新的靶点。