嗜碱性粒细胞在类风湿性关节炎T、B淋巴细胞免疫应答失衡中的调节机制研究

Imbalance of T and B lymphocytes immune response play a key role in the development of rheumatoid arthritis (RA). Basophils can migrate into the l lymph nodes and inflammatory sites and regulate the immune response of T and B cells by expression of various immune molecules (CD40/CD40L/CD62L/ HLA-DR/BAFF/ CCRs etc) and secret series of media (IL-4/6/13 and histamine etc) after activation, but in terms of rheumatoid arthritis (RA) have not been reported. We found that peripheral basophils of RA patients were activated and decreased in counting, and can be detected in the synovial fluid of RA patients and the lymph nodes of mouse models. So, we propose a hypothesis that basophils involved in RA by regulating the immune response of T and B cells. The project intends to adopt clinical patients, in vitro and animal experiments to study following questions: ⑴ To explore the relationship between changes of periphery basophils with Th1/Th2/Th17 imbalance, B cell activation and disease activity by the detection of blood samples of RA patients; ⑵ To explore the mechanisms of activation of periphery basophils of RA patients and the impact on CD4+ Naive and Effector Memory T cell and B cell function in vitro; ⑶ To explore the impact of adjustment of basophils activation state and number on the disease progression of RA model mice. This project will help to explore the new mechanisms of RA disease, and provide new clues for RA therapeutic strategies.

T、B细胞免疫应答失衡是类风湿性关节炎(RA)发病的核心。嗜碱性粒细胞(Ba)表达多种免疫分子(CD40/CD40L/CD62L/HLA-DR/BAFF/CCRs等)，活化后分泌系列介质(IL-4/6/13和组胺等)，可迁徙至淋巴结和炎症部位调节T、B细胞免疫应答，但在RA未见报道。我们发现RA患者外周Ba高度活化且减少，并可在患者关节滑液和模型小鼠淋巴结中检出，进而提出Ba通过调节T、B细胞免疫应答参与RA发病的假说，拟用临床标本、体外细胞和动物实验对假说进行验证：⑴检测临床标本，明确Ba变化与Th1/Th2/Th17应答失衡、B细胞过度活化和疾病活动度的关系⑵体外研究RA患者Ba活化机制和活化后对CD4+Naive和Effector memory T、B细胞免疫应答的调节作用⑶调整Ba活化和数量对RA模型小鼠疾病进展的影响。该研究有助于明确RA发病的新机制，并为新的治疗策略提供线索。

T、B细胞免疫应答失衡是类风湿性关节炎(rheumatoid arthritis, RA)发病的核心。已报道，嗜碱性粒细胞(basophil, Ba)活化后功能强大，表达多种免疫分子，分泌系列介质，并可迁徙至淋巴结和炎症部位调节T、B细胞免疫应答。本研究发现：在发病早期，嗜碱性粒细胞活化所诱发的Th2应答失衡可决定其是否进展为RA，是关键发病环节之一。在RA发病中晚期，嗜碱性粒细胞活化后可趋化至关节滑膜，促进滑膜细胞增殖并生成大量炎症因子，进而加重局部关节炎症。同时，在RA发病中晚期，嗜碱性粒细胞活化后可介导自身反应性B 细胞克隆增殖，进而产生大量自身抗体加剧RA 发病。该研究进一步明确了RA发病的新机制，并为靶向嗜碱性粒细胞防治RA提供了依据。