青蒿琥酯通过IRF4调控B细胞功能治疗干燥综合征的作用与机制研究

原发性干燥综合征（pSS）为临床疑难自身免疫病，严重降低患者生活质量。目前该病发病机制不清，临床缺乏有效治疗的药物。近期研究发现B细胞过度激活和分化是其发病的重要机制之一，提示阻断B细胞激活通路可能是治疗pSS的有效策略。中药青蒿提取物青蒿素的衍生物青蒿琥酯（ART）具有免疫调节作用并可治疗多种自身免疫性疾病。申请人前期研究发现ART可显著改善实验性干燥综合征小鼠（ESS）疾病症状，减少唾液腺组织淋巴细胞浸润，并抑制B细胞的激活和浆细胞的分化成熟。基于现有文献支持和前期实验数据，申请人推测ART可抑制B细胞的过度激活和浆细胞的分化，降低自身抗体表达，有效缓解ESS发病，进而起到治疗作用。本研究拟从IRF4信号通路调控B细胞功能角度出发，验证ART治疗ESS的效果并阐明其发挥免疫调节作用的分子机制，为pSS的治疗提供研究新靶点和新方向，进而为临床治疗pSS的药物研发及转化研究提供新思路。

Primary Sjogren’s syndrome (pSS) is a chronic autoimmune disease, severely affecting the quality of life in patients. The etiology of pSS remains currently unclear and there is a lack of effective treatment for this disease. Recent studies have suggested a critical involvement of overactivation and differentiation of B cells in pSS pathogenesis, indicating that targeting B cell activation may represent an effective therapeutic strategy. Artesunate (ART), a derivative from Artemisinin, has been extensively used for treating various autoimmune disorders. Our pilot studies found that ART treatment potently inhibited B cell activation and significantly attenuated the development of experimental SS in mice. Based on available evidence and our preliminary results, we propose that ART can treat ESS via suppressing B cell function and autoantibody production. In this project, we will investigate the immunomodulatory function of ART and underlying mechanisms by which ART regulates IRF4 signaling pathway and affects B cell function. The expected findings may identify novel therapeutic target and provide new treatment strategy for pSS.