原发性干燥综合征中调节性B细胞功能缺陷及TACI对其调控机制研究

原发性干燥综合征（pSS）是以外分泌腺受累为主的慢性自身免疫性疾病，主要表现为B细胞高度活化。课题组前期研究发现pSS患者B细胞亚群存在偏倚，调节性B细胞（Breg）比例显著增加，但其所分泌具有抑炎作用的IL-10水平下降，同时其表面跨膜蛋白活化因子钙离子信号调节亲环素配体耦合子（TACI）表达下调。本课题将以上述发现为切入点，探讨是否由于Breg细胞TACI表达下调，B细胞活化因子（BAFF）不能通过其促进Breg细胞核转录因子激活蛋白1（AP-1）活化，进而导致IL-10转录及合成减少，致使Breg细胞不能有效发挥对T细胞的调控，不能有效迁移至炎症组织中发挥抑炎作用。同时课题组拟在pSS小鼠模型中利用体内试验进一步证实BAFF-TACI-AP-1-IL-10这一环节受损对Breg细胞调节功能的影响，并且TACI是该环节的关键因子。期望上述发现能够对pSS靶向治疗提供新的思路。

Primary Sjogren’s syndrome (pSS) is a chronic autoimmune disorder that typically affects exocrine glands-mainly labial and lacrimal. Our previous study revealed that the phenotype and function of peripheral blood B cell subsets were abnormal in pSS patients, especially the regulatory B cells (Breg). Breg cells could down-regulate immune response by IL-10 secretion, but the IL-10 level secreted by Breg cells was reduced in pSS patients, and meanwhile the transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) on the Breg cells were down-regulated. The objective of this research is to elucidate the complicated functional deficiency of Breg cells with IL-10 and the interaction with T cells in pSS patients, then to investigate whether and how Breg cells fail to regulate the hyper-responsiveness of inflammation in pSS patients and if the absence of TACI is the key point in the Breg cells development and excitation. We then will further verify in vivo how the BAFF-TACI-AP-1-IL-10 pathway regulating the function of Breg cells in the experimental SS mouse model. The research may help to explicit the immune-regulatory role of B cells in pSS and it will be the experimental basis of new optimal treatment to pSS patients.