调节性B细胞在肝纤维化进程中的免疫调控作用及机制研究

肝纤维化的免疫调控机制受到重视，新近发现B细胞可分化为调节性B细胞(Bregs)，通过分泌IL-10或与细胞直接作用，调节免疫耐受及免疫应答。我们在研的国家自然科学基金课题表明乙肝肝纤维化进程趋于免疫耐受状态，Treg/Th17稳态向Treg的偏移可影响HSCs促纤维化功能；而Bregs是Tregs依赖的免疫耐受所必须的，我们预实验在HBV慢性感染小鼠与患者体内检测到Bregs差异表达。本次申请以观察慢性乙肝患者与HBV慢性感染小鼠各B细胞亚型(特别是Bregs)与肝纤维化分级分期关系为基础，以Bregs对CD4+T细胞与HSCs功能影响为主线，通过细胞共培养、获得性Bregs转移等途径探讨肝纤维化时Bregs调控CD4+T细胞功能、诱导Tregs生成影响Treg/Th17平衡及调节HSCs促纤维化功能及机制，深入阐述Bregs对肝纤维化进程的免疫调控作用，为免疫治疗肝纤维化提供理论基础。

The immunological modulation in liver fibrosis is increasingly focused on and has shed new light on related researches. Since the immunoregulations of T cells, NK cells and NKT cells have been gradually clarified, do B cells, which represent 10% of the whole lymphocytes, also play regulatory roles in the process? Recent studies indicate B cells are no longer bystanders and influence the process of liver fibrosis independent on antibodies. State of the art, B cells are reported to differentiate into a new subset-regulatory B cells (Bregs), which can regulate T cell-mediated responses and induce the production of regulatory T cells (Tregs) via cell-contact or secreting IL-10, hence suppressing overactive immune responses and modulating immune tolerance. Supported by our research of the NSFC (No. 81070341), the process of hepatitis B-induced fibrosis inclined to a state of immune tolerance and the Treg/Th17 imbalance exhibiting as Treg dominance affected the fibrogenic function of HSCs, indicating there's a bidirectional regulation between the immune state and the process of liver fibrosis. Apart from Tregs, do Bregs contribute to immune tolerance in liver fibrosis as well? Bregs are proposed to be indispensable for Tregs-induced immune tolerance and in our preliminary experiments Bregs actually represented different frequencies in both spleen of chronic HBV-infected mice models and peripheral blood of chronic hepatitis B patients. Interestingly, our performed research of NSFC (No.30300151) also verified that HSCs could migrate into portal area and interact with lymphocytes there in the process of liver fibrosis. Therefore, this research will firstly observe the relation between B cell subsets especially Bregs and pathological grades and stages of liver fibrosis in chronic HBV-infected mice models and chronic hepatitis B patients. Secondly, Bregs-conducted influence on functions of CD4+T cells and HSCs will be mainly focused on via in vitro cells co-culture and adoptive transfer of Bregs, in details: 1) how Bregs affect CD4+T cell proliferation, maintenance, cytokine secretion as well as the balance of T cell subsets especially between Tregs and Th17; 2) how Bregs regulate the profibrotic functions of HSCs and reversely how HSCs affect proliferation and cytokine secretion of B cells in the process of liver fibrosis. Based on the above-mentioned research, we look forward to a better understanding of the role of Bregs in the immunoregulation in hepatitis B-induced fibrosis, hence enriching our acquisition about immune microenvironment of liver fibrosis and also providing theoretical foundations and application basis for its clinical immunotherapy.