乙肝表面抗体（抗-HBs）不足导致的免疫应答紊乱是阻碍慢性HBV感染者实现“功能性治愈”的重要原因之一。HBsAg特异性非典型记忆B细胞（atMBC）功能缺陷是抗-HBs不足的重要诱因，机制尚未阐明。申请人首次发现，HBsAg特异性atMBC细胞无法向浆细胞分化，高表达抑制性共受体分子CTLA4，且BCR信号通路中SHP1等蛋白磷酸化水平异常，信号传导受阻；在拮抗CTLA4蛋白功能后可部分恢复BCR信号传导，细胞分化和抗-HBs分泌。故推测，CTLA4蛋白可能通过SHP1蛋白抑制BCR信号通路蛋白磷酸化水平阻碍BCR信号胞内传递，从而抑制细胞分化和抗-HBs分泌。本项目拟从CHB队列、细胞和小鼠模型入手，阐明HBsAg特异性atMBC细胞上调表达CTLA4造成抗-HBs分泌障碍的机制，探讨拮抗CTLA4作为CHB患者辅助治疗的可行性。

The disordered immune response caused by the deficiency of anti-HBs is one of the important reasons that hinder the "functional cure" of chronic HBV infection. Defected anti-HBs secretion by HBsAg specific atypical memory B cell (atMBC) is an important cause of anti-HBs deficiency, and the mechanism remains unelucidated. The preliminary study for the first time found that HBsAg specific atMBC cells had high expression of the inhibitory co-receptor molecule CTLA4, defected plasma cell differeation and its expression level was negatively correlated with the efficacy of patients The disordered immune response caused by the deficiency of anti-HBs is one of the important reasons that hinder the "functional cure" of chronic HBV infection. Defected anti-HBs secretion by HBsAg specific atypical memory B cell (atMBC) is an important cause of anti-HBs deficiency, and the mechanism remains unelucidated. The preliminary study for the first time found that HBsAg specific atMBC cells had high expression of the inhibitory co-receptor molecule CTLA4, the phosphorylation level of some signal proteins in the BCR pathway was abnormal, and BCR pathway was blocked. By antagonizing the function of CTLA4, BCR signaling and anti-HBs secretion could be restored to a certain extent. These results suggest that by interacted with SHP1, CTLA4 may inhibit the intracellular transmission of BCR signal by altering the phosphorylation level of downstream proteins in the BCR signaling pathway, thereby inhibiting the secretion of anti-HBs. Through the researches on CHB cohort, hbv-transfected cells and mouse model, this project aims to investigate the phenomenon and mechanism of anti-HBs secretion deficiency caused by up-regulated expression of CTLA4 in HBsAg specific atMBC cells, so as to provide theoretical and experimental evidences for designing new immunotherapy strategies of "functional cure".