IFNα治疗后PD-1调控B淋巴细胞功能在HBsAg清除中的作用机制研究

HBsAg clearance represents a cure for hepatitis B, but it is extremely difficult to obtain, which seriously hinders the exploration of the immunological mechanism of HBsAg clearance. In the early stages, we established a large clinical cohort of interferon (IFN α) therapy for HBsAg carriers and obtained a large number of cases and series of specimens of HBsAg clearance. We found that the serum PD-1 level decreased and the number of B lymphocytes increased. Does PD-1 regulate B cell function infect the HBsAg clearance? Therefore, we propose that after IFNα treatment, the level of PD-1 expression on the surface of B cells decreases, and the function of B cells increases, resulting in more anti-HBs antibodies, which eventually contributes to HBsAg clearance. This project aims to analyze the changes of B cells and their PD-1 expression level after IFNα therapy, and to investigate the correlation between B cells secretion of anti-HBs antibody and HBsAg clearance. Finally, the mechanism of PD-1 regulating B cell function in HBsAg clearance was studied in vitro. This study is expected to provide a basis for the development of a new hepatitis B cure scheme, and provide a new target for the development of hepatitis B cure drugs.

HBsAg清除代表乙肝治愈，但临床极难获得，这严重阻碍了对HBsAg清除免疫学机制的探索。前期我们建立了干扰素（IFNα）治疗HBsAg携带者大型临床队列，获得大量HBsAg清除病例及系列标本。而且发现清除者血清PD-1水平明显下降、B淋巴细胞数量明显增加。我们设想PD-1调控B细胞功能可能在HBsAg清除中起重要作用，据此提出：IFNα治疗后，B细胞表面PD-1表达水平下降，B细胞功能增强，产生更多抗-HBs抗体，最终有助于HBsAg清除。本项目拟在已有队列基础上，分析IFNα治疗后B细胞及其PD-1表达水平变化、探讨B细胞及其亚群分泌抗-HBs抗体能力与HBsAg清除的相关性。最后通过体外试验对PD-1调控B细胞功能在HBsAg清除中的作用机制进行深入研究。本研究有望为制定乙肝治愈新方案提供依据，为研发乙肝治愈药物提供新靶点。

HBV感染呈全球性流行，我国现有慢性HBV感染者约9300万，每年高达33万人死于乙肝肝硬化及肝癌。HBsAg清除/转换是目前评估乙肝抗病毒治疗的最佳疗效标准，代表乙肝治愈，但现有的两种抗病毒药物不能彻底清除HBV，HBsAg清除率极低。探讨HBsAg清除相关的免疫学机制意义重大，可为研发治愈乙肝药物提供新靶点。B淋巴细胞亚群及其功能在慢性HBV感染中起重要作用，但既往研究对于B淋巴细胞介导的体液免疫却少有关注。. 本项目在已有干扰素治疗非活动性HBsAg携带者的队列基础上，分析了IFNα治疗后HBsAg清除者及未清除者B淋巴细胞及其PD-1表达水平变化、B细胞及其亚群与HBsAg清除的相关性，从而探讨PD-1调控B细胞功能在HBsAg清除中的作用。本研究发现B淋巴细胞及浆细胞与HBsAg清除相关，HBsAg清除者在干扰素治疗过程中总B细胞及浆细胞数量明显高于未清除者。亚群分析显示HBsAg清除者PD1+B淋巴细胞数量明显低于未清除者。HBsAg清除者IgG+naive B细胞频数明显高于未清除者。另外提出血清IgG及其亚类水平降低与HBsAg清除相关，可作为预测HBsAg清除的新型标志物。. 本项目培养博士生1名，硕士生3名。负责人曹振环晋升主任医师、获得北京市扬帆计划项目资助。团队覃岭晋升副研究员。发表SCI文章7篇，总影响因子37.061分。.