B细胞在清除慢性乙肝患者HBsAg中的作用机制

HBV-specific B-cell immune responses not only influence the disease progression, but also affects the efficacy of antiviral treatment in patients with chronic hepatitis B (CHB). However, several key issues remain unclear on B cell-mediated humoral immune responses in chronic HBV infection, such as how are B cells impaired in CHB patients with different stages? Whether is the impairment of B cells induced by high titer of HBsAg in vivo? Regarding these issues, we performed a preliminary study and found that HBV-specific B cell responses including HBV-specific neutralizing antibody production were significantly enhancedwith the occurrence of HBsAg seroconversio. Basing on these data, we hypothesize that HBV-specific B cell responses play an important role in clearing HBV and leading disease resolution of chronic HBV infection. To address the issues, we will enroll four cohorts with various levels HBsAg titer. We will characterize HBV-specific B cell responses and uncover the dynamic of B cells during the process of HBsAg seroconversion. Furthermore, we will confirm this key role of B cells in clearing HBV infection in a clinical trial and HBsAg transgenic mice model using neutralizing antibody treatment. These findings, for the first time, define the dynamic of B cell responses in chronic HBV infection and will be helpful in finding novel marker predicting antiviral efficacy, perfecting the antiviral regimen and providing new therapeutic targets in clinic.

HBsAg血清学转换是慢性乙肝临床抗病毒治疗的理想终点。然而，以B细胞为主的体液免疫在慢性乙肝临床转归中的作用特点及其机制至今尚未阐明。我们前期的研究发现：慢性乙肝患者在HBsAg血清学转换过程中，HBV特异性B细胞功能及其分泌表面抗体的能力显著增加。据此，我们提出：抗HBV特异的B细胞免疫应答在慢性乙肝的康复过程中发挥了关键作用。本项目将利用我院丰富的临床资源，重点阐明慢性乙肝不同时期以及HBsAg血清学转换过程中，B细胞免疫应答的特点、变化规律和及其与清除病毒的关系；同时，结合慢性乙肝患者接受高效价HBsAb抗体治疗的临床研究和相关的动物模型分析，我们将进一步证实B细胞免疫在清除HBV感染中的关键作用及其机制。该研究将揭示慢性HBV感染过程中，HBV特异性的B细胞免疫应答规律及其与临床抗病毒治疗预后的关系，为研发新的治疗策略和进一步提高临床疗效提供科学依据。

HBsAg血清学转换是慢性乙肝临床抗病毒治疗的理想终点。然而，以B细胞为主的体液免疫在慢性乙肝临床转归中的作用特点及其机制至今尚未阐明。据此我们研究了慢性乙肝临床进展不同阶段中B细胞的频率、表型以及功能特点，发现慢性乙型肝炎IA期患者B细胞处于超活化状态并有HBsAg特异性B细胞功能损害，并且可以在PR患者中恢复。上述研究结果展示了乙型肝炎中B细胞功能新的视角，提示针对HBsAg特异性B细胞研究将是针对乙型肝炎的一种新型治疗策略。