Role of humoral immunity against hepatitis B virus core antigen in the pathogenesis of acute liver failure
Role of humoral immunity against hepatitis B virus core antigen in the pathogenesis of acute liver failure
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DOI：
10.1073/pnas.1809028115
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发表时间：
2018-11-27
影响因子：
11.1
通讯作者：
Farci, Patrizia
中科院分区：
文献类型：
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作者：
Chen, Zhaochun;Diaz, Giacomo;Farci, Patrizia
B型肝炎病毒（HBV）相关的急性肝功能衰竭（ALF）是一种引人注目的临床综合征，导致80%的病例死亡或肝移植。由于ALF的临床过程非常迅速，难以获得肝脏标本，并且缺乏动物模型，其发病机制在很大程度上仍不清楚。在此，我们对HBV相关ALF肝组织中的病毒和宿主进行了全面的遗传和功能表征，并将结果与黑猩猩经典急性B型肝炎的结果进行了比较。与急性B型肝炎相反，在ALF肝脏中检测到的HBV毒株显示高度突变的HBV核心抗原（HBcAg），与体外HBcAg表达增加相关，这与病毒复制水平无关。结合基因和miRNA表达谱显示显性B细胞疾病特征，在生殖细胞构型中广泛产生IgM和IgG，专门靶向具有亚纳摩尔亲和力的HBcAg和补体沉积。因此，HBV ALF似乎是一种异常的T细胞非依赖性、HBV核心驱动的B细胞疾病，其由具有异常B细胞应答的宿主与具有高度突变的核心抗原的感染病毒之间的罕见和不幸的遭遇引起。
Hepatitis B virus (HBV)-associated acute liver failure (ALF) is a dramatic clinical syndrome leading to death or liver transplantation in 80% of cases. Due to the extremely rapid clinical course, the difficulties in obtaining liver specimens, and the lack of an animal model, the pathogenesis of ALF remains largely unknown. Here, we performed a comprehensive genetic and functional characterization of the virus and the host in liver tissue from HBV-associated ALF and compared the results with those of classic acute hepatitis B in chimpanzees. In contrast with acute hepatitis B, HBV strains detected in ALF livers displayed highly mutated HBV core antigen (HBcAg), associated with increased HBcAg expression ex vivo, which was independent of viral replication levels. Combined gene and miRNA expression profiling revealed a dominant B cell disease signature, with extensive intrahepatic production of IgM and IgG in germline configuration exclusively targeting HBcAg with subnanomolar affinities, and complement deposition. Thus, HBV ALF appears to be an anomalous T cell-independent, HBV core-driven B cell disease, which results from the rare and unfortunate encounter between a host with an unusual B cell response and an infecting virus with a highly mutated core antigen.