Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Department of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy.
Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):E11369-E11378. doi: 10.1073/pnas.1809028115. Epub 2018 Nov 12.
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.
乙型肝炎病毒（HBV）相关的急性肝衰竭（ALF）是一种严重的临床综合征，导致 80%的病例死亡或需要进行肝移植。由于其极快的临床病程、获取肝组织标本的困难以及缺乏动物模型，ALF 的发病机制在很大程度上仍然未知。在这里，我们对 HBV 相关 ALF 患者肝组织中的病毒和宿主进行了全面的遗传和功能表征，并将结果与黑猩猩中的经典急性乙型肝炎进行了比较。与急性乙型肝炎不同，在 ALF 肝脏中检测到的 HBV 株显示出高度突变的 HBV 核心抗原（HBcAg），与体外 HBcAg 表达增加相关，而与病毒复制水平无关。联合基因和 miRNA 表达谱分析显示出主导的 B 细胞疾病特征，具有广泛的肝内产生 IgM 和 IgG 的同种型，仅以亚纳摩尔亲和力针对 HBcAg，并伴有补体沉积。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，是由宿主具有不寻常的 B 细胞反应和感染病毒具有高度突变的核心抗原这一罕见而不幸的遭遇所导致的。
