Significance Hepatitis B virus (HBV)-associated acute liver failure (ALF), also known as fulminant hepatitis B, is a rare but often fatal complication of acute HBV infection. The pathogenesis of ALF is still largely unknown due to the lack of experimental systems and the difficulties in obtaining liver samples. Our comprehensive study of both liver tissue and serum samples from ALF patients using cutting-edge technologies allowed us to identify viral and host factors uniquely associated with this disease. In contrast to classic acute hepatitis B where the liver damage appears to be T cell-mediated, this study demonstrates a major role of the humoral immunity in the pathogenesis of HBV-associated ALF, which may open new avenues for the diagnosis and treatment of this dramatic disease. 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.
【저자키워드】 Pathogenesis, Humoral immunity, acute liver failure, Hepatitis B virus, hepatitis B core antigen,