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Next‐generation sequencing of the intrahepatic antibody repertoire delineates a unique B‐cell response in HBV‐associated acute liver failure

Hepatitis B virus (HBV) is a major cause of acute liver failure (ALF) worldwide. While liver damage in classic acute hepatitis B is believed to be T‐cell mediated, the pathogenesis of HBV‐associated ALF remains largely unknown. Access to liver specimens from well‐characterized patients with HBV‐associated ALF provided us with the opportunity to perform next‐generation sequencing (NGS) of the entire VH repertoires of IgM and IgG from the livers of four ALF patients, a control liver donor and a patient with chronic HBV infection. We found that ALF is not associated with expansion of specific B‐cell lineages. However, NGS showed that the intrahepatic VH repertoires from ALF patients were characterized by the abundant presence of antibodies in germline configuration in contrast to their marginal prevalence in controls. Moreover, NGS identified a large number of VH genes in germline configuration with identical VDJ sequences in the IgM and IgG repertoires in all four ALF patients, indicating that isotype switch from IgM to IgG had occurred without somatic hypermutation. The results of this study indicate that the presence of intrahepatic antibodies in unmutated germline configuration is a broad phenomenon in the global antibody repertoire generated from total RNA derived from whole‐liver tissue that is strongly associated with ALF, suggesting a major role of T cell–independent humoral immunity in the pathogenesis of ALF.