Modulation of the Outcome and Severity of Hepadnaviral Hepatitis in Woodchucks by Antibodies to Hepatic Asialoglycoprotein Receptor

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Abstract
Viral hepatitis is frequently accompanied by humoral autoimmune responses toward both organ–nonspecific and liver–specific antigens, but contribution of these reactivities to liver injury remains unrecognized. Infection with woodchuck hepatitis virus (WHV) has been identified as a potent inducer of autoantibodies against asialoglycoprotein receptor (anti–ASGPR), a molecule essentially unique to hepatocytes that mediates clearance of desialylated serum proteins. In this study, we applied the WHV–woodchuck model of hepatitis B to examine the effect of experimentally elicited anti–ASGPR on the progression and the severity of WHV hepatitis in initially healthy animals immunized with the receptor and then infected with WHV and in woodchucks with ongoing chronic WHV hepatitis. The results implied that the induction of anti–ASGPR prior to WHV infection tends to modulate acute viral hepatitis toward chronic outcome and, in animals with established chronic WHV infection, exacerbates histologic severity of liver lesions. The findings also suggest that the liver compromised by chronic hepadnavirus infection might be prone to anti–ASGPR–directed complement–mediated hepatocellular injury and that this is associated with formation of the ASGPR–anti–ASGPR immune complexes on hepatocyte surface. In conclusion, the host's immune response mounted against a hepatocyte–specific autoantigen may modulate both the outcome and the severity of liver injury in viral hepatitis.

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