Virus-induced anti-asialoglycoprotein receptor autoimmunity in experimental hepadnaviral hepatitis.
The relationship between hepatitis virus invasion and emergence of liver-specific autoantibodies against asialoglycoprotein receptor (anti-ASGPR) and the occurrence patterns, prognostic value, and specificity of these autoantibodies toward polypeptides of host ASGPR were investigated in experimental viral hepatitis in the woodchuck system. Sequential sera (n = 231) obtained before and after inoculation with woodchuck hepatitis virus (WHV) from animals which resolved acute infection (n = 7) or developed chronic hepatitis (n = 6) were tested for anti-ASGPR using radio and enzyme-immunodetection assays. In addition, the outcome of WHV hepatitis was analyzed in 30 other woodchucks whose preinoculation sera were tested for anti-ASGPR. The receptor subunit specificity of virus-induced anti-ASGPR was determined by Western blotting and compared with that of anti-ASGPR raised in woodchucks challenged with a heterologous (rabbit) receptor. The results revealed that WHV infection triggered anti-ASGPR in all except one of the initially autoantibody nonreactive animals (eight of nine; 89.9%). Once induced, anti-ASGPR were detectable throughout the entire follow-up independent of histological severity of liver damage or the outcome of hepatitis. In healthy WHV-naive woodchucks, anti-ASGPR occurred at low titers in approximately one third of the animals. Importantly, woodchucks reactive for anti-ASGPR before WHV inoculation developed chronic hepatitis with a significantly greater frequency (55.5%) than those autoantibody negative (15.6%; P < .05). In contrast to anti-ASGPR elicited by immunization with a heterologous receptor, which initially recognized only the ASGPR 40-kd polypeptide, anti-ASGPR emerging after virus invasion reacted with both the ASGPR 40- and 47-kd subunits from the moment of their appearance. This study provides the first direct evidence that hepatitis virus in the natural host triggers autoantibodies against a unique hepatocyte antigen and shows that anti-ASGPR autoimmunity existing before virus infection is associated with a high rate of progression to chronic disease in experimental hepadnaviral hepatitis.
Diao
J
J
Molecular Virology and Hepatology Research, Division of Basic Medical Sciences, Memorial University of Newfoundland, St. John's, Canada.
Michalak
T I
TI
D000818:Animals; D037263:Asialoglycoprotein Receptor; D001323:Autoantibodies / Q000097:blood*; D015153:Blotting, Western; D003429:Cross Reactions / Q000276:immunology; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D017919:Hepatitis B Virus, Woodchuck / Q000276:immunology*; D008392:Marmota; D011956:Receptors, Cell Surface / Q000276:immunology*
D037263:Asialoglycoprotein Receptor; D001323:Autoantibodies; D011956:Receptors, Cell Surface