VIRUS-INDUCED ANTI-ASIALOGLYCOPROTEIN RECEPTOR AUTOIMMUNITY IN EXPERIMENTAL HEPADNAVIRAL HEPATITIS

The relationship between hepatitis virus invasion and emergence of liv er-specific autoantibodies against asialoglycoprotein receptor (anti-A SGPR) and the occurrence patterns, prognostic value, and specificity o f these autoantibodies toward polypeptides of host ASGPR were investig ated in experimental viral hepatitis in the woodchuck system. Sequenti al 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 outco me of WHV hepatitis was analyzed in 30 other woodchucks whose preinocu lation sera were tested for anti-ASGPR. The receptor subunit specifici ty 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 infect ion triggered anti-ASGPR in all except one of the initially autoantibo dy nonreactive animals (eight of nine; 89.9%). Once induced, anti-ASGP R were detectable throughout the entire follow-up independent of histo logical severity of liver damage or the outcome of hepatitis. In healt hy WHV-naive woodchucks, anti-ASGPR occurred at low titers in approxim ately one third of the animals. Importantly, woodchucks reactive for a nti-ASGPR before WHV inoculation developed chronic hepatitis with a si gnificantly 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 ASGP R 40-kd polypeptide, anti-ASGPR emerging after virus invasion reacted with both the ASGPR 40- and 47-kd subunits from the moment of their ap pearance. This study provides the first direct evidence that hepatitis virus in the natural host triggers autoantibodies against a unique he patocyte antigen and shows that anti-ASGPR autoimmunity existing befor e virus infection is associated with a high rate of progression to chr onic disease in experimental hepadnaviral hepatitis.