autoimmunity existing before virus infection is associ-The relationship between hepatitis virus invasion and ated with a high rate of progression to chronic disease emergence of liver-specific autoantibodies against asiin experimental hepadnaviral hepatitis. (HEPATOLOGY aloglycoprotein receptor (anti-ASGPR) and the occur-1997;25:689-696.) rence patterns, prognostic value, and specificity of these autoantibodies toward polypeptides of host ASGPR were investigated in experimental viral hepatitis in the
The induction of organ-specific autoimmunity by viruses woodchuck system. Sequential sera (n Γ
231) obtained and the contribution of this self-reactivity toward the develbefore and after inoculation with woodchuck hepatitis opment and perpetuation of tissue injury have been postuvirus (WHV) from animals which resolved acute infeclated, but convincing evidence remains sparse. 1-3 Chronic vition (n Γ
7) or developed chronic hepatitis (n Γ
6) were ral hepatitis, in particular that related to hepatitis B virus tested for anti-ASGPR using radio and enzyme-immuno-(HBV) infection, is frequently accompanied by circulating audetection assays. In addition, the outcome of WHV hepatoantibodies to both nonorgan and liver specific constittitis was analyzed in 30 other woodchucks whose preinuents. [4][5][6][7][8][9] It is presumed that the virus plays a causal role in oculation sera were tested for anti-ASGPR. The receptor the triggering of these self-directed responses, but little has subunit specificity of virus-induced anti-ASGPR was debeen firmly established. The studies in this field are hamtermined by Western blotting and compared with that pered by difficulty to precisely define the moment of virus of anti-ASGPR raised in woodchucks challenged with a invasion, the status of autoimmunity before infection, and heterologous (rabbit) receptor. The results revealed that ability to conduct longitudinal studies in a clinical situation WHV infection triggered anti-ASGPR in all except one that requires repeated serum and tissue sampling. This relaof the initially autoantibody nonreactive animals (eight tionship can be examined however, through investigation of of nine; 89.9%). Once induced, anti-ASGPR were detectappropriate animal models. In the case of HBV infection, able throughout the entire follow-up independent of hisit has been documented that the woodchuck infected with tological severity of liver damage or the outcome of hepwoodchuck hepatitis virus (WHV) reflects, with a high degree atitis. In healthy WHV-naive woodchucks, anti-ASGPR of accuracy, molecular, immunovirological, and pathological occurred at low titers in approximately one third of the events occurring in humans. 10,11 This disease model has preanimals. Importantly, woodchucks reactive for antiviously been employed in this laboratory to determine the ASGPR before WHV inoculation developed chronic hepimpact of hepadnavirus infection on the induction of nonoratitis with a significantly greater frequency (55.5%) than gan-specific autoantibody response. 12 Among others, it has those autoantibody negative (15.6%; P Γ΅ .05). In contrast been shown that the appearance of antibodies to smooth musto anti-ASGPR elicited by immunization with a heterolocle (SMA) is a stable feature of WHV infection and that, gous receptor, which initially recognized only the interestingly, in woodchucks, this event precedes the onset ASGPR 40-kd polypeptide, anti-ASGPR emerging after of viral serological markers and enzymatic indicators of liver virus invasion reacted with both the ASGPR 40-and 47injury. kd subunits from the moment of their appearance. This
With respect to the liver-specific antibody responses in pastudy provides the first direct evidence that hepatitis tients with viral hepatitis, autoantibodies to hepatic asialovirus in the natural host triggers autoantibodies against glycoprotein receptor (anti-ASGPR) were encountered with a a unique hepatocyte antigen and shows that anti-ASGPR high frequency (up to 73%) in patients with HBV hepatitis, 5,8,13 but rarely in individuals with hepatitis C. 14 Among liver diseases, chronic autoimmune hepatitis is most often accompa-Abbreviations: HBV, hepatitis B virus; WHV, woodchuck hepatitis virus; SMA, smooth muscle autoantibody; anti-ASGPR, autoantibody to hepatic asialoglycoprotein receptor; nied by these autoantibodies. 15 The target antigen for anti-WcASGPR, woodchuck hepatic ASGPR; RbASGPR, rabbit ASGPR; anti-WHC, antibody ASGPR is a purifiable, hepatocyte surface-associated receptor against woodchuck hepatitis core antigen; ELISA, enzyme-linked immunosorbent assay;
(hepatic lectin) that seemingly facilitates physiological removal AH, acute hepatitis; SLAH, self-limited acute hepatitis; CH, chronic hepatitis; WHsAg, and degradation of circulating desialated glycoproteins carwoodchuck hepatitis virus surface antigen; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; RIA, radioimmunoassay; Ig, immunoglobulin; w.p.i., weeks post-rying galactose-terminal oligosaccharides. The structure and WHV innoculation. biological properties of ASGPR have been extensively studied From