COMPLEMENT-MEDIATED CYTOTOXICITY AND INHIBITION OF LIGAND-BINDING TO HEPATOCYTES BY WOODCHUCK HEPATITIS VIRUS-INDUCED AUTOANTIBODIES TO ASIALOGLYCOPROTEIN RECEPTOR
Jy. Diao et al., COMPLEMENT-MEDIATED CYTOTOXICITY AND INHIBITION OF LIGAND-BINDING TO HEPATOCYTES BY WOODCHUCK HEPATITIS VIRUS-INDUCED AUTOANTIBODIES TO ASIALOGLYCOPROTEIN RECEPTOR, Hepatology, 27(6), 1998, pp. 1623-1631
Hepadnavirus invasion in woodchucks has been identified as a potent in
ducer of autoantibodies against asialoglycoprotein receptor (anti-ASGP
R), a molecule essentially unique to hepatocytes that mediate clearanc
e of desialylated serum proteins. We evaluated the possible pathogenet
ic importance of anti-ASGPR triggered by woodchuck hepatitis virus (WH
V), using anti-ASGPR-reactive serum immunoglobulins (Igs) from five an
imals with different stages of WHV hepatitis or self-limited WHV infec
tion and isolated woodchuck hepatocytes or HepGZ cells as targets. The
results revealed that WHV-induced anti-ASGPR can specifically inhibit
asialoglycoprotein recognition by both homologous and heterologous li
ver cells, as tested in an asialofetuin (ASFN)-binding radioassay. How
ever, the extent of the interference significantly varied (from 85% in
hibition to none) for anti-ASGPR with similar titer from different ani
mals, indicating a high degree of heterogeneity in the ASGPR epitope s
pecificity and in the potential biological effects of these autoantibo
dies. The WHV triggered anti-ASGPR also induced complement-mediated he
patocytolysis in a microculture tetrazolium (MTT) assay, which ranged
from 8.9% +/- 0.3% to 33.6% +/- 3.6% (mean +/- SD) for different anima
ls and target cell numbers. This cytopathic effect was strictly ASGPR-
specific, complement-dependent, and was not related to the anti-ASGPR
ability to inhibit ligand-hepatocyte binding. Our findings indicate th
at among pathways by which anti-ASGPR autoimmunity could cause liver d
amage, hepadnavirus-induced anti-ASGPR might impair hepatocytes by bot
h disrupting clearance of desialylated proteins and activation of the
complement-mediated cytolysis. These cytopathic effects might contribu
te to the pathogenesis, aggravate severity, and prolong recovery from
liver injury in viral hepatitis.