Immunopathogenesis in hepatitis C virus cirrhosis.
HCV (hepatitis C virus) has a high propensity to persist and to cause chronic hepatitis C, eventually leading to cirrhosis. Since HCV itself is not cytopathic, liver damage in chronic hepatitis C is commonly attributed to immune-mediated mechanisms. HCV proteins interact with several pathways in the host's immune response and disrupt pathogen-associated pattern recognition pathways, interfere with cellular immunoregulation via CD81 binding and subvert the activity of NK (natural killer) cells as well as CD4(+) and CD8(+) T-cells. Finally, HCV-specific T-cells become increasingly unresponsive and apparently disappear, owing to several possible mechanisms, such as escape mutations in critical viral epitopes, lack of sufficient help, clonal anergy or expansion of regulatory T-cells. The role of neutralizing antibodies remains uncertain, although it is still possible that humoral immunity contributes to bystander damage of virally coated cells via antibody-dependent cellular cytotoxicity. Cytotoxic lymphocytes kill HCV-infected cells via the perforin/granzyme pathway, but also release Fas ligand and inflammatory cytokines such as IFNgamma (interferon gamma). Release of soluble effector molecules helps to control HCV infection, but may also destroy uninfected liver cells and can attract further lymphocytes without HCV specificity to invade the liver. Bystander damage of these non-specific inflammatory cells will expand the tissue damage triggered by HCV infection and ultimately activate fibrogenesis. A clear understanding of these processes will eventually help to develop novel treatment strategies for HCV liver disease, independent from direct inhibition of HCV replication.
Spengler
Ulrich
U
Department of Internal Medicine 1, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany. ulrich.spengler@ukb.uni-bonn.de
Nattermann
Jacob
J
D000914:Antibodies, Viral / Q000096:biosynthesis; D016174:Hepacivirus / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D008103:Liver Cirrhosis / Q000276:immunology* / Q000821:virology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology
D000914:Antibodies, Viral; D051193:Toll-Like Receptors