Between Scylla and Charybdis: The role of the human immune system in the pathogenesis of hepatitis C

Abstract

Hepatitis C virus (HCV) frequently elicits only mild immune responses so that it can often establish chronic infection. In this case HCV antigens persist and continue to stimulate the immune system. Antigen persistence then leads to profound changes in the infected host’s immune responsiveness, and eventually contributes to the pathology of chronic hepatitis. This topic highlight summarizes changes associated with chronic hepatitis C concerning innate immunity (interferons, natural killer cells), adaptive immune responses (immunoglobulins, T cells, and mechanisms of immune regulation (regulatory T cells). Our overview clarifies that a strong anti-HCV immune response is frequently associated with acute severe tissue damage. In chronic hepatitis C, however, the effector arms of the immune system either become refractory to activation or take over regulatory functions. Taken together these changes in immunity may lead to persistent liver damage and cirrhosis. Consequently, effector arms of the immune system will not only be considered with respect to antiviral defence but also as pivotal mechanisms of inflammation, necrosis and progression to cirrhosis. Thus, avoiding Scylla - a strong, sustained antiviral immune response with inital tissue damage - takes the infected host to virus-triggered immunopathology, which ultimately leads to cirrhosis and liver cancer - the realm of Charybdis.

Keywords: Natural killer cells, CD4⁺ T helper cells, Regulatory T cells, Interferon, Hepatitis C, Hepatic stellate cells, Hepatocytes, Immunoglobulin, Retinoic acid inducible gene-I, Toll like receptors

Core tip: This topic highlight on the immunopathogenesis of chronic hepatitis C addresses changes in innate immunity (interferons and natural killer cells), adaptive immunity and immunoregulation (regulatory T cells). Our review provides a succinct but comprehensive overview and presents the concept, that effective antiviral immunity is associated with pronounced acute liver damage, while during chronic infection the arms of immunity will acquire new functions, which will cause and maintain tissue damage. Thus, the immune response becomes part of the mechanisms that eventually lead to progressive inflammation, liver cirrhosis and death in chronic hepatitis C.