Immunodisregulation in chronic hepatitis C infection: the mechanisms of autoantibody production

Chronic hepatitis C virus infection produces several alterations of immunological reactivity which may contribute to the disease progression and influence response to antiviral therapy and development of hepatocellular carcinoma. In this study, which includes 117 patients and 20 healthy volunteers, the presence of autoantibodies and their correlation with the degree of liver damage, host response to viral antigens, response to interferon-α (IFN-α) therapy and virus genotype, as well as T cell phenotype, NK cell activity and relevant cytokines production were analysed. The main findings include a direct correlation between the number of autoantibodies tested and Knodell's Score of liver damage and a direct correlation between HCV core IgM production and presence of antimitochondrial antibodies. There was no significant difference in overall frequency of autoantibodies in HCV-PCR positive and negative groups of patients. However, antimitochondrial autoantibodies as well as HCV-core IgM were associated with presence of HCV in the serum and non-responsiveness to IFN-α therapy. Geno (sero) type 4 was dominant in the analysed group of patients and, again, the presence of IgM to core antigens and antimitochondrial antibodies correlated with non-responsiveness to IFN-α in this subgroup. Further, non-responsiveness to IFN-α, therapy correlated with higher interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β) production, higher percentage of CD25+ cells and lower NK cell cytotoxic activity in vitro. Taken together the data obtained demonstrate that the viral genotype and immune response of the host define the outcome of hepatitis C virus infection and response to IFN-α therapy. They suggest for the first time that antimitochondrial autoantibodies may be surrogate parameter of virus persistence and support the notion that cytokine interplay, in particular, with TGF-β production and the activity of putative -regulatory CD25+ cells may influence the natural history of HCV infection and response to antiviral therapy.