Molecular Mimicry of Human Cytochrome P450 by Hepatitis C Virus at the Level of Cytotoxic T Cell Recognition

Kammer, Andreas R.; van der Burg, Sjoerd H.; Grabscheid, Benno; Hunziker, Isabelle P.; Kwappenberg, Kitty M.C.; Reichen, Jürg; Melief, Cornelis J.M.; Cerny, Andreas

The clinical observation that HCV infection is preceding the development of LKM-1-positive AIH is in accordance with our hypothesis that antiviral immune response has to predate autoimmunity (41, 42) . Moreover, the presence of autoreactive T cells in the blood and the liver of AIH type 2 patients has been demonstrated, indicating a role for both CD4 Ï© and CD8 Ï© T cells in the pathogenesis of this disease (4, 5) . Cross-reactive CTLs may contribute to liver cell damage by lysis of infected and uninfected hepatocytes during ongoing viral infection and by lysis of uninfected autoantigenexpressing hepatocytes after viral clearance. However, the presence of virus-inducible autoreactive CTLs alone is not sufficient to lead to typical AIH, as none of the tested HCV patients had markers for AIH (LKM-1 autoantibodies). Probably the presence of autoreactive CD8 Ï© as well as autoreactive CD4 Ï© helper T cells is required for the induction of AIH. LKM-1 antigen (CYP2D6)-specific CD4 Ï© T cells detected in AIH patients would be needed for the activation of B cells secreting the AIH marker LKM-1 autoantibodies. Furthermore, autoreactive CD4 Ï© T cells could maintain the autoreactive CD8 T cell response after viral clearance, comparable with chronic viral infections where CD4 Ï© T cells are essential for maintaining the CTL response (43) (44) (45) (46) .