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

In summary, several arguments underscore the biological relevance of our findings. First, the viral epitope as well as the self-epitopes are naturally processed and presented by human host cells. Second, the self-epitopes and the viral epitope are coexpressed and colocalize to the liver in natural HCV infection, and expression of CYP2A6 is even enhanced in HCVinfected livers (47) . Third, the absence of CYP-inducible CTLs in the peripheral blood suggests that central or peripheral tolerance mechanisms are operational, indicating that the self-epitopes are presented to T cells in vivo. Fourth, the data presented show a high level of cross-recognition of virally induced CTLs against the self-peptides, suggesting that they can mediate liver cell damage to uninfected cells. Fifth, another line of evidence links HCV infection to autoimmune hepatitis type 2 (6). This disease has been described to occur subsequent to HCV infection (42) and, interestingly, in association with HLA-A2 (48) . Typically, it is associated with the presence of autoantibodies directed against cytochrome P450 2D6 (3, 6), as well as autoreactive CYP2D6-specific T cells, suggesting the parallel occurrence of autoreactivity against cytochrome P450 at the level of B and T cells (4, 5) . It can be hypothesized that liver cell damage mediated by virus-specific CTLs leads to the release of intracellular proteins like CYP2D6, uptake of these autoantigens by professional APCs, and autoantibody formation in the presence of autoreactive CD4 Ï© T and B cells. After viral clearance, the autoimmune disease is upheld by ongoing hepatocyte lysis by cross-reactive, HCV-induced CTLs maintained by autoreactive helper T cells. The coincidence of HCV, autoreactive B cells, and autoreactive CD8 Ï© and CD4 Ï© T cells is thus required for the induction of HCV-associated AIH. This would explain the relatively low frequency of AIH among HCV patients despite the high number of individuals with cross-reactive CTLs.