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

A utoimmune hepatitis (AIH) 1 is a chronic liver disease of unknown etiology characterized by a persistent inflammatory reaction in the liver. The hallmarks of AIH are high titers of serum autoantibodies against different autoantigens and the presence of a hepatic, predominantly mononuclear cell infiltrate associated with liver cell damage. Several reports have shown the presence of autoreactive T cells in AIH patients. CD4 Ï© or CD8 Ï© liver-infiltrating T cells proliferate in response to autologous hepatocytes and some of them express high cytolytic activity (1) . Peripheral T cell clones from AIH patients also proliferate in response to liver-specific lipoprotein and the asialoglycoprotein receptor (2) . Type 2 AIH is defined by the presence of type I antiliver kidney microsome antibodies (LKM-1) recognizing cytochrome P450 (CYP)2D6 (3). In the liver and blood of patients with AIH type 2, CD4 Ï© and CD8 Ï© autoreactive T cells recognizing CYP2D6 have been detected, indicating a role of T cells in the pathogenesis of this disease (4, 5) . AIH type 2 appears to be epidemiologically linked to hepatitis C virus (HCV) infection. Some patients with AIH type 2 have been shown to be positive for anti-HCV antibodies (6) and also for HCV RNA (7) , suggesting that HCV may cause a secondary autoimmune response. MHC class I-restricted CD8 Ï© CTLs are a major defense mechanism in viral infections. It has been suggested that the CTL response may This work was presented in part at the 5th International Meeting on Hepatitis C Virus and Related Viruses in Venice, Italy, June 25-28, 1998. contribute to viral clearance as well as to liver cell injury during HCV infection and might therefore play a role in the induction of autoreactive antibodies and CD4 Ï© helper T cells. CTLs recognize endogenously processed antigenic peptides in combination with MHC class I molecules presented on the cell surface. Several HCV-derived immunogenic CTL epitopes have been described thus far (8) (9) (10) (11) (12) (13) . Amino acid sequence comparison of HLA-A2-restricted HCV-derived CTL epitopes revealed the presence of two human CYP sequences related to HCV core 178-187, i.e., (Table I) . Compared with the HCV core 178 epitope, they display an eight amino acid sequence identity, one conservative substitution at the NH 2 -terminal anchor position (Leu to Val), and one nonconservative substitution at position 6 (Ser to Val or Ser to Ala). Both CYP sequences still contain the HLA-A2 binding motif, because both Leu and Val can serve as anchor residues (14, 15) . Therefore, the HCV core 178 peptide is a candidate for molecular mimicry, that is, similarity of infectious agents with host antigens. Such similarity may lead to an inability of the host immune system to recognize the foreign antigen or it may lead to an autoreactive immune response at the level of antibodies or T cells (16) (17) (18) .