Molecular mimicry of human cytochrome P450 by hepatitis C virus at the level of cytotoxic T cell recognition.
Hepatitis C virus (HCV) is thought to be involved in the pathogenesis of autoimmune hepatitis (AIH) type 2, which is defined by the presence of type I antiliver kidney microsome autoantibodies directed mainly against cytochrome P450 (CYP)2D6 and by autoreactive liver infiltrating T cells. Virus-specific CD8(+) cytotoxic T lymphocytes (CTLs) that recognize infected cells and contribute to viral clearance and tissue injury during HCV infection could be involved in the induction of AIH. To explore whether the antiviral cellular immunity may turn against self-antigens, we characterized the primary CTL response against an HLA-A*0201-restricted HCV-derived epitope, i.e., HCV core 178-187, which shows sequence homology with human CYP2A6 and CYP2A7 8-17. To determine the relevance of these homologies for the pathogenesis of HCV-associated AIH, we used synthetic peptides to induce primary CTL responses in peripheral blood mononuclear cells of healthy blood donors and patients with chronic HCV infection. We found that the naive CTL repertoire of both groups contains cross-reactive CTLs inducible by the HCV peptide recognizing both CYP2A6 and CYP2A7 peptides as well as endogenously processed CYP2A6 protein. Importantly, we failed to induce CTLs with the CYP-derived peptides that showed a lower capacity to form stable complexes with the HLA-A2 molecule. These findings demonstrate the potential of HCV to induce autoreactive CD8(+) CTLs by molecular mimicry, possibly contributing to virus-associated autoimmunity.
Kammer
A R
AR
Department of Internal Medicine, University Hospital, Inselspital, 3010 Bern, Switzerland.
van der Burg
S H
SH
Grabscheid
B
B
Hunziker
I P
IP
Kwappenberg
K M
KM
Reichen
J
J
Melief
C J
CJ
Cerny
A
A
D000595:Amino Acid Sequence; D001189:Aryl Hydrocarbon Hydroxylases; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003429:Cross Reactions; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000235:genetics; D015789:HLA-A2 Antigen; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology; D018936:Hepatitis C Antigens / Q000235:genetics; D006801:Humans; D008099:Liver / Q000276:immunology; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000276:immunology; D018716:Molecular Mimicry; D017386:Sequence Homology, Amino Acid; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000939:Epitopes; D015789:HLA-A2 Antigen; D018936:Hepatitis C Antigens; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6