LKM1 autoantibodies in chronic hepatitis C infection: a case of molecular mimicry?
Anti-liver-kidney microsome type 1 (LKM1) autoantibodies directed against the cytochrome P450 2D6 (CYP2D6) are considered specific markers of type 2 autoimmune hepatitis, but are also found in 5% of sera from patients chronically infected by hepatitis C virus (HCV). Molecular mimicry between HCV proteins and CYP2D6 has been proposed to explain the emergence of these autoantibodies. Anti-LKM1 autoantibodies from hepatitis C-infected patients were affinity-purified against immobilized CYP2D6 protein and used to screen a phage display library. CYP2D6 conformational epitopes were identified using phage display analysis and the identification of statistically significant pairs (SSPs). Cross-reactivity between CYP2D6 and HCV protein candidates was tested by immunoprecipitation. Nineteen different clones were isolated, and their sequencing resulted in the mapping of a conformational epitope to the region of amino acids 254-288 of CYP2D6. Candidate HCV proteins for molecular mimicry included: core, E2, NS3 and NS5a. Affinity-purified autoantibodies from HCV+/LKM1+ patients immunoprecipitated either NS3, NS5a, or both, and these reactivities were specifically inhibited by immobilized CYP2D6. In conclusion, HCV+/LKM1+ sera recognize a specific conformational epitope on CYP2D6 between amino acids 254 to 288, the region that contains the major linear epitope in type 2 autoimmune hepatitis patients. Cross-reactivity due to molecular mimicry at the B-cell level was shown between the CYP2D6 and the HCV NS3 and NS5a proteins and could explain the presence of anti-LKM1 in patients chronically infected with HCV. Further investigation of the role played by this molecular mimicry in HCV-infected patients may lead to more specific strategies for diagnosis and treatment.
Marceau
Gabriel
G
Service de gastroentérologie, hépatologie et nutrition, Hôpital Sainte-Justine, Montréal, Québec, Canada.
Lapierre
Pascal
P
Béland
Kathie
K
Soudeyns
Hugo
H
Alvarez
Fernando
F
D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000235:genetics; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D018716:Molecular Mimicry / Q000276:immunology*; D011487:Protein Conformation; D014764:Viral Proteins / Q000235:genetics
D001323:Autoantibodies; D014764:Viral Proteins; C060729:anti-liver kidney microsome antibody; D019389:Cytochrome P-450 CYP2D6