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LKM1 autoantibodies in chronic hepatitis C infection: A case of molecular mimicry?
Author(s) -
Marceau Gabriel,
Lapierre Pascal,
Béland Kathie,
Soudeyns Hugo,
Alvarez Fernando
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20816
Subject(s) - molecular mimicry , autoantibody , ns5a , hepatitis c virus , epitope , ns3 , virology , epitope mapping , biology , hepatitis c , hepacivirus , antibody , microbiology and biotechnology , immunology , virus
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. (H EPATOLOGY 2005.)