LKM1 autoantibodies in chronic hepatitis C infection: A case of molecular mimicry?

Authors

  • Gabriel Marceau,

    1. Service de gastroentérologie, hépatologie et nutrition, Hôpital Sainte-Justine, Montréal, Québec, Canada
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    • Gabriel Marceau and Pascal Lapierre contributed equally to this work.

  • Pascal Lapierre,

    1. Service de gastroentérologie, hépatologie et nutrition, Hôpital Sainte-Justine, Montréal, Québec, Canada
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    • Gabriel Marceau and Pascal Lapierre contributed equally to this work.

  • Kathie Béland,

    1. Service de gastroentérologie, hépatologie et nutrition, Hôpital Sainte-Justine, Montréal, Québec, Canada
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  • Hugo Soudeyns,

    1. Unité d'immunopathologie virale, Hôpital Sainte-Justine, Montréal, Québec, Canada
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  • Fernando Alvarez

    Corresponding author
    1. Service de gastroentérologie, hépatologie et nutrition, Hôpital Sainte-Justine, Montréal, Québec, Canada
    • Service de gastroentérologie, hépatologie et nutrition, Hôpital Sainte-Justine, 3175 Côte Ste-Catherine, Montréal, Québec, Canada H3T 1C5
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    • fax: 514-345-4999


  • Potential conflict of interest: Nothing to report.

Abstract

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. (HEPATOLOGY 2005.)

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