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

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). Crossreactivity 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;42:675-682.)

Hepatitis A vaccine associated with autoimmune hepatitis

“…This study also demonstrated a cross reactivity between the same cytochrome and hepatitis C virus infection which is associated with a high incidence of autoantibody development. More recent work has shown molecular mimicry between cytochrome P2D6 and the NS3 and NS5a proteins of HCV [8] . Cytochrome P2D6 is the target of anti-LKM1 antibodies, the classic diagnostic marker of type 2 autoimmune hepatitis.…”

Influence of genes, sex, age and environment on the onset of autoimmune hepatitis

“…Five to 10% of HCV infected patients show autoimmune features that are generally associated with AIH such as anti-LKM1, anti-LC1 and/or anti-SLA autoantibodies [87][88][89] . Purified anti-LKM1 antibodies from HCV-infected patients cross-reacted with the NS3 and NS5a purified proteins sug gesting that CYP2D6 and those viral proteins shared similar structures [90] . A molecular mimicry at the B-cell level between a structural motif of CYP2D6 and HCV proteins could explain the production of anti-LKM1 antibodies in HCV-infected patients [90,91] .…”

“…Purified anti-LKM1 antibodies from HCV-infected patients cross-reacted with the NS3 and NS5a purified proteins sug gesting that CYP2D6 and those viral proteins shared similar structures [90] . A molecular mimicry at the B-cell level between a structural motif of CYP2D6 and HCV proteins could explain the production of anti-LKM1 antibodies in HCV-infected patients [90,91] . Another link between P450 and HCV was found at the T cell level by Kammer et al [92] who reported T cell cross-reactivity between P450 and the HCV core protein.…”

“…Hepatitis A virus Case reports [94][95][96] Hepatitis B virus Case reports [97,98] Hepatitis C virus Specific AIH autoantibodies [87][88][89] Cross-Reactivity at T and B-cell level [90][91][92] Epstein-Barr virus Case reports [66][67][68][69] Human herpes virus 6 Sequence similarities [99] Herpes simplex virus Sequence similarities [102] Cross-reactivity at B-cell level [102] 1030…”

Autoimmune liver disease: overlap and outliers

“…Centrilobular injury with prominent hepatocyte necrosis and mononuclear inflammation may be seen in some cases of AIH; in most cases, the typical portal-based inflammatory pattern of injury is also present. 17 The current general consensus is that interferon therapy is usually safe in HCV patients with anti-LKM1 autoantibodies. Patients with chronic viral hepatitis should be screened for autoantibodies before starting interferon therapy and monitored carefully.…”