Differences in immune recognition of cytochrome P4502D6 by liver kidney microsomal (LKM) antibody in autoimmune hepatitis and chronic hepatitis C virus infection

Abstract

SUMMARY LKM-1 antibody, which characterizes a subtype of autoimmune hepatitis (AIH), is also found in some patients with chronic hepatitis C virus (HCV) infection. It has been suggested that HCV initiates autoimmunity through molecular mimicry, because there is partial identity between HCV and cytochrome P4502D6 (CYP2D6), the putative target of LKM-1. Whether CYP2D6 is the target of LKM-1 in HCV-related liver disease, however, is controversial. To clarify this issue, we have studied by phage plaque assay and Western blot the reactivity to recombinant CYP2D6, isolated from a human liver cDNA library, in 55 patients with LKM-1, 18 (14 females, median age 12 years) anti-HCV-negative, with classical AIH, and 37 (27 females, median age 52 years) anti-HCV-positive. Reactivity to CYP2D6 was found in 72% of the anti-HCV-negative, but only in 27% of the anti-HCV-positive patients (P < 0.001), although immunofluorescence LKM-1 titres were similar in the two groups. In addition, to investigate whether the antibody responsible for the LKM-1 fluorescent pattern also reacts with CYP2D6, we have determined the specificity of LKM-1 antibodies present in the supernatant of lymphoblastoid B cell lines obtained from two patients with LKM-l-positive AIH. An oligo/monoclonal antibody thus generated gave both the typical fluorescent pattern and reacted with CYP2D6. Our results show that whilst antibodies producing the characteristic LKM-l fluorescent pattern can react with CYP2D6, not all LKM-1-positive sera do so, particularly if obtained from patients with chronic HCV infection. This suggests that LKM-1 in HCV infection recognizes epitopes or antigens different from those targeted in AIH.

Genetic predisposition and environmental danger signals initiate chronic autoimmune hepatitis driven by CD4+T cells

“…While studies trying to identify environmental triggers have largely focused on molecular identity, we show with our experiments that molecular similarity is as efficient in triggering chronic autoimmunity . This broadens the spectrum of potential environmental agents which could lead to a loss of tolerance against tissue‐specific self‐antigens.…”

Autoimmune hepatitis: current challenges and future prospects

“…ANA is present in ~30% of patients with CHC 54. LKM antibodies are found in some patients with CHC 55. In general, molecular mimicry could explain the positivity of LKM antibodies in patients with HCV infection 56.…”

Clearance of hepatitis C virus and T cell response in a child with anti‐liver kidney microsomal‐1 antibodies treated with steroids

“…There is evidence of sequence homology between HCV core peptides and human cytochrome enzymes specifically CYP2D6. This similarity between infectious agents and host antigens or ‘molecular mimicry’ may lead to an inability of the host immune system to distinguish between infectious agent and self, and hence initiate an autoimmune response at the level of antibodies or T cells 4 . It is possible that the combination of HCV infection and increased autoantibody production led to greater inflammation in the liver than would be caused by HCV infection alone.…”