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

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‐1‐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‐1 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.