Differences in immune recognition of cytochrome P4502D6 by liver kidney microsomal (LKM) antibody in autoimmune hepatitis and chronic hepatitis C virus infection.
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.
Ma
Y
Y
Department of Immunology, King's College School of Medicine and Dentistry, London, UK.
Peakman
M
M
Lobo-Yeo
A
A
Wen
L
L
Lenzi
M
M
Gäken
J
J
Farzaneh
F
F
Mieli-Vergani
G
G
Bianchi
F B
FB
Vergani
D
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D000918:Antibody Specificity; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens; D001327:Autoimmune Diseases / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology*; D005260:Female; D006505:Hepatitis / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D006521:Hepatitis, Chronic / Q000276:immunology*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; D011993:Recombinant Fusion Proteins; C060729:anti-liver kidney microsome antibody; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6