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Cytochrome P4502D6_193–212: A New Immunodominant Epitope and Target of Virus/Self Cross-Reactivity in Liver Kidney Microsomal Autoantibody Type 1-Positive Liver Disease ¹

Nanda Kerkar^*,, Kaushik Choudhuri^*, Yun Ma^*, Ayman Mahmoud^*, Dimitrios P. Bogdanos^*, Luigi Muratori, Francesco Bianchi, Roger Williams^*, Giorgina Mieli-Vergani and Diego Vergani^2,*,

^* Institute of Hepatology, University College, London, United Kingdom; Institute of Liver Studies, King’s College Hospital, Denmark Hill, London, United Kingdom; and Department of Internal Medicine, Cardioangiology, Hepatology, University of Bologna, Bologna, Italy

Cytochrome P4502D6 (CYP2D6), target of liver kidney microsomal autoantibody type 1 (LKM1), characterizes autoimmune hepatitis type 2 (AIH2) but is also found in patients with chronic hepatitis C virus (HCV) infection. To provide a complete linear epitope B cell map of CYP2D6, we tested peptides spanning the entire sequence of CYP2D6. In addition to confirming previously described antigenic sites, we identified four new epitopes (193–212, 238–257, 268–287, and 478–497). CYP2D6_193–212 is immunodominant and was the target of 12 of 13 (93%) patients with AIH2 and 5 of 10 (50%) HCV/LKM1-positive patients. Because LKM1 is present in both AIH2 and a viral infection, we tested whether Abs to CYP2D6_193–212 arise through cross-reactive immunity between virus and self. We identified a hexameric sequence "RLLDLA" sharing 5 of 6 aa with "RLLDLS" of HCV_2985–2990 and all 6 aa with CMV_130–135. Of 17 CYP2D6_193–212-reactive sera, 11 (7 AIH and 4 HCV) reacted by ELISA with the HCV homologue, 8 (5 AIH and 3 HCV) with the CMV homologue, and 8 (5 AIH and 3 HCV) showed double reactivity. Autoantibody binding to CYP2D6_193–212 was inhibited by preincubation with HCV_2977–2996 or CMV_121–140. Recombinant HCV-nonstructural protein 5 and CMV-UL98 proteins also inhibited Ab binding to CYP2D6_193–212. Affinity-purified CYP2D6_193–212-specific Ab inhibited the metabolic activity of CYP2D6. The demonstrated similarity and cross-reactivity between CYP2D6_193–212 and two unrelated viruses suggests that multiple exposure to viruses mimicking self may represent an important pathway to the development of autoimmunity.

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