title: Epitope spreading of the anti-CYP2D6 antibody response in patients with autoimmune hepatitis and in the CYP2D6 mouse model.
abstract: Autoimmune hepatitis (AIH) is a serious chronic inflammatory disease of the liver with yet unknown etiology and largely uncertain immunopathology. The hallmark of type 2 AIH is the generation of liver kidney microsomal-1 (LKM-1) autoantibodies, which predominantly react to cytochrome P450 2D6 (CYP2D6). The identification of disease initiating factors has been hampered in the past, since antibody epitope mapping was mostly performed using serum samples collected late during disease resulting in the identification of immunodominant epitopes not necessarily representing those involved in disease initiation. In order to identify possible environmental triggers for AIH, we analyzed for the first time the spreading of the anti-CYP2D6 antibody response over a prolonged period of time in AIH patients and in the CYP2D6 mouse model, in which mice infected with Adenovirus-human CYP2D6 (Ad-h2D6) develop antibodies with a similar specificity than AIH patients. Epitope spreading was analyzed in six AIH-2-patients and in the CYP2D6 mouse model using SPOTs membranes containing peptides covering the entire CYP2D6 protein. Despite of a considerable variation, both mice and AIH patients largely focus their humoral immune response on an immunodominant epitope early after infection (mice) or diagnosis (patients). The CYP2D6 mouse model revealed that epitope spreading is initiated at the immunodominant epitope and later expands to neighboring and remote regions. Sequence homologies to human pathogens have been detected for all identified epitopes. Our study demonstrates that epitope spreading does indeed occur during the pathogenesis of AIH and supports the concept of molecular mimicry as a possible initiating mechanism for AIH.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Klinikum der Goethe Universität Frankfurt, Theodor-Stern Kai 7, Goethe University Hospital, Frankfurt am Main, Germany.
authors.forename: Edith
authors.initials: E
authors.lastname: Hintermann
authors.forename: Martin
authors.initials: M
authors.lastname: Holdener
authors.forename: Monika
authors.initials: M
authors.lastname: Bayer
authors.forename: Stephanie
authors.initials: S
authors.lastname: Loges
authors.forename: Josef M
authors.initials: JM
authors.lastname: Pfeilschifter
authors.forename: Claude
authors.initials: C
authors.lastname: Granier
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Urs
authors.initials: U
authors.lastname: Christen
mesh_terms: D000256:Adenoviridae / Q000737:chemistry / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis* / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D002648:Child; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D005260:Female; D005822:Genetic Vectors / Q000737:chemistry / Q000276:immunology; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000235:genetics / Q000276:immunology* / Q000821:virology; D019693:Hepatitis, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000821:virology; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D018716:Molecular Mimicry; D008969:Molecular Sequence Data
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D016056:Immunodominant Epitopes; C060729:anti-liver kidney microsome antibody; D019389:Cytochrome P-450 CYP2D6