title: Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection.
abstract: Autoimmune liver diseases, such as autoimmune hepatitis (AIH) and primary biliary cirrhosis, often have severe consequences for the patient. Because of a lack of appropriate animal models, not much is known about their potential viral etiology. Infection by liver-tropic viruses is one possibility for the breakdown of self-tolerance. Therefore, we infected mice with adenovirus Ad5 expressing human cytochrome P450 2D6 (Ad-2D6). Ad-2D6-infected mice developed persistent autoimmune liver disease, apparent by cellular infiltration, hepatic fibrosis, "fused" liver lobules, and necrosis. Similar to type 2 AIH patients, Ad-2D6-infected mice generated type 1 liver kidney microsomal-like antibodies recognizing the immunodominant epitope WDPAQPPRD of cytochrome P450 2D6 (CYP2D6). Interestingly, Ad-2D6-infected wild-type FVB/N mice displayed exacerbated liver damage when compared with transgenic mice expressing the identical human CYP2D6 protein in the liver, indicating the presence of a stronger immunological tolerance in CYP2D6 mice. We demonstrate for the first time that infection with a virus expressing a natural human autoantigen breaks tolerance, resulting in a chronic form of severe, autoimmune liver damage. Our novel model system should be instrumental for studying mechanisms involved in the initiation, propagation, and precipitation of virus-induced autoimmune liver diseases.
authors.affiliation: Pharmazentrum Frankfurt/Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit, Johann Wolfgang Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Holdener
authors.forename: Edith
authors.initials: E
authors.lastname: Hintermann
authors.forename: Monika
authors.initials: M
authors.lastname: Bayer
authors.forename: Antje
authors.initials: A
authors.lastname: Rhode
authors.forename: Evelyn
authors.initials: E
authors.lastname: Rodrigo
authors.forename: Gudrun
authors.initials: G
authors.lastname: Hintereder
authors.forename: Eric F
authors.initials: EF
authors.lastname: Johnson
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Matthias von G
authors.initials: Mv
authors.lastname: Herrath
authors.forename: Urs
authors.initials: U
authors.lastname: Christen
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000257:Adenoviridae Infections / Q000201:enzymology* / Q000276:immunology*; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D019389:Cytochrome P-450 CYP2D6 / Q000276:immunology*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance; D008099:Liver / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic
chemical_list: D001324:Autoantigens; D049452:Green Fluorescent Proteins; D019389:Cytochrome P-450 CYP2D6