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¹ Pharmazentrum Frankfurt/Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit and ² Zentrallabor, Johann Wolfgang Goethe University, 60590 Frankfurt am Main, Germany
³ La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037
⁴ The Scripps Research Institute, La Jolla, CA 92037
⁵ National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
⁶ Medizinische Hochschule Hannover, 30623 Hannover, Germany

CORRESPONDENCE Urs Christen: christen{at}med.uni-frankfurt.de

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.

Abbreviations used: Ad-2D6, adenovirus Ad5 expressing human cytochrome P450 2D6; Ad-GFP, adenovirus Ad5 expressing GFP; AIH, autoimmune hepatitis; ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase; CYP2D6, cytochrome P450 2D6; GGT, glutamyl transpeptidase; HCV, hepatitis C virus; ICP4, infected cell protein 4; LDS, liver damage score; LKM-1, type 1 liver kidney microsomal antibody; PBC, primary biliary cirrhosis.

M. Holdener and E. Hintermann contributed equally to this work.

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