Published online May 12, 2008
doi:10.1084/jem.20071859
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Holdener et al.
Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection
Martin Holdener1,
Edith Hintermann1,
Monika Bayer1,
Antje Rhode3,
Evelyn Rodrigo3,
Gudrun Hintereder2,
Eric F. Johnson4,
Frank J. Gonzalez5,
Josef Pfeilschifter1,
Michael P. Manns6,
Matthias von G. Herrath3, and
Urs Christen1
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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