Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection

  • 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.

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Author:Martin Holdener, Edith Hintermann, Monika Bayer, Antje Rhode, Evelyn Rodrigo, Gudrun Hintereder, Eric F. Johnson, Frank J. Gonzalez, Josef Martin PfeilschifterGND, Michael P. Manns, Matthias G. von Herrath, Urs Christen
URN:urn:nbn:de:hebis:30-68430
DOI:https://doi.org/10.1084/jem.20071859
ISSN:1540-9538
ISSN:1540-9358
ISSN:0022-1007
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/18474629
Parent Title (English):Journal of experimental medicine
Publisher:Rockefeller Univ. Press
Place of publication:New York, NY
Document Type:Article
Language:English
Date of Publication (online):2009/08/19
Date of first Publication:2008/05/12
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2009/08/19
Volume:205
Issue:6, Art. 1409
Page Number:14
First Page:1409
Last Page:1422
Note:
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
HeBIS-PPN:215051718
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Medizin / Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Sammlungen:Sammlung Biologie / Sondersammelgebiets-Volltexte
Licence (German):License LogoCreative Commons - Namensnennung-Keine kommerzielle Nutzung-Weitergabe unter gleichen Bedingungen