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 HintermannORCiDGND, Monika Bayer, Antje Rhode, Evelyn Rodrigo, Gudrun HinterederORCiD, Eric F. Johnson, Frank J. Gonzalez, Josef PfeilschifterGND, Michael P. MannsORCiDGND, Matthias G. von HerrathGND, Urs ChristenORCiDGND
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
Fachübergreifende Einrichtungen / Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (ZAFES)
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