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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 fo...

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Autores principales: Holdener, Martin, Hintermann, Edith, Bayer, Monika, Rhode, Antje, Rodrigo, Evelyn, Hintereder, Gudrun, Johnson, Eric F., Gonzalez, Frank J., Pfeilschifter, Josef, Manns, Michael P., Herrath, Matthias von G., Christen, Urs
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2413037/
https://www.ncbi.nlm.nih.gov/pubmed/18474629
http://dx.doi.org/10.1084/jem.20071859
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author Holdener, Martin
Hintermann, Edith
Bayer, Monika
Rhode, Antje
Rodrigo, Evelyn
Hintereder, Gudrun
Johnson, Eric F.
Gonzalez, Frank J.
Pfeilschifter, Josef
Manns, Michael P.
Herrath, Matthias von G.
Christen, Urs
author_facet Holdener, Martin
Hintermann, Edith
Bayer, Monika
Rhode, Antje
Rodrigo, Evelyn
Hintereder, Gudrun
Johnson, Eric F.
Gonzalez, Frank J.
Pfeilschifter, Josef
Manns, Michael P.
Herrath, Matthias von G.
Christen, Urs
author_sort Holdener, Martin
collection PubMed
description 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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spelling pubmed-24130372008-12-09 Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection Holdener, Martin Hintermann, Edith Bayer, Monika Rhode, Antje Rodrigo, Evelyn Hintereder, Gudrun Johnson, Eric F. Gonzalez, Frank J. Pfeilschifter, Josef Manns, Michael P. Herrath, Matthias von G. Christen, Urs J Exp Med Articles 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. The Rockefeller University Press 2008-06-09 /pmc/articles/PMC2413037/ /pubmed/18474629 http://dx.doi.org/10.1084/jem.20071859 Text en © 2008 Holdener et al. 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/).
spellingShingle Articles
Holdener, Martin
Hintermann, Edith
Bayer, Monika
Rhode, Antje
Rodrigo, Evelyn
Hintereder, Gudrun
Johnson, Eric F.
Gonzalez, Frank J.
Pfeilschifter, Josef
Manns, Michael P.
Herrath, Matthias von G.
Christen, Urs
Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection
title Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection
title_full Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection
title_fullStr Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection
title_full_unstemmed Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection
title_short Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection
title_sort breaking tolerance to the natural human liver autoantigen cytochrome p450 2d6 by virus infection
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2413037/
https://www.ncbi.nlm.nih.gov/pubmed/18474629
http://dx.doi.org/10.1084/jem.20071859
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