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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Veröffentlicht in:The Journal of experimental medicine Jg. 205; H. 6; S. 1409
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 09.06.2008
Schlagworte:
Adenoviridae - genetics
Adenoviridae Infections - enzymology
Adenoviridae Infections - immunology
Animals
Autoantigens - immunology
Cytochrome P-450 CYP2D6 - immunology
Genes, Reporter
Green Fluorescent Proteins - genetics
Humans
Immune Tolerance
Liver - enzymology
Liver - immunology
Mice
Mice, Inbred Strains
Mice, Transgenic
ISSN:1540-9538, 1540-9538
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Zusammenfassung: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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ISSN:1540-9538
1540-9538
DOI:10.1084/jem.20071859