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.
Holdener
Martin
M
Pharmazentrum Frankfurt/Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit, Johann Wolfgang Goethe University, 60590 Frankfurt am Main, Germany.
Hintermann
Edith
E
Bayer
Monika
M
Rhode
Antje
A
Rodrigo
Evelyn
E
Hintereder
Gudrun
G
Johnson
Eric F
EF
Gonzalez
Frank J
FJ
Pfeilschifter
Josef
J
Manns
Michael P
MP
Herrath
Matthias von G
Mv
Christen
Urs
U
D000256:Adenoviridae / Q000235:genetics; D000257:Adenoviridae Infections / Q000201:enzymology* / Q000276:immunology*; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D019389:Cytochrome P-450 CYP2D6 / Q000276:immunology*; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance; D008099:Liver / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic
D001324:Autoantigens; D049452:Green Fluorescent Proteins; D019389:Cytochrome P-450 CYP2D6