Virus-induced autoimmune hepatitis

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J Exp Med. 2008 May 12 [Epub ahead of print]

Breaking tolerance to the natural human liver autoantigen cytochrome

P450 2D6 by virus infection.

Holdener M, Hintermann E, Bayer M, Rhode A, Rodrigo E, Hintereder G,

EF, FJ, Pfeilschifter J, Manns MP, Herrath MV,

Christen U

Pharmazentrum furt/Zentrum für Arzneimittelforschung,

Entwicklung und Sicherheit and 2Zentrallabor, Johann Wolfgang Goethe

University, 60590 furt am Main, Germany.

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.

PMID: 18474629

http://www.ncbi.nlm.nih.gov/pubmed/18474629