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Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection

Academic Article
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Overview

authors

  • Holdener, M.
  • Hintermann, E.
  • Bayer, M.
  • Rhode, A.
  • Rodrigo, E.
  • Hintereder, G.
  • Johnson, Eric
  • Gonzalez, F. J.
  • Pfeilschifter, J.
  • Manns, M. P.
  • Herrath, M. V.
  • Christen, U.

publication date

  • June 2008

journal

  • Journal of Experimental Medicine  Journal

abstract

  • 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.

subject areas

  • Adenoviridae
  • Adenoviridae Infections
  • Animals
  • Autoantigens
  • Cytochrome P-450 CYP2D6
  • Genes, Reporter
  • Green Fluorescent Proteins
  • Humans
  • Immune Tolerance
  • Liver
  • Mice
  • Mice, Inbred Strains
  • Mice, Transgenic
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Identity

PubMed Central ID

  • PMC2413037

International Standard Serial Number (ISSN)

  • 0022-1007

Digital Object Identifier (DOI)

  • 10.1084/jem.20071859

PubMed ID

  • 18474629
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Additional Document Info

start page

  • 1409

end page

  • 1422

volume

  • 205

issue

  • 6

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