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Medullary thymic epithelial cell depletion leads to autoimmune hepatitis
Anthony J. Bonito, … , Matthew C. Walsh, Konstantina Alexandropoulos
Anthony J. Bonito, … , Matthew C. Walsh, Konstantina Alexandropoulos
Published July 15, 2013
Citation Information: J Clin Invest. 2013;123(8):3510-3524. https://doi.org/10.1172/JCI65414.
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Research Article Immunology Article has an altmetric score of 50

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

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Abstract

TRAF6, an E3 ubiquitin protein ligase, plays a critical role in T cell tolerance by regulating medullary thymic epithelial cell (mTEC) development. mTECs regulate T cell tolerance by ectopically expressing self-antigens and eliminating autoreactive T cells in the thymus. Here we show that mice with mTEC depletion due to conditional deletion of Traf6 expression in murine thymic epithelial cells (Traf6ΔTEC mice) showed a surprisingly narrow spectrum of autoimmunity affecting the liver. The liver inflammation in Traf6ΔTEC mice exhibited all the histological and immunological characteristics of human autoimmune hepatitis (AIH). The role of T cells in AIH establishment was supported by intrahepatic T cell population changes and AIH development after transfer of liver T cells into immunodeficient mice. Despite a 50% reduction in natural Treg thymic output, peripheral tolerance in Traf6ΔTEC mice was normal, whereas compensatory T regulatory mechanisms were evident in the liver of these animals. These data indicate that mTECs exert a cell-autonomous role in central T cell tolerance and organ-specific autoimmunity, but play a redundant role in peripheral tolerance. These findings also demonstrate that Traf6ΔTEC mice are a relevant model with which to study the pathophysiology of AIH, as well as autoantigen-specific T cell responses and regulatory mechanisms underlying this disease.

Authors

Anthony J. Bonito, Costica Aloman, M. Isabel Fiel, Nichole M. Danzl, Sungwon Cha, Erica G. Weinstein, Seihwan Jeong, Yongwon Choi, Matthew C. Walsh, Konstantina Alexandropoulos

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Figure 2

Liver inflammation in Traf6ΔTEC mice exhibits pathognomonic features of AIH.

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Liver inflammation in Traf6ΔTEC mice exhibits pathognomonic features of ...
(A–C) Paraffin-embedded liver sections of approximately 6-month-old WT and Traf6ΔTEC mice were stained with H&E. Portal inflammation, interface hepatitis, and lobular inflammation (arrows) was scored by a pathologist as described in Methods. (D) Picrosirius red staining was used for quantification of liver fibrosis as described in Methods. Serum ALT levels were determined by reflectance spectrophotometry. n = 8 per genotype in A–D. Red bars represent mean. Scale bars: 100 μm (A–C); 200 μm (D). *P < 0.05; **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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