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Originally published in Science Express on 10 October 2002
Science 15 November 2002:
Vol. 298. no. 5597, pp. 1395 - 1401
DOI: 10.1126/science.1075958
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Research Articles

Projection of an Immunological Self Shadow Within the Thymus by the Aire Protein

Mark S. Anderson,1 Emily S. Venanzi,1 Ludger Klein,2 Zhibin Chen,1 Stuart P. Berzins,1 Shannon J. Turley,1 Harald von Boehmer,2 Roderick Bronson,3 Andrée Dierich,4 Christophe Benoist,1* Diane Mathis1*

Humans expressing a defective form of the transcription factor AIRE (autoimmune regulator) develop multiorgan autoimmune disease. We used aire- deficient mice to test the hypothesis that this transcription factor regulates autoimmunity by promoting the ectopic expression of peripheral tissue- restricted antigens in medullary epithelial cells of the thymus. This hypothesis proved correct. The mutant animals exhibited a defined profile of autoimmune diseases that depended on the absence of aire in stromal cells of the thymus. Aire-deficient thymic medullary epithelial cells showed a specific reduction in ectopic transcription of genes encoding peripheral antigens. These findings highlight the importance of thymically imposed "central" tolerance in controlling autoimmunity.

1 Section on Immunology and Immunogenetics, Joslin Diabetes Center; Department of Medicine, Brigham and Women's Hospital; Harvard Medical School, 1 Joslin Place, Boston, MA 02215, USA.
2 Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
3 Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
4 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 rue Laurent Fries, 67404 Strasbourg, France.
*   To whom correspondence should be addressed. E-mail: cbdm{at}joslin.harvard.edu

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Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity.
I. Gavanescu, B. Kessler, H. Ploegh, C. Benoist, and D. Mathis (2007)
PNAS 104, 4583-4587
   Abstract »    Full Text »    PDF »
Aire-Dependent Alterations in Medullary Thymic Epithelium Indicate a Role for Aire in Thymic Epithelial Differentiation.
G. O. Gillard, J. Dooley, M. Erickson, L. Peltonen, and A. G. Farr (2007)
J. Immunol. 178, 3007-3015
   Abstract »    Full Text »    PDF »
Autoimmune Polyendocrine Syndrome Type 1 in Norway: Phenotypic Variation, Autoantibodies, and Novel Mutations in the Autoimmune Regulator Gene.
A. S. B. Wolff, M. M. Erichsen, A. Meager, N. F. Magitta, A. G. Myhre, J. Bollerslev, K. J. Fougner, K. Lima, P. M. Knappskog, and E. S. Husebye (2007)
J. Clin. Endocrinol. Metab. 92, 595-603
   Abstract »    Full Text »    PDF »
PDGFR{alpha}-expressing mesenchyme regulates thymus growth and the availability of intrathymic niches.
W. E. Jenkinson, S. W. Rossi, S. M. Parnell, E. J. Jenkinson, and G. Anderson (2007)
Blood 109, 954-960
   Abstract »    Full Text »    PDF »
Pituitary autoantibodies in autoimmune polyendocrine syndrome type 1.
S. Bensing, S. O. Fetissov, J. Mulder, J. Perheentupa, J. Gustafsson, E. S. Husebye, M. Oscarson, O. Ekwall, P. A. Crock, T. Hokfelt, et al. (2007)
PNAS 104, 949-954
   Abstract »    Full Text »    PDF »
Thymus Medulla Formation and Central Tolerance Are Restored in IKK{alpha}-/- Mice That Express an IKK{alpha} Transgene in Keratin 5+ Thymic Epithelial Cells.
D. Lomada, B. Liu, L. Coghlan, Y. Hu, and E. R. Richie (2007)
J. Immunol. 178, 829-837
   Abstract »    Full Text »    PDF »
NF-{kappa}B2 Is Required for the Control of Autoimmunity by Regulating the Development of Medullary Thymic Epithelial Cells.
B. Zhang, Z. Wang, J. Ding, P. Peterson, W. T. Gunning, and H.-F. Ding (2006)
J. Biol. Chem. 281, 38617-38624
   Abstract »    Full Text »    PDF »
RPE Cells Resist Bystander Killing by CTLs, but Are Highly Susceptible to Antigen-Dependent CTL Killing.
D. S. Gregerson, K. L. Lew, S. W. McPherson, N. D. Heuss, and D. A. Ferrington (2006)
Invest. Ophthalmol. Vis. Sci. 47, 5385-5394
   Abstract »    Full Text »    PDF »
Distinct and Non-Overlapping T Cell Receptor Repertoires Expanded by DNA Vaccination in Wild-Type and HER-2 Transgenic BALB/c Mice.
S. Rolla, C. Nicolo, S. Malinarich, M. Orsini, G. Forni, F. Cavallo, and F. Ria (2006)
J. Immunol. 177, 7626-7633
   Abstract »    Full Text »    PDF »
Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells.
D. H. D. Gray, N. Seach, T. Ueno, M. K. Milton, A. Liston, A. M. Lew, C. C. Goodnow, and R. L. Boyd (2006)
Blood 108, 3777-3785
   Abstract »    Full Text »    PDF »
Spontaneous autoimmunity prevented by thymic expression of a single self-antigen.
J. DeVoss, Y. Hou, K. Johannes, W. Lu, G. I. Liou, J. Rinn, H. Chang, R. R. Caspi, L. Fong, and M. S. Anderson (2006)
J. Exp. Med. 203, 2727-2735
   Abstract »    Full Text »    PDF »
Heat shock proteins induce T cell regulation of chronic inflammation.
F Hauet-Broere, L Wieten, T Guichelaar, S Berlo, R van der Zee, and W Van Eden (2006)
Ann Rheum Dis 65, iii65-iii68
   Abstract »    Full Text »    PDF »


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