Science 2002 Oct 10;
Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins S, Turley SJ, Von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D.
Section on Immunology and Immunogenetics, Joslin Diabetes Center; Department of Medicine, Brigham and Women's Hospital; Harvard Medical School, 1 Joslin Place, Boston, MA, USA., Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA., Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA., Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/ULP, 1 rue Laurent Fries, 67404 Strasbourg, France.
Humans expressing a defective form of the transcription factor aire (autoimmune regulator) develop multi-organ autoimmune disease.
We employed 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