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
