Projection of an immunological self shadow within the thymus by the aire protein.
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.
Anderson
Mark S
MS
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.
Venanzi
Emily S
ES
Klein
Ludger
L
Chen
Zhibin
Z
Berzins
Stuart P
SP
Turley
Shannon J
SJ
von Boehmer
Harald
H
Bronson
Roderick
R
Dierich
Andrée
A
Benoist
Christophe
C
Mathis
Diane
D
D000375:Aging; D000818:Animals; D001323:Autoantibodies / Q000032:analysis / Q000097:blood; D001324:Autoantigens / Q000096:biosynthesis / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018390:Gene Targeting; D006801:Humans; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011828:Radiation Chimera; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017634:Self Tolerance; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000096927:AIRE Protein
D001323:Autoantibodies; D001324:Autoantigens; D014157:Transcription Factors; D000096927:AIRE Protein