Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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AIRE Protein
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Aging
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Animals
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Autoantibodies / analysis
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Autoantibodies / blood
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Autoantigens / biosynthesis
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Autoantigens / genetics
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology
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Autoimmune Diseases / metabolism
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Autoimmunity
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Epithelial Cells / physiology
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Female
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Gene Expression Profiling
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Gene Expression Regulation
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Gene Targeting
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Humans
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Lymphocytes / immunology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Polyendocrinopathies, Autoimmune / genetics
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Polyendocrinopathies, Autoimmune / immunology
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Polyendocrinopathies, Autoimmune / metabolism
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Radiation Chimera
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Reverse Transcriptase Polymerase Chain Reaction
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Self Tolerance*
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Stromal Cells / immunology
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Stromal Cells / metabolism
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T-Lymphocytes / immunology*
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Thymus Gland / cytology
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Thymus Gland / immunology*
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Thymus Gland / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
Substances
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Autoantibodies
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Autoantigens
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Transcription Factors