The Journal of Experimental Medicine
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Published 18 October 2004. doi:10.1084/jem.20040581
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 8, 1015-1026
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Gene Dosage–limiting Role of Aire in Thymic Expression, Clonal Deletion, and Organ-specific Autoimmunity

Adrian Liston1, Daniel H.D. Gray2, Sylvie Lesage1,3, Anne L. Fletcher2, Judith Wilson1, Kylie E. Webster4, Hamish S. Scott4, Richard L. Boyd2, Leena Peltonen5, and Christopher C. Goodnow1

1 John Curtin School of Medical Research and The Australian Phenomics Facility, The Australian National University, Canberra 2601, Australia
2 Department of Pathology and Immunology, Monash University, Melbourne 3181, Australia
3 CHUM Research Centre, Montreal University, Montreal H2L 4M1, Canada
4 The Walter and Eliza Hall Institute of Medical Research, 3052 Melbourne, Australia
5 Department of Medical Genetics and Molecular Medicine, University of Helsinki and National Public Health Institute, Biomedicum Helsinki, 00290 Helsinki, Finland

Address correspondence to Christopher C. Goodnow, John Curtin School of Medical Research, Mills Rd., P.O. Box 334, The Australian National University, Canberra 2601, Australia. Phone: 61-2-6125-3621; Fax: 61-2-6125-8512; email: Chris.Goodnow{at}anu.edu.au

Inactivation of the autoimmune regulator (Aire) gene causes a rare recessive disorder, autoimmune polyendocrine syndrome 1 (APS1), but it is not known if Aire-dependent tolerance mechanisms are susceptible to the quantitative genetic changes thought to underlie more common autoimmune diseases. In mice with a targeted mutation, complete loss of Aire abolished expression of an insulin promoter transgene in thymic epithelium, but had no effect in pancreatic islets or the testes. Loss of one copy of Aire diminished thymic expression of the endogenous insulin gene and the transgene, resulting in a 300% increase in islet-reactive CD4 T cells escaping thymic deletion in T cell receptor transgenic mice, and dramatically increased progression to diabetes. Thymic deletion induced by antigen under control of the thyroglobulin promoter was abolished in Aire homozygotes and less efficient in heterozygotes, providing an explanation for thyroid autoimmunity in APS1. In contrast, Aire deficiency had no effect on thymic deletion to antigen controlled by a systemic H-2K promoter. The sensitivity of Aire-dependent thymic deletion to small reductions in function makes this pathway a prime candidate for more subtle autoimmune quantitative trait loci, and suggests that methods to increase Aire activity would be a potent strategy to lower the incidence of organ-specific autoimmunity.

Key Words: diabetes mellitus type I • autoimmune diseases • clonal deletion • immune tolerance • thymus

Abbreviations used in this paper: Aire, autoimmune regulator; APS1, autoimmune polyendocrine syndrome 1; DP, double positive; HEL, hen egg lysozyme; SP, single positive.


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