title: Gene dosage--limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity.
abstract: 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.
authors.affiliation: John Curtin School of Medical Research, The Australian Phenomics Facility, The Australian National University, Canberra 2601, Australia.
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.forename: Daniel H D
authors.initials: DH
authors.lastname: Gray
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lesage
authors.forename: Anne L
authors.initials: AL
authors.lastname: Fletcher
authors.forename: Judith
authors.initials: J
authors.lastname: Wilson
authors.forename: Kylie E
authors.initials: KE
authors.lastname: Webster
authors.forename: Hamish S
authors.initials: HS
authors.lastname: Scott
authors.forename: Richard L
authors.initials: RL
authors.lastname: Boyd
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
mesh_terms: D000818:Animals; D015551:Autoimmunity; D017637:Clonal Deletion; D018628:Gene Dosage; D015870:Gene Expression; D007108:Immune Tolerance; D007328:Insulin / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013950:Thymus Gland / Q000378:metabolism*; D013961:Thyroid Gland / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D000096927:AIRE Protein
chemical_list: D007328:Insulin; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D000096927:AIRE Protein