title: Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire.
abstract: Homozygous loss-of-function mutations in AIRE cause autoimmune polyglandular syndrome type 1 (APS 1), which manifests in a classic triad of hypoparathyroidism, adrenal insufficiency, and candidiasis. Interestingly, a kindred with a specific G228W AIRE variant presented with an autosomal dominant autoimmune phenotype distinct from APS 1. We utilized a novel G228W-knockin mouse model to show that this variant acted in a dominant-negative manner to cause a unique autoimmunity syndrome. In addition, the expression of a large number of Aire-regulated thymic antigens was partially inhibited in these animals, demonstrating the importance of quantitative changes in thymic antigen expression in determining organ-specific autoimmunity. Furthermore, the dominant-negative effect of the G228W variant was exerted through recruitment of WT Aire away from active sites of transcription in the nucleus of medullary thymic epithelial cells in vivo. Together, these results may demonstrate a mechanism by which autoimmune predisposition to phenotypes distinct from APS 1 can be mediated in a dominant-negative fashion by Aire.
authors.affiliation: Diabetes Center, Department of Pediatric, UCSF, San Francisco, California 94143, USA.
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Su
authors.forename: Karen
authors.initials: K
authors.lastname: Giang
authors.forename: Kristina
authors.initials: K
authors.lastname: Zumer
authors.forename: Huimin
authors.initials: H
authors.lastname: Jiang
authors.forename: Irena
authors.initials: I
authors.lastname: Oven
authors.forename: John L
authors.initials: JL
authors.lastname: Rinn
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Devoss
authors.forename: Kellsey P A
authors.initials: KP
authors.lastname: Johannes
authors.forename: Wen
authors.initials: W
authors.lastname: Lu
authors.forename: James
authors.initials: J
authors.lastname: Gardner
authors.forename: Angela
authors.initials: A
authors.lastname: Chang
authors.forename: Paula
authors.initials: P
authors.lastname: Bubulya
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.forename: B Matija
authors.initials: BM
authors.lastname: Peterlin
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D025063:Chromosome Disorders; D004195:Disease Models, Animal; D005123:Eye / Q000276:immunology; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007765:Lacrimal Apparatus / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics* / Q000503:physiopathology; D012469:Salivary Glands / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000096927:AIRE Protein
chemical_list: D001324:Autoantigens; D014157:Transcription Factors; D000096927:AIRE Protein