Author/Editor		Su, MA; Giang, K; Zumer, K; Jiang, H; Oven, I; Rinn, JL; Devoss, JJ; Johannes, KP; Lu, W; Gardner, J; Chang, A; Bubulya, P; Chang, HY; Peterlin, BM; Anderson, MS
Title		Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire
Type		članek
Source		J Clin Invest
Vol. and No.		Letnik 118, št. 5
Publication year		2008
Volume		str. 1712-26
Language		eng
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.
Descriptors		MUTATION ANIMALS AUTOANTIGENS DISEASE MODELS, ANIMAL EYE GENE EXPRESSION REGULATION LACRIMAL APPARATUS MICE MICE, INBRED C57BL MICE, INBRED NOD MICE, TRANSGENIC PHENOTYPE POLYENDOCRINOPATHIES, AUTOIMMUNE SALIVARY GLANDS THYMUS GLAND TRANSCRIPTION FACTORS