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Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire.


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.

Pubmed ID: 18414681


  • 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


The Journal of clinical investigation

Publication Data

May 2, 2008

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI035297
  • Agency: NEI NIH HHS, Id: EY016408
  • Agency: NIAID NIH HHS, Id: K08 AI076429
  • Agency: NICHD NIH HHS, Id: K12-HD00850
  • Agency: NIDDK NIH HHS, Id: L40 DK072682
  • Agency: NIDDK NIH HHS, Id: L40 DK072682-03A1
  • Agency: NIDDK NIH HHS, Id: P30 DK063720

Mesh Terms

  • Animals
  • Autoantigens
  • Chromosome Disorders
  • Disease Models, Animal
  • Eye
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Lacrimal Apparatus
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Polyendocrinopathies, Autoimmune
  • Salivary Glands
  • Thymus Gland
  • Transcription Factors