A decade of AIRE

Abstract

In 1997, the autoimmune regulator (AIRE) gene was identified as the locus underlying susceptibility to the polyendocrine autoimmune disease known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). In the intervening 10 years, it has become increasingly clear that this rare disorder has provided us with an illuminative window on one of the most fundamental processes of the immune system — the establishment and maintenance of self tolerance.

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Figure 1: Aire: from transcriptional regulation to tolerance induction.

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Acknowledgements

The Benoist–Mathis Laboratory's work on Aire has been supported by the National Institutes of Health (NIH; ROI DK59658), and by the William T. Young Chair in Diabetes Research. We would like to thank the following laboratory members for their important contributions: J. Abramson, M.S. Anderson, I. Gavanescu, M. Giraud, D. Gray, M. Guerau-Vilanova, W. Jiang, J. Johnnidis, A. Koh, E. Venanzi and J. Villasenor.

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Glossary

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

(APECED). A rare human autoimmune disorder that is inherited in an autosomal recessive manner and is characterized by various endocrine deficiencies, chronic mucocutaneous candidiasis and ectodermal dystrophies. It is caused by a number of different mutations in the gene that encodes autoimmune regulator (AIRE).

E3-ubiquitin ligase

An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the position and number of the ubiquitin molecules that are attached, the ubiquitin tag can target proteins for degradation in the proteasomal complex, sort them to specific subcellular compartments or modify their biological activity.

Non-obese diabetic mice

(NOD mice). Mice that spontaneously develop a form of autoimmunity that closely resembles human type 1 diabetes.

Nude mice

Mice homozygous for a mutation in the Foxn1 gene, which causes both hairlessness and defective formation of the thymus, and therefore results in a lack of mature T cells.

PML nuclear bodies

One type of nuclear speckles of unknown function that contains several proteins, including the promyelocytic leukaemia protein PML.

Scurfy mice

Mice with a spontaneous mutation in the FOXP3 transcription factor (also known as Scurfin), which leads to a rapidly fatal lymphoproliferative disease, causing death by about 4 weeks of age. FOXP3-deficient mice lack the population of CD25+ regulatory T cells.

SP100 family of transcriptional co-activators

The nuclear-matrix-associated protein SP100 belongs to a family of related proteins that contain nuclear-localization signals, dimerization domains and DNA-binding domains. They interact with other transcription factors to co-activate gene transcription.

Stromal cells

Cells of non-lymphoid origin that form the framework of each organ. These cells can support adhesion, proliferation and survival of distinct cell subsets.

Tolerance

A term that denotes lymphocyte non-responsiveness to antigen, but implies an active process, not simply a passive lack of response.

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Mathis, D., Benoist, C. A decade of AIRE. Nat Rev Immunol 7, 645–650 (2007). https://doi.org/10.1038/nri2136

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