Autoimmune regulator

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The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene.[1] AIRE is a transcription factor expressed in the medulla (inner part) of the thymus. It is part of the mechanism which eliminates self-reactive T cells that would cause autoimmune disease. It exposes T cells to normal, healthy proteins from all parts of the body, and T cells that react to those proteins are destroyed.

Each T cell recognizes a specific antigen when it is presented in complex with a MHC molecule by an antigen presenting cell. This recognition is accomplished by the T cell receptors expressed on the cell surface. T cells receptors are generated by randomly shuffled gene segments which results in a highly diverse population of T cells - each with a unique antigen specificity. Subsequently, T cells with receptors that recognize the body's own proteins need to be eliminated while still in the thymus. Through the action of AIRE, medullary thymic epithelial cells (mTEC) express major proteins from elsewhere in the body (so called "tissue-restricted antigens" - TRA) and T cells that respond to those proteins are eliminated through cell death (apoptosis). Thus AIRE drives negative selection of self-recognizing T cells.[2] When AIRE is defective, T cells that recognize antigens normally produced by the body can exit the thymus and enter circulation. This can result in a variety of autoimmune diseases.


In the thymus, the AIRE causes transcription of a wide selection of organ-specific genes that create proteins that are usually only expressed in peripheral tissues, creating an "immunological self-shadow" in the thymus.[3][4] It is important that self-reactive T cells that bind strongly to self-antigen are eliminated in the thymus (via the process of negative selection), otherwise they may later encounter and bind to their corresponding self-antigens and initiate an autoimmune reaction. So the expression of non-local proteins by AIRE in the thymus reduces the threat of autoimmunity by promoting the elimination of auto-reactive T cells that bind antigens not normally found in the thymus. Furthermore, it has been found that AIRE is expressed in a population of stromal cells located in secondary lymphoid tissues, however these cells appear to express a distinct set of TRAs compared to mTECs[5]

Research in knockout mice has demonstrated that AIRE functions through initiating the transcription of a diverse set of self-antigens, such as insulin, in the thymus.[3] This expression then allows maturing thymocytes to become tolerant towards peripheral organs, thereby suppressing autoimmune disease.[4]

The AIRE gene is expressed in many other tissues as well.[6] AIRE gene is also expressed in the 33D1+ subset of dendritic cells in mouse and in human dendritic cells.[7]


The AIRE gene is mutated in the rare autoimmune syndrome Autoimmune Polyendocrinopathy Syndrome type 1 (APS-1), also known as Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED). Disruption of AIRE results in the development of a range of autoimmune diseases, the most common clinical conditions in the syndrome are hypoparathyroidism, primary adrenocortical failure and chronic mucocutaneous candidiasis.[8]

A gene knockout of the murine homolog of Aire has created a transgenic mouse model that is used to study the mechanism of disease in human patients.[9]


Autoimmune regulator has been shown to interact with CREB binding protein.[10][11]

See also


  1. "An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains". Nat. Genet. 17 (4): 399–403. December 1997. doi:10.1038/ng1297-399. PMID 9398840.
  2. Anderson M, Su M (2011). "Aire and T cell development". Curr. Opin. Immunol. 23 (2): 198–206. doi:10.1016/j.coi.2010.11.007. PMC 3073725. PMID 21163636.
  3. 3.0 3.1 Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (November 2002). "Projection of an immunological self shadow within the thymus by the aire protein". Science. 298 (5597): 1395–401. doi:10.1126/science.1075958. PMID 12376594.
  4. 4.0 4.1 Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC (April 2003). "Aire regulates negative selection of organ-specific T cells". Nat. Immunol. 4 (4): 350–4. doi:10.1038/ni906. PMID 12612579.
  5. Gardner J, Devoss J, Friedman R, et al. (2008). "Deletional tolerance mediated by extrathymic Aire-expressing cells". Science. 321 (5890): 843–847. doi:10.1126/science.1159407. PMC 2532844. PMID 18687966.
  6. "AIRE Gene expression/activity chart". BioGPS - your Gene Portal System. Archived from the original on 2009-12-30. Retrieved 2009-12-19.
  7. Lindmark E, Chen Y, Georgoudaki AM, Dudziak D, Lindh E, Adams WC, Loré K, Winqvist O, Chambers BJ, Karlsson MC, et al. (2013). "AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment". Journal of Autoimmunity. 42: 62–70. doi:10.1016/j.jaut.2012.11.004. PMID 23265639.
  8. OMIM
  9. Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A, Kämpe O, Eskelin P, Pelto-Huikko M, Peltonen L (2002). "Aire deficient mice develop multiple features of APECED phenotype and show altered immune response". Hum. Mol. Genet. 11 (4): 397–409. doi:10.1093/hmg/11.4.397. PMID 11854172.
  10. Pitkänen J, Doucas V, Sternsdorf T, Nakajima T, Aratani S, Jensen K, Will H, Vähämurto P, Ollila J, Vihinen M, Scott HS, Antonarakis SE, Kudoh J, Shimizu N, Krohn K, Peterson P (June 2000). "The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein". J. Biol. Chem. 275 (22): 16802–9. doi:10.1074/jbc.M908944199. PMID 10748110.
  11. Iioka T, Furukawa K, Yamaguchi A, Shindo H, Yamashita S, Tsukazaki T (August 2003). "P300/CBP acts as a coactivator to cartilage homeoprotein-1 (Cart1), paired-like homeoprotein, through acetylation of the conserved lysine residue adjacent to the homeodomain". J. Bone Miner. Res. 18 (8): 1419–29. doi:10.1359/jbmr.2003.18.8.1419. PMID 12929931.

Further reading

  • Björses P, Aaltonen J, Horelli-Kuitunen N, et al. (1998). "Gene defect behind APECED: a new clue to autoimmunity". Hum. Mol. Genet. 7 (10): 1547–53. doi:10.1093/hmg/7.10.1547. PMID 9735375.
  • Heino M, Peterson P, Kudoh J, Shimizu N, Antonarakis SE, Scott HS, Krohn K (September 2001). "APECED mutations in the autoimmune regulator (AIRE) gene". Hum. Mutat. 18 (3): 205–11. doi:10.1002/humu.1176. PMID 11524731.
  • Sato K, Nakajima K, Imamura H, Deguchi T, Horinouchi S, Yamazaki K, Yamada E, Kanaji Y, Takano K (December 2002). "A novel missense mutation of AIRE gene in a patient with autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), accompanied with progressive muscular atrophy: case report and review of the literature in Japan". Endocr. J. 49 (6): 625–33. doi:10.1507/endocrj.49.625. PMID 12625412.
  • Ruan QG, She JX (March 2004). "Autoimmune polyglandular syndrome type 1 and the autoimmune regulator". Clin. Lab. Med. 24 (1): 305–17. doi:10.1016/j.cll.2004.01.008. PMID 15157567.
  • Holmdahl R (March 2007). "Aire-ing self antigen variability and tolerance". Eur. J. Immunol. 37 (3): 598–601. doi:10.1002/eji.200737152. PMID 17323409.
  • Aaltonen J, Björses P, Sandkuijl L, Perheentupa J, Peltonen L (September 1994). "An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21". Nat. Genet. 8 (1): 83–7. doi:10.1038/ng0994-83. PMID 7987397.
  • Aaltonen J, Horelli-Kuitunen N, Fan JB, Björses P, Perheentupa J, Myers R, Palotie A, Peltonen L (August 1997). "High-resolution physical and transcriptional mapping of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy locus on chromosome 21q22.3 by FISH". Genome Res. 7 (8): 820–9. doi:10.1101/gr.7.8.820. PMID 9267805.
  • Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N (December 1997). "Positional cloning of the APECED gene". Nat. Genet. 17 (4): 393–8. doi:10.1038/ng1297-393. PMID 9398839.
  • Scott HS, Heino M, Peterson P, Mittaz L, Lalioti MD, Betterle C, Cohen A, Seri M, Lerone M, Romeo G, Collin P, Salo M, Metcalfe R, Weetman A, Papasavvas MP, Rossier C, Nagamine K, Kudoh J, Shimizu N, Krohn KJ, Antonarakis SE (August 1998). "Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins". Mol. Endocrinol. 12 (8): 1112–9. doi:10.1210/me.12.8.1112. PMID 9717837.
  • Heino M, Scott HS, Chen Q, Peterson P, Mäebpää U, Papasavvas MP, Mittaz L, Barras C, Rossier C, Chrousos GP, Stratakis CA, Nagamine K, Kudoh J, Shimizu N, Maclaren N, Antonarakis SE, Krohn K (1999). "Mutation analyses of North American APS-1 patients". Hum. Mutat. 13 (1): 69–74. doi:10.1002/(SICI)1098-1004(1999)13:1<69::AID-HUMU8>3.0.CO;2-6. PMID 9888391.
  • Björses P, Pelto-Huikko M, Kaukonen J, Aaltonen J, Peltonen L, Ulmanen I (February 1999). "Localization of the APECED protein in distinct nuclear structures". Hum. Mol. Genet. 8 (2): 259–66. doi:10.1093/hmg/8.2.259. PMID 9931333.
  • Rinderle C, Christensen HM, Schweiger S, Lehrach H, Yaspo ML (February 1999). "AIRE encodes a nuclear protein co-localizing with cytoskeletal filaments: altered sub-cellular distribution of mutants lacking the PHD zinc fingers". Hum. Mol. Genet. 8 (2): 277–90. doi:10.1093/hmg/8.2.277. PMID 9931335.
  • Björses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, Perheentupa J, Ulmanen I, Peltonen L (February 2000). "Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein". Am. J. Hum. Genet. 66 (2): 378–92. doi:10.1086/302765. PMC 1288090. PMID 10677297.
  • Pitkänen J, Doucas V, Sternsdorf T, Nakajima T, Aratani S, Jensen K, Will H, Vähämurto P, Ollila J, Vihinen M, Scott HS, Antonarakis SE, Kudoh J, Shimizu N, Krohn K, Peterson P (June 2000). "The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein". J. Biol. Chem. 275 (22): 16802–9. doi:10.1074/jbc.M908944199. PMID 10748110.
  • Pitkänen J, Vähämurto P, Krohn K, Peterson P (June 2001). "Subcellular localization of the autoimmune regulator protein. characterization of nuclear targeting and transcriptional activation domain". J. Biol. Chem. 276 (22): 19597–602. doi:10.1074/jbc.M008322200. PMID 11274163.
  • Saugier-Veber P, Drouot N, Wolf LM, Kuhn JM, Frébourg T, Lefebvre H (April 2001). "Identification of a novel mutation in the autoimmune regulator (AIRE-1) gene in a French family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy". Eur. J. Endocrinol. 144 (4): 347–51. doi:10.1530/eje.0.1440347. PMID 11275943.

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