View source for Autoimmune regulator

{{redirects|AIRE|other uses|Aire (disambiguation){{!}}Aire}}
{{Infobox_gene}}
The '''autoimmune regulator''' (''AIRE'') is a [[protein]] that in humans is encoded by the ''AIRE'' [[gene]].<ref name="pmid9398840">{{cite journal | title = An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains | journal = Nat. Genet. | volume = 17 | issue = 4 | pages = 399–403 |date=December 1997 | pmid = 9398840 | doi = 10.1038/ng1297-399 }}</ref> AIRE is a [[transcription factor]] expressed in the [[Thymus#Medulla|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 [[Major histocompatibility complex|MHC molecule]] by an [[Antigen-presenting cell|antigen presenting cell]].  This recognition is accomplished by the [[T-cell receptor|T cell receptors]] expressed on the cell surface. T cells receptors are generated by [[V(D)J recombination|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 (immunology)|negative selection]] of self-recognizing T cells.<ref name="pmid21163636">{{cite journal |vauthors=Anderson M, Su M| title = Aire and T cell development. | journal = Curr. Opin. Immunol. | volume = 23 | issue = 2 | pages = 198–206 | year = 2011 | pmid = 21163636 | doi = 10.1016/j.coi.2010.11.007 | pmc=3073725}}</ref> 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 disease|autoimmune diseases]].

==Function==
In the thymus, the AIRE causes [[Transcription (genetics)|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.<ref name="pmid12376594">{{cite journal |vauthors=Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D | title = Projection of an immunological self shadow within the thymus by the aire protein | journal = Science | volume = 298 | issue = 5597 | pages = 1395–401 |date=November 2002 | pmid = 12376594 | doi = 10.1126/science.1075958 }}</ref><ref name="pmid12612579">{{cite journal |vauthors=Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC | title = Aire regulates negative selection of organ-specific T cells | journal = Nat. Immunol. | volume = 4 | issue = 4 | pages = 350–4 |date=April 2003 | pmid = 12612579 | doi = 10.1038/ni906 }}</ref> 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 (immunology)|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<ref name="pmid18687966">{{cite journal |vauthors=Gardner J, Devoss J, Friedman R | title = Deletional tolerance mediated by extrathymic Aire-expressing cells | journal = Science | volume = 321 | issue = 5890 | pages = 843–847| year = 2008 | pmid = 18687966 | doi = 10.1126/science.1159407 | pmc=2532844|display-authors=etal}}</ref>

Research in [[knockout mouse|knockout mice]] has demonstrated that AIRE functions through initiating the [[Transcription (genetics)|transcription]] of a diverse set of self-antigens, such as [[insulin]], in the [[thymus]].<ref name="pmid12376594"/> This expression then allows maturing [[thymocytes]] to become [[central tolerance|tolerant]] towards peripheral organs, thereby suppressing autoimmune disease.<ref name="pmid12612579"/>

The AIRE gene is expressed in many other tissues as well.<ref name="urlBioGPS - your Gene Portal System">{{cite web | url = http://biogps.gnf.org/#goto=genereport&id=326 | title = AIRE Gene expression/activity chart | work = BioGPS - your Gene Portal System | publisher =  | accessdate = 2009-12-19 | archiveurl = https://web.archive.org/web/20091230141946/http://biogps.gnf.org/#goto=genereport&id=326 | archivedate = 2009-12-30 | deadurl = yes | df =  }}</ref> AIRE gene is also expressed in the 33D1+ subset of dendritic cells in mouse and in human dendritic cells.<ref name="PMID23265639">{{cite journal |vauthors=Lindmark E, Chen Y, Georgoudaki AM, Dudziak D, Lindh E, Adams WC, Loré K, Winqvist O, Chambers BJ, Karlsson MC | title = AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment. | journal = Journal of Autoimmunity | volume = 42 | pages =  62–70| year = 2013 | PMID= 23265639 | doi=10.1016/j.jaut.2012.11.004 |display-authors=etal}}</ref>

==Pathology==
The AIRE gene is mutated in the rare autoimmune syndrome Autoimmune Polyendocrinopathy Syndrome type 1 ([[APECED#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 insufficiency|primary adrenocortical failure]] and [[chronic mucocutaneous candidiasis]].<ref name = "Disease characteristics">[https://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=240300 OMIM]</ref>

A [[knockout mouse|gene knockout]] of the murine homolog of ''Aire'' has created a [[Laboratory mouse#Laboratory mice|transgenic mouse model]] that is used to study the mechanism of disease in human patients.<ref name="pmid11854172">{{cite journal |vauthors=Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A, Kämpe O, Eskelin P, Pelto-Huikko M, Peltonen L | title = Aire deficient mice develop multiple features of APECED phenotype and show altered immune response | journal = Hum. Mol. Genet. | volume = 11 | issue = 4 | pages = 397–409 | year = 2002 | pmid = 11854172 | doi = 10.1093/hmg/11.4.397 }}</ref>

==Interactions==
Autoimmune regulator has been shown to [[Protein-protein interaction|interact]] with [[CREB binding protein]].<ref name="pmid10748110">{{cite journal |vauthors=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 | title = The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein | journal = J. Biol. Chem. | volume = 275 | issue = 22 | pages = 16802–9 |date=June 2000 | pmid = 10748110 | doi = 10.1074/jbc.M908944199 }}</ref><ref name="pmid12929931">{{cite journal |vauthors=Iioka T, Furukawa K, Yamaguchi A, Shindo H, Yamashita S, Tsukazaki T | title = 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 | journal = J. Bone Miner. Res. | volume = 18 | issue = 8 | pages = 1419–29 |date=August 2003 | pmid = 12929931 | doi = 10.1359/jbmr.2003.18.8.1419 }}</ref>

==See also==
*[[List of human clusters of differentiation]] for a list of CD molecules
*[[Immune system]]
*[[Immune tolerance]]

==References==
{{Reflist}}

==Further reading==
{{refbegin | 2}}
* {{cite journal  | author=Björses P |title=Gene defect behind APECED: a new clue to autoimmunity |journal=Hum. Mol. Genet. |volume=7 |issue= 10 |pages= 1547–53 |year= 1998 |pmid= 9735375 |doi=10.1093/hmg/7.10.1547  |name-list-format=vanc| author2=Aaltonen J  | author3=Horelli-Kuitunen N  | display-authors=3  | last4=Yaspo  | first4=ML  | last5=Peltonen  | first5=L  }}
* {{cite journal |vauthors=Heino M, Peterson P, Kudoh J, Shimizu N, Antonarakis SE, Scott HS, Krohn K | title = APECED mutations in the autoimmune regulator (AIRE) gene | journal = Hum. Mutat. | volume = 18 | issue = 3 | pages = 205–11 |date=September 2001 | pmid = 11524731 | doi = 10.1002/humu.1176 }}
* {{cite journal |vauthors=Sato K, Nakajima K, Imamura H, Deguchi T, Horinouchi S, Yamazaki K, Yamada E, Kanaji Y, Takano K | title = 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 | journal = Endocr. J. | volume = 49 | issue = 6 | pages = 625–33 |date=December 2002 | pmid = 12625412 | doi = 10.1507/endocrj.49.625 }}
* {{cite journal |vauthors=Ruan QG, She JX | title = Autoimmune polyglandular syndrome type 1 and the autoimmune regulator | journal = Clin. Lab. Med. | volume = 24 | issue = 1 | pages = 305–17 |date=March 2004 | pmid = 15157567 | doi = 10.1016/j.cll.2004.01.008 }}
*{{cite journal | author = Holmdahl R | title = Aire-ing self antigen variability and tolerance | journal = Eur. J. Immunol. | volume = 37 | issue = 3 | pages = 598–601 |date=March 2007 | pmid = 17323409 | doi = 10.1002/eji.200737152 }}
*{{cite journal |vauthors=Aaltonen J, Björses P, Sandkuijl L, Perheentupa J, Peltonen L | title = An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21 | journal = Nat. Genet. | volume = 8 | issue = 1 | pages = 83–7 |date=September 1994 | pmid = 7987397 | doi = 10.1038/ng0994-83 }}
* {{cite journal |vauthors=Aaltonen J, Horelli-Kuitunen N, Fan JB, Björses P, Perheentupa J, Myers R, Palotie A, Peltonen L | title = High-resolution physical and transcriptional mapping of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy locus on chromosome 21q22.3 by FISH | journal = Genome Res. | volume = 7 | issue = 8 | pages = 820–9 |date=August 1997 | pmid = 9267805 | doi = 10.1101/gr.7.8.820 }}
*{{cite journal |vauthors=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 | title = Positional cloning of the APECED gene | journal = Nat. Genet. | volume = 17 | issue = 4 | pages = 393–8 |date=December 1997 | pmid = 9398839 | doi = 10.1038/ng1297-393 }}
*{{cite journal |vauthors=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 | title = Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins | journal = Mol. Endocrinol. | volume = 12 | issue = 8 | pages = 1112–9 |date=August 1998 | pmid = 9717837 | doi = 10.1210/me.12.8.1112 }}
* {{cite journal |vauthors=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 | title = Mutation analyses of North American APS-1 patients | journal = Hum. Mutat. | volume = 13 | issue = 1 | pages = 69–74 | year = 1999 | pmid = 9888391 | doi = 10.1002/(SICI)1098-1004(1999)13:1<69::AID-HUMU8>3.0.CO;2-6 | url = }}
* {{cite journal |vauthors=Björses P, Pelto-Huikko M, Kaukonen J, Aaltonen J, Peltonen L, Ulmanen I | title = Localization of the APECED protein in distinct nuclear structures | journal = Hum. Mol. Genet. | volume = 8 | issue = 2 | pages = 259–66 |date=February 1999 | pmid = 9931333 | doi = 10.1093/hmg/8.2.259 }}
* {{cite journal |vauthors=Rinderle C, Christensen HM, Schweiger S, Lehrach H, Yaspo ML | title = AIRE encodes a nuclear protein co-localizing with cytoskeletal filaments: altered sub-cellular distribution of mutants lacking the PHD zinc fingers | journal = Hum. Mol. Genet. | volume = 8 | issue = 2 | pages = 277–90 |date=February 1999 | pmid = 9931335 | doi = 10.1093/hmg/8.2.277 }}
*{{cite journal |vauthors=Björses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, Perheentupa J, Ulmanen I, Peltonen L | title = Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein | journal = Am. J. Hum. Genet. | volume = 66 | issue = 2 | pages = 378–92 |date=February 2000 | pmid = 10677297 | pmc = 1288090 | doi = 10.1086/302765 }}
* {{cite journal |vauthors=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 | title = The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein | journal = J. Biol. Chem. | volume = 275 | issue = 22 | pages = 16802–9 |date=June 2000 | pmid = 10748110 | doi = 10.1074/jbc.M908944199 }}
* {{cite journal |vauthors=Pitkänen J, Vähämurto P, Krohn K, Peterson P | title = Subcellular localization of the autoimmune regulator protein. characterization of nuclear targeting and transcriptional activation domain | journal = J. Biol. Chem. | volume = 276 | issue = 22 | pages = 19597–602 |date=June 2001 | pmid = 11274163 | doi = 10.1074/jbc.M008322200  }}
* {{cite journal |vauthors=Saugier-Veber P, Drouot N, Wolf LM, Kuhn JM, Frébourg T, Lefebvre H | title = Identification of a novel mutation in the autoimmune regulator (AIRE-1) gene in a French family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy | journal = Eur. J. Endocrinol. | volume = 144 | issue = 4 | pages = 347–51 |date=April 2001 | pmid = 11275943 | doi = 10.1530/eje.0.1440347 }}
{{refend}}

==External links==
* {{MeshName|AIRE+protein}}
* {{UCSC gene info|AIRE}}

{{PDB Gallery|geneid=326}}
{{Transcription factors|g2}}

[[Category:Immune system]]
[[Category:Immunology]]
[[Category:Transcription factors]]