Autoimmune regulator

AIRE
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2LRI, 1XWH, 2KE1, 2KFT
Identifiers
Aliases	AIRE, AIRE1, APECED, APS1, APSI, PGA1, autoimmune regulator
External IDs	OMIM: 607358 MGI: 1338803 HomoloGene: 327 GeneCards: AIRE
Gene ontology Molecular function • DNA binding • RNA polymerase II regulatory region sequence-specific DNA binding • transcriptional activator activity, RNA polymerase II transcription regulatory region sequence-specific binding • histone binding • chromatin binding • transcription cofactor activity • translation regulator activity • metal ion binding • protein binding • identical protein binding • transcription regulatory region DNA binding • zinc ion binding Cellular component • cytoplasm • intracellular • nuclear body • Q40260 Biological process • regulation of transcription, DNA-templated • transcription, DNA-templated • negative thymic T cell selection • humoral immune response • immune response • regulation of translation • positive regulation of transcription from RNA polymerase II promoter • transcription from RNA polymerase II promoter • peripheral T cell tolerance induction • central tolerance induction to self antigen • chemokine production • positive regulation of transcription, DNA-templated • thymus epithelium morphogenesis • regulation of thymocyte migration Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	326	11634
Ensembl	ENSG00000160224	ENSMUSG00000000731
UniProt	O43918	Q9Z0E3
RefSeq (mRNA)	NM_000383 NM_000658 NM_000659	NM_001271549 NM_001271550 NM_001271551 NM_001271552 NM_001271553 NM_001271554 NM_001271555 NM_001271556 NM_001271557 NM_001271558 NM_001271559 NM_009646
RefSeq (protein)	NP_000374	NP_001258478 NP_001258479 NP_001258480 NP_001258481 NP_001258482 NP_001258483 NP_001258484 NP_001258485 NP_001258486 NP_001258487 NP_001258488 NP_033776
Location (UCSC)	Chr 21: 44.29 – 44.3 Mb	Chr 10: 78.03 – 78.04 Mb
PubMed search	[1]	[2]
Wikidata
View/Edit Human View/Edit Mouse

The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene.^[3] AIRE is a transcription factor expressed in the medulla (inner part) of the thymus and controls a mechanism that prevents the immune system from attacking the body.

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.^[4] 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.

Function

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.^[5][6] 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^[7]

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.^[5] This expression then allows maturing thymocytes to become tolerant towards peripheral organs, thereby suppressing autoimmune disease.^[6]

The AIRE gene is expressed in many other tissues as well.^[8] AIRE gene is also expressed in the 33D1+ subset of dendritic cells in mouse and in human dendritic cells.^[9]

Pathology

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.^[10]

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.^[11]

Interactions

Autoimmune regulator has been shown to interact with CREB binding protein.^[12][13]

See also

• List of human clusters of differentiation for a list of CD molecules
• Immune system
• Immune tolerance

References

Further reading

External links

• AIRE protein at the US National Library of Medicine Medical Subject Headings (MeSH)
• Human AIRE genome location and AIRE gene details page in the UCSC Genome Browser.

PDB gallery
1xwh: NMR structure of the first phd finger of autoimmune regulator protein (AIRE1): insights into apeced