Autoimmune regulator
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The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene.[5] It is a 13kb gene on chromosome 21q22.3 that has 545 amino acids.[6] 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
The gene was first reported by two independent research groups Aaltonen et al. and Nagamine et al. in 1997 who were able to isolate and clone the gene from human chromosome 21q22.3. Their work was able to show that mutations in the AIRE gene are responsible for the pathogenesis of Autoimmune polyglandular syndrome type I.[5][8] More insight into the AIRE protein was later provided by Heino et al. in 2000. They showed that AIRE protein is mainly expressed in the thymic medullary epithelial cells using immunohistochemistry.[9]
Function
In the thymus, the AIRE causes
Research in
The AIRE gene is expressed in many other tissues as well.[13] The AIRE gene is also expressed in the 33D1+ subset of dendritic cells in mouse and in human dendritic cells.[14]
Structure
AIRE is composed of a multidomain structure that is able to bind to chromatin and act as a regulator of gene transcription. The specific makeup of AIRE includes a
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An integral characteristic of AIRE is its ability to homomerize into dimers and trimers which allows it to bind to specific oligonucleotide motifs.
Mechanism
Instead of binding to consensus sequences of target
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). Different mutations are more common among certain populations in the world.[26] The most common exonic mutations of AIRE occur on exons 1, 2, 6, 8, and 10. Exons 1 and 2 encode the HSR, exon 6 encodes the SAND domain, exon 8 is in the PHD-1 domain, and exon 10 is located in the proline-rich region between the two PHD finger domains.[27] Known mutations in AIRE include Arg139X, Arg257X, and Leu323SerfsX51.[28]
Disruption of AIRE results in the development of a range of autoimmune diseases, the most common clinical conditions in the syndrome are
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.[30]
Interactions
Autoimmune regulator has been shown to
See also
- List of human clusters of differentiation for a list of CD molecules
- Immune system
- Immune tolerance
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000160224 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000731 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ S2CID 29785642.
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- PMID 21163636.
- S2CID 1583134.
- PMID 10940877.
- ^ S2CID 13989491.
- ^ S2CID 4561402.
- PMID 18687966.
- ^ "AIRE Gene expression/activity chart". BioGPS - your Gene Portal System. Archived from the original on 2009-12-30. Retrieved 2009-12-19.
- PMID 23265639.
- PMID 24275490.
- PMID 9697411.
- S2CID 42505863.
- PMID 7701562.
- S2CID 84265877.
- S2CID 27962035.
- ^ S2CID 2518676.
- PMID 17938200.
- ^ PMID 17997173.
- S2CID 39198636.
- PMID 22310661.
- PMID 9717837.
- PMID 10677297.
- S2CID 202671335.
- ^ "OMIM".
- PMID 11854172.
- S2CID 8125330.
Further reading
- Björses P, Aaltonen J, Horelli-Kuitunen N, Yaspo ML, Peltonen L (1998). "Gene defect behind APECED: a new clue to autoimmunity". Human Molecular Genetics. 7 (10): 1547–53. 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". Human Mutation. 18 (3): 205–11. S2CID 40379449.
- Sato K, Nakajima K, Imamura H, Deguchi T, Horinouchi S, Yamazaki K, et al. (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". Endocrine Journal. 49 (6): 625–33. PMID 12625412.
- Ruan QG, She JX (March 2004). "Autoimmune polyglandular syndrome type 1 and the autoimmune regulator". Clinics in Laboratory Medicine. 24 (1): 305–17. PMID 15157567.
- Holmdahl R (March 2007). "Aire-ing self antigen variability and tolerance". European Journal of Immunology. 37 (3): 598–601. S2CID 26685751.
- 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" (PDF). Nature Genetics. 8 (1): 83–7. S2CID 20365290.
- Aaltonen J, Horelli-Kuitunen N, Fan JB, Björses P, Perheentupa J, Myers R, et al. (August 1997). "High-resolution physical and transcriptional mapping of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy locus on chromosome 21q22.3 by FISH". Genome Research. 7 (8): 820–9. PMID 9267805.
- Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. (December 1997). "Positional cloning of the APECED gene". Nature Genetics. 17 (4): 393–8. S2CID 1583134.
- Scott HS, Heino M, Peterson P, Mittaz L, Lalioti MD, Betterle C, et al. (August 1998). "Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins". Molecular Endocrinology. 12 (8): 1112–9. PMID 9717837.
- Heino M, Scott HS, Chen Q, Peterson P, Mäebpää U, Papasavvas MP, et al. (1999). "Mutation analyses of North American APS-1 patients". Human Mutation. 13 (1): 69–74. S2CID 27558091.
- Björses P, Pelto-Huikko M, Kaukonen J, Aaltonen J, Peltonen L, Ulmanen I (February 1999). "Localization of the APECED protein in distinct nuclear structures". Human Molecular Genetics. 8 (2): 259–66. 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". Human Molecular Genetics. 8 (2): 277–90. PMID 9931335.
- Björses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, et al. (February 2000). "Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein". American Journal of Human Genetics. 66 (2): 378–92. PMID 10677297.
- Pitkänen J, Doucas V, Sternsdorf T, Nakajima T, Aratani S, Jensen K, et al. (June 2000). "The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein". The Journal of Biological Chemistry. 275 (22): 16802–9. 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". The Journal of Biological Chemistry. 276 (22): 19597–602. 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". European Journal of Endocrinology. 144 (4): 347–51. PMID 11275943.
External links
- AIRE+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Human AIRE genome location and AIRE gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: O43918 (Autoimmune regulator) at the PDBe-KB.
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