自體免疫調節因子

自體免疫調節因子
已知的結構
PDB直系同源搜索: PDBe RCSB
識別號
别名AIRE;, AIRE1, APECED, APS1, APSI, PGA1, autoimmune regulator
外部IDOMIM607358 MGI1338803 HomoloGene327 GeneCardsAIRE
相關疾病
第一型自體免疫多內分泌症[1]
基因位置(人类
21號染色體
染色体21號染色體[2]
21號染色體
自體免疫調節因子的基因位置
自體免疫調節因子的基因位置
基因座21q22.3起始44,285,838 bp[2]
终止44,298,648 bp[2]
RNA表达模式
查阅更多表达数据
直系同源
物種人類小鼠
Entrez
Ensembl
UniProt
mRNA​序列

NM_000383
​NM_000658
​NM_000659

蛋白序列

NP_000374

基因位置​(UCSC)Chr 21: 44.29 – 44.3 MbChr 10: 77.87 – 77.88 Mb
PubMed​查找[4][5]
維基數據
檢視/編輯人類檢視/編輯小鼠

自體免疫調節因子(Autoimmune regulator)是人體內由AIRE基因表現的蛋白質[6]。AIRE是在胸腺髓質表現的轉錄因子,使人體不會被自身的免疫系統攻擊。

每個T細胞都會辨識由抗原呈現細胞MHC分子複合體呈現的特定抗原,这一识别需要T細胞表面的T細胞受体。T細胞受体由VDJ重組片段所製造,所以T細胞多樣性很高,而每個T細胞都有專一性。接著,會辨識自身蛋白質的T細胞受器必須在還在胸腺內時消除。透過AIRE作用,胸腺髓質上皮細胞(mTEC)會表現身體其他各個地方的主要蛋白質(所謂的 TRA),而且將會和這些蛋白質反應的T細胞透過細胞程序性死亡(细胞凋亡)的方式消除。因此AIRE針對自體辨識的T細胞進行負向篩選英语Negative selection (immunology)[7]。當AIRE受損時,會辨識人體自身抗原的T細胞會離開胸腺,進入血液循環,並可能導致許多的自體免疫疾病

功能

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在胸腺中,AIRE會促進一個大範圍的特定器官基因的轉錄,並製造出只在周邊組織表現的蛋白質,在胸腺中創造「免疫的影子」[8][9]透過負向篩選英语Negative selection (immunology),將在胸腺中會和自身抗原強烈結合的T細胞消除是很重要的,否則之後他們可能會遇到能強烈結合的自身抗原,引發自體免疫反應。所以在胸腺內藉由AIRE表現非當地的蛋白質,消除和自身抗原反應的T細胞,可以降低自體免疫的威脅。再者,AIRE被發現會在次級淋巴組織中一群間質細胞中表現,然而這些細胞表現出的TRAs和mTECs所表現出的不同。[10]

基因改造鼠相關的研究指出AIRE藉由在胸腺內啟動多樣的自身抗原(例如:胰島素)的轉錄而作用[8]。這個表現允許成熟中的胸腺細胞對周邊器官展現耐受性,進而抑制自體免疫疾病[9]

AIRE基因亦會在很多其他組織中表現[11]。AIRE也會在老鼠中的33D1+的樹突細胞及人類樹突細胞[12]

病理

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AIRE基因突變發生於一種罕見的自體免疫疾病,APS-1(Autoimmune Polyendocrinopathy Syndrome type 1),又稱作APECED( Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy)。AIRE的阻斷會產生許多自體免疫疾病,臨床上最常見的案例是甲狀旁腺功能減退症英语Hypoparathyroidism原發性腎上腺皮質功能衰竭英语Adrenal insufficiency慢性黏膜皮膚念珠菌病英语Chronic mucocutaneous candidiasis[13]

為了探討人類的疾病機制,會使用剔除AIRE基因的轉基因小鼠模型來進行研究[14]

相關條目

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參考資料

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  1. ^ 與自體免疫調節因子相關的疾病;在維基數據上查看/編輯參考. 
  2. ^ 2.0 2.1 2.2 GRCh38: Ensembl release 89: ENSG00000160224 - Ensembl, May 2017
  3. ^ 3.0 3.1 3.2 GRCm38: Ensembl release 89: ENSMUSG00000000731 - Ensembl, May 2017
  4. ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  5. ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine. 
  6. ^ An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. December 1997, 17 (4): 399–403. PMID 9398840. doi:10.1038/ng1297-399. 
  7. ^ Anderson M, Su M. Aire and T cell development.. Curr. Opin. Immunol. 2011, 23 (2): 198–206. PMC 3073725可免费查阅. PMID 21163636. doi:10.1016/j.coi.2010.11.007. 
  8. ^ 8.0 8.1 Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D. Projection of an immunological self shadow within the thymus by the aire protein. Science. November 2002, 298 (5597): 1395–401. PMID 12376594. doi:10.1126/science.1075958. 
  9. ^ 9.0 9.1 Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC. Aire regulates negative selection of organ-specific T cells. Nat. Immunol. April 2003, 4 (4): 350–4. PMID 12612579. doi:10.1038/ni906. 
  10. ^ Gardner J, Devoss J, Friedman R, et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science. 2008, 321 (5890): 843–847. PMC 2532844可免费查阅. PMID 18687966. doi:10.1126/science.1159407. 
  11. ^ AIRE Gene expression/activity chart. BioGPS - your Gene Portal System. [2009-12-19]. (原始内容存档于2009年12月30日). 
  12. ^ Lindmark E, Chen Y, Georgoudaki AM, Dudziak D, Lindh E, Adams WC, Loré K, Winqvist O, Chambers BJ, Karlsson MC, et al. AIRE expressing marginal zone dendritic cells balances adaptive immunity and T-follicular helper cell recruitment.. Journal of Autoimmunity. 2013, 42: 62–70. PMID 23265639. doi:10.1016/j.jaut.2012.11.004. 
  13. ^ OMIM. [2018-05-21]. (原始内容存档于2009-10-19). 
  14. ^ Ramsey C, Winqvist O, Puhakka L, Halonen M, Moro A, Kämpe O, Eskelin P, Pelto-Huikko M, Peltonen L. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum. Mol. Genet. 2002, 11 (4): 397–409. PMID 11854172. doi:10.1093/hmg/11.4.397. 

延伸閱讀

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

外部連結

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