Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Inbal Benhar
  • Jakub AbramsonEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101979


Historical Background

One of the hallmarks of the adaptive immune system is its ability to distinguish between self and nonself, in order to be able to protect the individual from invading pathogens, while avoiding a potentially-destructive immune response against the body’s own tissues. Collectively known as immune tolerance, this ability is governed by an array of tightly regulated processes that are at the heart of immunological research. Much of our understanding of the mechanisms underlying immune tolerance has come from studying various cases of autoimmune disorders, which occur as a consequence of breakdown of self-tolerance mechanisms. Autoimmune polyglandular syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a monogenic autoimmune disorder characterized by devastating multiorgan pathological manifestations. In 1997, two research consortia cloned the gene...

This is a preview of subscription content, log in to check access.


  1. Abramson J, Goldfarb Y. AIRE: from promiscuous molecular partnerships to promiscuous gene expression. Eur J Immunol. 2016;46:22–33.  https://doi.org/10.1002/eji.201545792.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Abramson J, Husebye ES. Autoimmune regulator and self-tolerance – molecular and clinical aspects. Immunol Rev. 2016;271:127–40.  https://doi.org/10.1111/imr.12419.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Abramson J, Giraud M, Benoist C, Mathis D. Aire’s partners in the molecular control of immunological tolerance. Cell. 2010;140:123–35.  https://doi.org/10.1016/j.cell.2009.12.030.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Anderson MS, Su MA. AIRE expands: new roles in immune tolerance and beyond. Nat Rev Immunol. 2016;16:247–58.  https://doi.org/10.1038/nri.2016.9.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 2002;298:1395–401.  https://doi.org/10.1126/science.1075958.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire + medullary thymic epithelial cells. Nat Immunol. 2007;8:351–8.  https://doi.org/10.1038/ni1444.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bjorses P, Pelto-Huikko M, Kaukonen J, Aaltonen J, Peltonen L, Ulmanen I. Localization of the APECED protein in distinct nuclear structures. Hum Mol Genet. 1999;8:259–66.  https://doi.org/10.1093/Hmg/8.2.259.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chuprin A, Avin A, Goldfarb Y, Herzig Y, Levi B, Jacob A, et al. The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance. Nat Immunol. 2015;16:737–45.  https://doi.org/10.1038/ni.3194.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Finnish-German AC. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 1997;17:399–403.  https://doi.org/10.1038/ng1297-399.CrossRefGoogle Scholar
  10. Fujikado N, Mann AO, Bansal K, Romito KR, Ferre EM, Rosenzweig SD, et al. Aire inhibits the generation of a perinatal population of interleukin-17A-producing gammadelta T cells to promote immunologic tolerance. Immunity. 2016;45:999–1012.  https://doi.org/10.1016/j.immuni.2016.10.023.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Haljasorg U, Bichele R, Saare M, Guha M, Maslovskaja J, Kond K, et al. A highly conserved NF-kappaB-responsive enhancer is critical for thymic expression of Aire in mice. Eur J Immunol. 2015;45:3246–56.  https://doi.org/10.1002/eji.201545928.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Heino M, Peterson P, Kudoh J, Nagamine K, Lagerstedt A, Ovod V, et al. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem Biophys Res Commun. 1999;257:821–5.  https://doi.org/10.1006/bbrc.1999.0308.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Herzig Y, Nevo S, Bornstein C, Brezis MR, Ben-Hur S, Shkedy A, et al. Transcriptional programs that control expression of the autoimmune regulator gene Aire. Nat Immunol. 2017;18.  https://doi.org/10.1038/ni.3638.PubMedCrossRefGoogle Scholar
  14. Husebye ES, Perheentupa J, Rautemaa R, Kampe O. Clinical manifestations and management of patients with autoimmune polyendocrine syndrome type I. J Intern Med. 2009;265:514–29.  https://doi.org/10.1111/j.1365-2796.2009.02090.x.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV, et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med. 2010;207:299–308.  https://doi.org/10.1084/jem.20091669.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Koh AS, Kingston RE, Benoist C, Mathis D. Global relevance of Aire binding to hypomethylated lysine-4 of histone-3. Proc Natl Acad Sci USA. 2010;107:13016–21.  https://doi.org/10.1073/pnas.1004436107.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Kumar PG, Laloraya M, Wang CY, Ruan QG, Davoodi-Semiromi A, Kao KJ, et al. The autoimmune regulator (AIRE) is a DNA-binding protein. J Biol Chem. 2001;276:41357–64.  https://doi.org/10.1074/jbc.M104898200.CrossRefPubMedPubMedCentralGoogle Scholar
  18. LaFlam TN, Seumois G, Miller CN, Lwin W, Fasano KJ, Waterfield M, et al. Identification of a novel cis-regulatory element essential for immune tolerance. J Exp Med. 2015;212:1993–2002.  https://doi.org/10.1084/jem.20151069.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Lee HM, Bautista JL, Scott-Browne J, Mohan JF, Hsieh CS. A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity. 2012;37:475–86.  https://doi.org/10.1016/j.immuni.2012.07.009.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Marx A, Hohenberger P, Hoffmann H, Pfannschmidt J, Schnabel P, Hofmann HS, et al. The autoimmune regulator AIRE in thymoma biology: autoimmunity and beyond. J Thorac Oncol. 2010;5:S266–72.  https://doi.org/10.1097/JTO.0b013e3181f1f63f.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Mathis D, Benoist C. Aire. Annu Rev Immunol. 2009;27:287–312.  https://doi.org/10.1146/annurev.immunol.25.022106.141532.CrossRefPubMedPubMedCentralGoogle Scholar
  22. Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, et al. Positional cloning of the APECED gene. Nat Genet. 1997;17:393–8.  https://doi.org/10.1038/ng1297-393.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Oftedal BE, Hellesen A, Erichsen MM, Bratland E, Vardi A, Perheentupa J, et al. Dominant mutations in the autoimmune regulator AIRE are associated with common organ-specific autoimmune diseases. Immunity. 2015;42:1185–96.  https://doi.org/10.1016/j.immuni.2015.04.021.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Perniola R, Musco G. The biophysical and biochemical properties of the autoimmune regulator (AIRE) protein. Biochim Biophys Acta. 2014;1842:326–37.  https://doi.org/10.1016/j.bbadis.2013.11.020.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Perry JS, Lio CW, Kau AL, Nutsch K, Yang Z, Gordon JI, et al. Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus. Immunity. 2014;41:414–26.  https://doi.org/10.1016/j.immuni.2014.08.007.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Pitkanen J, Doucas V, Sternsdorf T, Nakajima T, Aratani S, Jensen K, et al. The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein. J Biol Chem. 2000;275:16802–9.  https://doi.org/10.1074/jbc.M908944199.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C, et al. Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med. 2010;207:291–7.  https://doi.org/10.1084/jem.20091983.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Yanagihara T, Sanematsu F, Sato T, Uruno T, Duan X, Tomino T, et al. Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus. Nat Commun. 2015;6:8820.  https://doi.org/10.1038/ncomms9820.CrossRefPubMedPubMedCentralGoogle Scholar
  29. Yang S, Fujikado N, Kolodin D, Benoist C, Mathis D. Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science. 2015;348:589–94.  https://doi.org/10.1126/science.aaa7017.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of ImmunologyWeizmann Institute of ScienceRehovotIsrael
  2. 2.Broad Institute of MIT and HarvardCambridgeUSA