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Review

Autoimmune regulator functions in autoimmunity control

Pages 891-900 | Published online: 10 Jan 2014

References

  • Kamradt T, Mitchison NA. Tolerance and autoimmunity. N. Engl. J. Med.344, 655–664 (2001).
  • Wanstrat A, Wakeland E. The genetics of complex autoimmune diseases: non-MHC susceptibility genes. Nat. Immunol.2, 802–809 (2001).
  • Nagamine K, Peterson P, Scott HS et al. Positional cloning of the APECED gene. Nat. Genet.17, 393–398 (1997).
  • Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet.17, 399–403 (1997).
  • Björses P, Aaltonen J,Horelli-Kuitunen N, Yaspo ML, Peltonen L. Gene defect behind APECED: a new clue to autoimmunity. Hum. Mol. Genet.7, 1547–1553 (1998).
  • Pitkänen J, Peterson P. Autoimmune regulator: from loss of function to autoimmunity. Genes Immun.4, 12–21 (2003).
  • Ulmanen I, Halonen M, Ilmarinen T, Peltonen L. Monogenic autoimmune diseases – lessons of self-tolerance. Curr. Opin. Immunol.17, 609–615 (2005).
  • Gibson TJ, Ramu C, Gemund C, Aasland R. The APECED polyglandular autoimmune syndrome protein, AIRE-1, contains the SAND domain and is probably a transcription factor. Trends Biochem. Sci.23, 242–244 (1998).
  • Uchida D, Hatakeyama S, Matsushima A et al. AIRE functions as an E3 ubiquitin ligase. J. Exp. Med.199, 167–172 (2004).
  • Kumar PG, Laloraya M, Wang CY et al. The autoimmune regulator (AIRE) is a DNA-binding protein. J. Biol. Chem.276, 41357–41364 (2001).
  • Heino M, Peterson P, Kudoh J et al. APECED mutations in the autoimmune regulator (AIRE) gene. Hum. Mutat.18, 205–211 (2001).
  • Ramsey C, Bukrinsky A, Peltonen L. Systematic mutagenesis of the functional domains of AIRE reveals their role in intracellular targeting. Hum. Mol. Genet.11, 3299–3308 (2002).
  • Björses P, Halonen M, Palvimo JJ et al. Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy protein. Am. J. Hum. Genet.66, 378–392 (2000).
  • Pitkänen J, Doucas V, Sternsdorf T et al. The autoimmune regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein. J. Biol. Chem.275, 16802–16809 (2000).
  • Halonen M, Kangas H, Ruppell T et al. APECED-causing mutations in AIRE reveal the functional domains of the protein. Hum. Mutat.23, 245–257 (2004).
  • Akiyoshi H, Hatakeyama S, Pitkanen J et al. Subcellular expression of autoimmune regulator (AIRE) is organized in a spatiotemporal manner. J. Biol. Chem.279, 33984–33991 (2004).
  • Pitkänen J, Vahamurto P, Krohn K, Peterson P. Subcellular localization of the autoimmune regulator protein. characterization of nuclear targeting and transcriptional activation domain. J. Biol. Chem.276, 19597–19602 (2001).
  • 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.8, 259–266 (1999).
  • Peterson P, Peltonen L. Autoimmune polyendocrinopathy syndrome type 1 (APS1) and AIRE gene: new views on molecular basis of autoimmunity. J. Autoimmun.25(Suppl.), 49–55 (2005).
  • Vogel A, Strassburg CP, Obermayer-Straub P, Brabant G, Manns MP. The genetic background of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy and its autoimmune disease components. J. Mol. Med.80, 201–211 (2002).
  • Heino M, Peterson P, Kudoh J et al. Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem. Biophys. Res. Commun.257, 821–825 (1999).
  • Kisielow P, Bluthmann H, Staerz UD, Steinmetz M, von Boehmer H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature333, 742–746 (1988).
  • Shevach EM. CD4+CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol.2, 389–400 (2002).
  • Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol.22, 531–562 (2004).
  • Kim JM, Rudensky A. The role of the transcription factor Foxp3 in the development of regulatory T cells. Immunol. Rev.212, 86–98 (2006).
  • Kyewski B, Derbinski J, Gotter J, Klein L. Promiscuous gene expression and central T-cell tolerance: more than meets the eye. Trends Immunol.23, 364–371 (2002).
  • Anderson MS, Venanzi ES, Klein L et al. Projection of an immunological self shadow within the thymus by the Aire protein. Science298, 1395–1401 (2002).
  • Kyewski B, Derbinski J. Self-representation in the thymus: an extended view. Nat. Rev. Immunol.4, 688–698 (2004).
  • Ramsey C, Winqvist O, Puhakka L et al. Aire deficient mice develop multiple features of APECED phenotype and show altered immune response. Hum. Mol. Genet.11, 397–409 (2002).
  • Kuroda N, Mitani T, Takeda N et al. Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice. J. Immunol.174, 1862–1870 (2005).
  • Liston A, Lesage S, Wilson J, Peltonen L, Goodnow CC. Aire regulates negative selection of organ-specific T cells. Nat. Immunol.4, 350–354 (2003).
  • Liston A, Gray DH, Lesage S et al. Gene dosage – limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity. J. Exp. Med.200, 1015–1026 (2004).
  • Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D. The cellular mechanism of Aire control of T cell tolerance. Immunity23, 227–239 (2005).
  • Klein L, Klein T, Ruther U, Kyewski B. CD4 T cell tolerance to human C-reactive protein, an inducible serum protein, is mediated by medullary thymic epithelium. J. Exp. Med.188, 5–16 (1998).
  • Gallegos AM, Bevan MJ. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med.200, 1039–1049 (2004).
  • Matsumoto M. Transcriptional regulation in thymic epithelial cells for the establishment of self tolerance. Arch. Immunol. Ther. Exp. (Warsz)55, 27–34 (2007).
  • Nakayama M, Abiru N, Moriyama H et al. Prime role for an insulin epitope in the development of Type 1 diabetes in NOD mice. Nature435, 220–223 (2005).
  • Niki S, Oshikawa K, Mouri Y et al. Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice. J. Clin. Invest.116, 1292–1301 (2006).
  • DeVoss J, Hou Y, Johannes K et al. Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med.203, 2727–2735 (2006).
  • Derbinski J, Schulte A, Kyewski B, Klein L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat. Immunol.2, 1032–1039 (2001).
  • Ramsey C, Hassler S, Marits P et al. Increased antigen presenting cell-mediated T cell activation in mice and patients without the autoimmune regulator. Eur. J. Immunol.36, 305–317 (2006).
  • Lee JW, Epardaud M, Sun J et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat. Immunol.8, 181–190 (2007).
  • Itoh M, Takahashi T, Sakaguchi N et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J. Immunol.162, 5317–5326 (1999).
  • Kekäläinen E, Tuovinen H, Joensuu J et al. A defect of regulatory T cells in patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. J. Immunol.178, 1208–1215 (2007).
  • Pontynen N, Miettinen A, Petteri Arstila T et al. Aire deficient mice do not develop the same profile of tissue-specific autoantibodies as APECED patients. J. Autoimmun.27, 96–104 (2006).
  • Mathis D, Benoist C. A decade of AIRE. Nat. Rev. Immunol.7, 645–650 (2007).
  • Apostolou I, Sarukhan A, Klein L, von Boehmer H. Origin of regulatory T cells with known specificity for antigen. Nat. Immunol.3, 756–763 (2002).
  • Jordan MS, Boesteanu A, Reed AJ et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol.2, 301–306 (2001).
  • Aschenbrenner K, D’Cruz LM, Vollmann EH et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat. Immunol.8, 351–358 (2007).
  • Gillard GO, Farr AG. Features of medullary thymic epithelium implicate postnatal development in maintaining epithelial heterogeneity and tissue-restricted antigen expression. J. Immunol.176, 5815–5824 (2006).
  • Halonen M, Eskelin P, Myhre AG et al. AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy phenotype. J. Clin. Endocrinol. Metab.87, 2568–2574 (2002).
  • Jiang W, Anderson MS, Bronson R, Mathis D, Benoist C. Modifier loci condition autoimmunity provoked by Aire deficiency. J. Exp. Med.202, 805–815 (2005).
  • Sakaguchi S, Sakaguchi N. Role of genetic factors in organ-specific autoimmune diseases induced by manipulating the thymus or T cells, and not self-antigens. Rev. Immunogenet.2, 147–153 (2000).
  • Estivill X. Complexity in a monogenic disease. Nat. Genet.12, 348–350 (1996).
  • Weatherall DJ. Single gene disorders or complex traits: lessons from the thalassaemias and other monogenic diseases. Br. Med. J.321, 1117–1120 (2000).
  • Cavadini P, Vermi W, Facchetti F et al. AIRE deficiency in thymus of 2 patients with Omenn syndrome. J. Clin. Invest.115, 728–732 (2005).
  • Marrella V, Poliani PL, Casati A et al. A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn syndrome. J. Clin. Invest.117, 1260–1269 (2007).
  • Zuklys S, Balciunaite G, Agarwal A, Fasler-Kan E, Palmer E, Holländer GA. Normal thymic architecture and negative selection are associated with Aire expression, the gene defective in the autoimmune-polyendocrinopathy– candidiasis–ectodermal dystrophy (APECED). J. Immunol.165, 1976–1983 (2000).
  • Turunen JA, Wessman M, Forsblom C et al. Association analysis of the AIRE and insulin genes in Finnish Type 1 diabetic patients. Immunogenetics58, 331–338 (2006).
  • Hamazaki Y, Fujita H, Kobayashi T et al. Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin. Nat. Immunol.8, 304–311 (2007).
  • Kajiura F, Sun S, Nomura T et al. NF-κB-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner. J. Immunol.172, 2067–2075 (2004).
  • Akiyama T, Maeda S, Yamane S et al. Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science308, 248–251 (2005).
  • Rossi SW, Kim MY, Leibbrandt A et al. RANK signals from CD4+3- inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med.204, 1267–1272 (2007).
  • Finke D. Fate and function of lymphoid tissue inducer cells. Curr. Opin. Immunol.17, 144–150 (2005).
  • Mebius RE. Organogenesis of lymphoid tissues. Nat. Rev. Immunol.3, 292–303 (2003).
  • Eberl G, Marmon S, Sunshine MJ, Rennert PD, Choi Y, Littman DR. An essential function for the nuclear receptor RORg(t) in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol.5, 64–73 (2004).
  • Taubert R, Schwendemann J, Kyewski B. Highly variable expression of tissue-restricted self-antigens in human thymus: implications for self-tolerance and autoimmunity. Eur. J. Immunol.37, 838–848 (2007).
  • Ruan QG, Tung K, Eisenman D et al. The autoimmune regulator directly controls the expression of genes critical for thymic epithelial function. J. Immunol.178, 7173–7180 (2007).
  • Gillard GO, Dooley J, Erickson M, Peltonen L, Farr AG. Aire-dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation. J. Immunol.178, 3007–3015 (2007).
  • Gillard GO, Farr AG. Contrasting models of promiscuous gene expression by thymic epithelium. J. Exp. Med.202, 15–19 (2005).
  • Derbinski J, Gabler J, Brors B et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med.202, 33–45 (2005).
  • Kyewski B, Klein L. A central role for central tolerance. Annu. Rev. Immunol.24, 571–606 (2006).
  • Peterson P, Perheentupa J, Krohn JE. Detection of candidal antigens in autoimmune polyglandular syndrome type I. Clin. Diagn. Lab. Immunol.3, 290–294 (1996).
  • Brännström J, Hässler S, Peltonen L, Herrmann B, Winqvist O. Defect internalization and tyrosine kinase activation in Aire deficient antigen presenting cells exposed to Candida albicans antigens. Clin. Immunol.121, 265–273 (2006).
  • Gavanescu I, Kessler B, Ploegh H, Benoist C, Mathis D. Loss of Aire-dependent thymic expression of a peripheral tissue antigen renders it a target of autoimmunity. Proc. Natl Acad. Sci. USA104, 4583–4587 (2007).

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