Advanced search
Publication Cover
Expert Review of Clinical Immunology Volume 9, 2013 - Issue 1
Submit an article Journal homepage
149
Views
9
CrossRef citations to date
0
Altmetric
Review

Alterations of the autoimmune regulator transcription factor and failure of central tolerance: APECED as a model

Vera Gallo Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy; Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy
,
Giuliana Giardino Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy; Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy
,
Donatella Capalbo Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy; Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy
,
Loredana Palamaro Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy; Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy
,
Rosa Romano Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy; Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy
,
Francesca Santamaria Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy; Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy
,
Filomena Maio Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy; Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy
,
Mariacarolina Salerno Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy; Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy
,
Pietro Vajro Department of Medicine and Surgery, Chair of Pediatrics, University of Salerno, Italy
&
Claudio Pignata Department of Pediatrics, ‘Federico II’ University, S Pansini 5, 8013 Naples, Italy. [email protected]
 show all
Pages 43-51 | Published online: 10 Jan 2014

References

  • Grammatikos AP, Tsokos GC. Immunodeficiency and autoimmunity: lessons from systemic lupus erythematosus. Trends Mol. Med. 18(2), 101–108 (2012).
  • Pessach IM, Notarangelo LD. X-linked primary immunodeficiencies as a bridge to better understanding X-chromosome related autoimmunity. J. Autoimmun. 33(1), 17–24 (2009).
  • Pignata C, Alessio M, Ramenghi U et al. Clustering of distinct autoimmune diseases associated with functional abnormalities of T cell survival in children. Clin. Exp. Immunol. 121(1), 53–58 (2000).
  • Griesemer AD, Sorenson EC, Hardy MA. The role of the thymus in tolerance. Transplantation 90(5), 465–474 (2010).
  • Cheroutre H. Starting at the beginning: new perspectives on the biology of mucosal T-cells. Annu. Rev. Immunol. 22, 217–246 (2004).
  • Brewer JA, Kanagawa O, Sleckman BP, Muglia LJ. Thymocyte apoptosis induced by T cell activation is mediated by glucocorticoids in vivo. J. Immunol. 169(4), 1837–1843 (2002).
  • Palmer E. Negative selection – clearing out the bad apples from the T-cell repertoire. Nat. Rev. Immunol. 3(5), 383–391 (2003).
  • Kyewski B, Klein L. A central role for central tolerance. Annu. Rev. Immunol. 24, 571–606 (2006).
  • Derbinski J, Gäbler J, Brors B et al. Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels. J. Exp. Med. 202(1), 33–45 (2005).
  • Anderson MS, Venanzi ES, Klein L et al. Projection of an immunological self shadow within the thymus by the aire protein. Science 298(5597), 1395–1401 (2002).
  • Derbinski J, Pinto S, Rösch S, Hexel K, Kyewski B. Promiscuous gene expression patterns in single medullary thymic epithelial cells argue for a stochastic mechanism. Proc. Natl Acad. Sci. USA 105(2), 657–662 (2008).
  • Gillard GO, Farr AG. Features of medullary thymic epithelium implicate postnatal development in maintaining epithelial heterogeneity and tissue-restricted antigen expression. J. Immunol. 176(10), 5815–5824 (2006).
  • Kyewski B, Peterson P. Aire, master of many trades. Cell 140(1), 24–26 (2010).
  • Mathis D, Benoist C. Aire. Annu. Rev. Immunol. 27, 287–312 (2009).
  • Gardner JM, Devoss JJ, Friedman RS et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 321(5890), 843–847 (2008).
  • Rooke R, Waltzinger C, Benoist C, Mathis D. Targeted complementation of MHC class II deficiency by intrathymic delivery of recombinant adenoviruses. Immunity 7(1), 123–134 (1997).
  • Klein L. Dead man walking: how thymocytes scan the medulla. Nat. Immunol. 10(8), 809–811 (2009).
  • Koble C, Kyewski B. The thymic medulla: a unique microenvironment for intercellular self-antigen transfer. J. Exp. Med. 206(7), 1505–1513 (2009).
  • Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 6(4), 331–337 (2005).
  • Cabarrocas J, Cassan C, Magnusson F et al. Foxp3+ CD25+ regulatory T-cells specific for a neo-self-antigen develop at the double-positive thymic stage. Proc. Natl Acad. Sci. USA 103(22), 8453–8458 (2006).
  • DeFranco S, Bonissoni S, Cerutti F et al. Defective function of Fas in patients with type 1 diabetes associated with other autoimmune diseases. Diabetes 50(3), 483–488 (2001).
  • Foy TM, Page DM, Waldschmidt TJ et al. An essential role for gp39, the ligand for CD40, in thymic selection. J. Exp. Med. 182(5), 1377–1388 (1995).
  • Kishimoto H, Sprent J. Several different cell surface molecules control negative selection of medullary thymocytes. J. Exp. Med. 190(1), 65–73 (1999).
  • Kishimoto H, Surh CD, Sprent J. A role for Fas in negative selection of thymocytes in vivo. J. Exp. Med. 187(9), 1427–1438 (1998).
  • Nagamine K, Peterson P, Scott HS et al. Positional cloning of the APECED gene. Nat. Genet. 17(4), 393–398 (1997).
  • Consortium F-GA. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 17(4), 399–403 (1997).
  • Aaltonen J, Horelli-Kuitunen N, Fan JB et al. High-resolution physical and transcriptional mapping of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy locus on chromosome 21q22.3 by FISH. Genome Res. 7(8), 820–829 (1997).
  • 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(2), 378–392 (2000).
  • Ferguson BJ, Alexander C, Rossi SW et al. AIRE’s CARD revealed, a new structure for central tolerance provokes transcriptional plasticity. J. Biol. Chem. 283(3), 1723–1731 (2008).
  • Ramsey C, Bukrinsky A, Peltonen L. Systematic mutagenesis of the functional domains of AIRE reveals their role in intracellular targeting. Hum. Mol. Genet. 11(26), 3299–3308 (2002).
  • Gibson TJ, Ramu C, Gemünd 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(7), 242–244 (1998).
  • Ilmarinen T, Eskelin P, Halonen M et al. Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation. Hum. Mutat. 26(4), 322–331 (2005).
  • Bottomley MJ, Stier G, Pennacchini D et al. NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease. J. Biol. Chem. 280(12), 11505–11512 (2005).
  • Meloni A, Incani F, Corda D, Cao A, Rosatelli MC. Role of PHD fingers and COOH-terminal 30 amino acids in AIRE transactivation activity. Mol. Immunol. 45(3), 805–809 (2008).
  • Savkur RS, Burris TP. The coactivator LXXLL nuclear receptor recognition motif. J. Pept. Res. 63(3), 207–212 (2004).
  • Wang CY, Shi JD, Davoodi-Semiromi A, She JX. Cloning of Aire, the mouse homologue of the autoimmune regulator (AIRE) gene responsible for autoimmune polyglandular syndrome type 1 (ASP1). Genomics 55(3), 322–326 (1999).
  • 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(4), 1862–1870 (2005).
  • Hubert FX, Kinkel SA, Crewther PE et al. Aire-deficient C57BL/6 mice mimicking the common human 13-base pair deletion mutation present with only a mild autoimmune phenotype. J. Immunol. 182(6), 3902–3918 (2009).
  • Johnnidis JB, Venanzi ES, Taxman DJ, Ting JP, Benoist CO, Mathis DJ. Chromosomal clustering of genes controlled by the aire transcription factor. Proc. Natl. Acad. Sci. USA 102(20), 7233–7238 (2005).
  • Abramson J, Giraud M, Benoist C, Mathis D. Aire’s partners in the molecular control of immunological tolerance. Cell 140(1), 123–135 (2010).
  • 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. 276(22), 19597–19602 (2001).
  • Kalkhoven E. CBP and p300: HATs for different occasions. Biochem. Pharmacol. 68(6), 1145–1155 (2004).
  • Peterson P, Org T, Rebane A. Transcriptional regulation by AIRE: molecular mechanisms of central tolerance. Nat. Rev. Immunol. 8(12), 948–957 (2008).
  • Liiv I, Rebane A, Org T et al. DNA-PK contributes to the phosphorylation of AIRE: importance in transcriptional activity. Biochim. Biophys. Acta 1783(1), 74–83 (2008).
  • Ilmarinen T, Kangas H, Kytömaa T et al. Functional interaction of AIRE with PIAS1 in transcriptional regulation. Mol. Immunol. 45(7), 1847–1862 (2008).
  • Aloj G, Giardino G, Valentino L et al. Severe combined immunodeficiencies: new and old scenarios. Int. Rev. Immunol. 31(1), 43–65 (2012).
  • Oven I, Brdicková N, Kohoutek J, Vaupotic T, Narat M, Peterlin BM. AIRE recruits P-TEFb for transcriptional elongation of target genes in medullary thymic epithelial cells. Mol. Cell. Biol. 27(24), 8815–8823 (2007).
  • Koh AS, Kuo AJ, Park SY et al. Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity. Proc. Natl. Acad. Sci. USA 105(41), 15878–15883 (2008).
  • Matsumoto M. Contrasting models for the roles of Aire in the differentiation program of epithelial cells in the thymic medulla. Eur. J. Immunol. 41(1), 12–17 (2011).
  • Yano M, Kuroda N, Han H et al. Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance. J. Exp. Med. 205(12), 2827–2838 (2008).
  • Poliani PL, Kisand K, Marrella V et al. Human peripheral lymphoid tissues contain autoimmune regulator-expressing dendritic cells. Am. J. Pathol. 176(3), 1104–1112 (2010).
  • Cavadini P, Vermi W, Facchetti F et al. AIRE deficiency in thymus of 2 patients with Omenn syndrome. J. Clin. Invest. 115(3), 728–732 (2005).
  • Notarangelo L, Casanova JL, Conley ME et al.; International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee Meeting in Budapest, 2005. J. Allergy Clin. Immunol. 117(4), 883–896 (2006).
  • Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J. Clin. Endocrinol. Metab. 91(8), 2843–2850 (2006).
  • Zlotogora J, Shapiro MS. Polyglandular autoimmune syndrome type I among Iranian Jews. J. Med. Genet. 29(11), 824–826 (1992).
  • 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. 8(1), 83–87 (1994).
  • Rosatelli MC, Meloni A, Meloni A et al. A common mutation in Sardinian autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients. Hum. Genet. 103(4), 428–434 (1998).
  • Wolff AS, Erichsen MM, Meager A et al. Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene. J. Clin. Endocrinol. Metab. 92(2), 595–603 (2007).
  • Capalbo D, Mazza C, Giordano R et al. Molecular background and genotype-phenotype correlation in autoimmune-polyendocrinopathy-candidiasis-ectodermal-distrophy patients from Campania and in their relatives. J. Endocrinol. Invest. 35(2), 169–173 (2012).
  • Clemente MG, Meloni A, Obermayer-Straub P, Frau F, Manns MP, De Virgiliis S. Two cytochromes P450 are major hepatocellular autoantigens in autoimmune polyglandular syndrome type 1. Gastroenterology 114(2), 324–328 (1998).
  • Meloni A, Perniola R, Faà V, Corvaglia E, Cao A, Rosatelli MC. Delineation of the molecular defects in the AIRE gene in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy. J. Clin. Endocrinol. Metab. 87(2), 841–846 (2002).
  • Cervato S, Mariniello B, Lazzarotto F et al. Evaluation of the autoimmune regulator (AIRE) gene mutations in a cohort of Italian patients with autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) and in their relatives. Clin. Endocrinol. 70(3), 421–428 (2009).
  • Giordano C, Modica R, Allotta ML et al. Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) in Sicily: confirmation that R203X is the peculiar AIRE gene mutation. J. Endocrinol. Invest. 35(4), 384–388 (2012).
  • Betterle C, Greggio NA, Volpato M. Clinical review 93: autoimmune polyglandular syndrome type 1. J. Clin. Endocrinol. Metab. 83(4), 1049–1055 (1998).
  • Ahonen P, Myllärniemi S, Sipilä I, Perheentupa J. Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients. N. Engl. J. Med. 322(26), 1829–1836 (1990).
  • Meager A, Visvalingam K, Peterson P et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 3(7), e289 (2006).
  • Alimohammadi M, Björklund P, Hallgren A et al. Autoimmune polyendocrine syndrome type 1 and NALP5, a parathyroid autoantigen. N. Engl. J. Med. 358(10), 1018–1028 (2008).
  • Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr. Rev. 23(3), 327–364 (2002).
  • Tóth B, Wolff AS, Halász Z et al. Novel sequence variation of AIRE and detection of interferon-omega antibodies in early infancy. Clin. Endocrinol. 72(5), 641–647 (2010).
  • Kisand K, Bøe Wolff AS, Podkrajsek KT et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207(2), 299–308 (2010).
  • Puel A, Döffinger R, Natividad A 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. 207(2), 291–297 (2010).
  • Ströbel P, Murumägi A, Klein R et al. Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1). J. Pathol. 211(5), 563–571 (2007).
  • Kisand K, Lilic D, Casanova JL, Peterson P, Meager A, Willcox N. Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur. J. Immunol. 41(6), 1517–1527 (2011).
  • Michels AW, Gottlieb PA. Autoimmune polyglandular syndromes. Nat. Rev. Endocrinol. 6(5), 270–277 (2010).
  • 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(6), 2568–2574 (2002).
  • 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(2), 1208–1215 (2007).
  • Laakso SM, Kekäläinen E, Rossi LH et al. IL-7 dysregulation and loss of CD8+ T cell homeostasis in the monogenic human disease autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J. Immunol. 187(4), 2023–2030 (2011).
  • Capalbo D, Elefante A, Spagnuolo MI et al. Posterior reversible encephalopathy syndrome in a child during an accelerated phase of a severe APECED phenotype due to an uncommon mutation of AIRE. Clin. Endocrinol. (Oxf) 69(3), 511–513 (2008).
  • Pignata C, Fiore M, de Filippo S, Cavalcanti M, Gaetaniello L, Scotese I. Apoptosis as a mechanism of peripheral blood mononuclear cell death after measles and varicella-zoster virus infections in children. Pediatr. Res. 43(1), 77–83 (1998).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.