Journal of Molecular Medicine

, 86:1139

Critical immunological pathways are downregulated in APECED patient dendritic cells

  • Nora Pöntynen
  • Mari Strengell
  • Niko Sillanpää
  • Juha Saharinen
  • Ismo Ulmanen
  • Ilkka Julkunen
  • Leena Peltonen
Original Article

Abstract

Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is a monogenic autoimmune disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE functions as a transcriptional regulator, and it has a central role in the development of immunological tolerance. AIRE regulates the expression of ectopic antigens in epithelial cells of the thymic medulla and has been shown to participate in the development of peripheral tolerance. However, the mechanism of action of AIRE has remained elusive. To further investigate the role of AIRE in host immune functions, we studied the properties and transcript profiles in in vitro monocyte-differentiated dendritic cells (moDCs) obtained from APECED patients and healthy controls. AIRE-deficient monocytes showed typical DC morphology and expressed DC marker proteins cluster of differentiation 86 and human leukocyte antigen class II. APECED patient-derived moDCs were functionally impaired: the transcriptional response of cytokine genes to pathogens was drastically reduced. Interestingly, some changes were observable already at the immature DC stage. Pathway analyses of transcript profiles revealed that the expression of the components of the host cell signaling pathways involved in cell–cell signalling, innate immune responses, and cytokine activity were reduced in APECED moDCs. Our observations support a role for AIRE in peripheral tolerance and are the first ones to show that AIRE has a critical role in DC responses to microbial stimuli in humans.

Keywords

AIRE APS1 Dendritic cell Transcript profile 

Supplementary material

109_2008_374_MOESM1_ESM.xls (194 kb)
ESM 1Supplemental data (XLS 198 KB).

References

  1. 1.
    Perheentupa J (2006) Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. J Clin Endocrinol Metab 91:2843–2850PubMedCrossRefGoogle Scholar
  2. 2.
    Halonen M, Kangas H, Ruppell T, Ilmarinen T, Ollila J, Kolmer M, Vihinen M, Palvimo J, Saarela J, Ulmanen I et al (2004) APECED-causing mutations in AIRE reveal the functional domains of the protein. Human Mutat 23:245–257CrossRefGoogle Scholar
  3. 3.
    Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, Von Boehmer H, Bronson R, Dierich A, Benoist C et al (2002) Projection of an immunological self shadow within the thymus by the AIRE protein. Science 298:1395–1401PubMedCrossRefGoogle Scholar
  4. 4.
    Liston A, Gray DH, Lesage S, Fletcher AL, Wilson J, Webster KE, Scott HS, Boyd RL, Peltonen L, Goodnow CC (2004) Gene dosage-limiting role of Aire in thymic expression, clonal deletion, and organ-specific autoimmunity. J Exp Med 200:1015–1026PubMedCrossRefGoogle Scholar
  5. 5.
    Cheng MH, Shum AK, Anderson MS (2007) What’s new in the Aire? Trends Immunol 28:321–327PubMedCrossRefGoogle Scholar
  6. 6.
    Heino M, Peterson P, Kudoh J, Nagamine K, Lagerstedt A, Ovod V, Ranki A, Rantala I, Nieminen M, Tuukkanen J et al (1999) Autoimmune regulator is expressed in the cells regulating immune tolerance in thymus medulla. Biochem Biophys Res Commun 257:821–825PubMedCrossRefGoogle Scholar
  7. 7.
    Kogawa K, Kudoh J, Nagafuchi S, Ohga S, Katsuta H, Ishibashi H, Harada M, Hara T, Shimizu N (2002) Distinct clinical phenotype and immunoreactivity in Japanese siblings with autoimmune polyglandular syndrome type 1 (APS-1) associated with compound heterozygous novel AIRE gene mutations. Clin Immunol 103:277–283PubMedCrossRefGoogle Scholar
  8. 8.
    Zheng X, Yin L, Liu Y, Zheng P (2004) Expression of tissue-specific autoantigens in the hematopoietic cells leads to activation-induced cell death of autoreactive T cells in the secondary lymphoid organs. Eur J Immunol 34:3126–3134PubMedCrossRefGoogle Scholar
  9. 9.
    Kogawa K, Nagafuchi S, Katsuta H, Kudoh J, Tamiya S, Sakai Y, Shimizu N, Harada M (2002) Expression of AIRE gene in peripheral monocyte/dendritic cell lineage. Immunol Lett 80:195–198PubMedCrossRefGoogle Scholar
  10. 10.
    Sillanpää N, Magureanu CG, Murumagi A, Reinikainen A, West A, Manninen A, Lahti M, Ranki A, Saksela K, Krohn K et al (2004) Autoimmune regulator induced changes in the gene expression profile of human monocytes–dendritic cell-lineage. Mol Immunol 41:1185–1198PubMedCrossRefGoogle Scholar
  11. 11.
    Ramsey C, Hassler S, Marits P, Kampe O, Surh CD, Peltonen L, Winqvist O (2006) Increased antigen presenting cell-mediated T cell activation in mice and patients without the autoimmune regulator. Eur J Immunol 36:305–317PubMedCrossRefGoogle Scholar
  12. 12.
    Kekäläinen E, Tuovinen H, Joensuu J, Gylling M, Franssila R, Pontynen N, Talvensaari K, Perheentupa J, Miettinen A, Arstila TP (2007) A defect of regulatory T cells in patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. J Immunol 178:1208–1215PubMedGoogle Scholar
  13. 13.
    Mahnke K, Schmitt E, Bonifaz L, Enk AH, Jonuleit H (2002) Immature, but not inactive: the tolerogenic function of immature dendritic cells. Immunol Cell Biol 80:477–483PubMedCrossRefGoogle Scholar
  14. 14.
    Steinman RM, Nussenzweig MC (2002) Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci USA 99:351–358PubMedCrossRefGoogle Scholar
  15. 15.
    Manuel SL, Rahman S, Wigdahl B, Khan ZK, Jain P (2007) Dendritic cells in autoimmune diseases and neuroinflammatory disorders. Front Biosci 12:4315–335PubMedCrossRefGoogle Scholar
  16. 16.
    Ahonen P, Myllarniemi S, Sipila I, Perheentupa J (1990) Clinical variation of autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) in a series of 68 patients. N Engl J Med 322:1829–1836PubMedGoogle Scholar
  17. 17.
    Björses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, Perheentupa J, Ulmanen I, Peltonen L (2000) Mutations in the AIRE gene: effects on sub-cellular location and transactivation function of the APECED protein. Am J Hum Genet 66:378–392PubMedCrossRefGoogle Scholar
  18. 18.
    Vandenplas S, Wiid I, Grobler-Rabie A, Brebner K, Ricketts M, Wallis G, Bester A, Boyd C, Mathew C (1984) Blot hybridisation analysis of genomic DNA. J Med Genet 21:164–172PubMedCrossRefGoogle Scholar
  19. 19.
    Veckman V, Miettinen M, Pirhonen J, Siren J, Matikainen S, Julkunen I (2004) Streptococcus pyogenes and Lactobacillus rhamnosus differentially induce maturation and production of Th1-type cytokines and chemokines in human monocyte-derived dendritic cells. J Leukoc Biol 75:764–771PubMedCrossRefGoogle Scholar
  20. 20.
    Veckman V, Julkunen I (2007) Streptococcus pyogenes activates human plasmacytoid and myeloid dendritic cells. J Leukoc Biol 83:296–304PubMedCrossRefGoogle Scholar
  21. 21.
    Osterlund P, Veckman V, Siren J, Klucher KM, Hiscott J, Matikainen S, Julkunen I (2005) Gene expression and antiviral activity of alpha/beta interferons and interleukin-29 in virus-infected human myeloid dendritic cells. J Virol 79:9608–9617PubMedCrossRefGoogle Scholar
  22. 22.
    Wu ZJ, Irizarry RA, Gentleman R, Martinez-Murillo F, Spencer F (2004) A model-based background adjustment for oligonucleotide expression arrays. J Am Stat Assoc 99:909–917CrossRefGoogle Scholar
  23. 23.
    Kiialainen A, Veckman V, Saharinen J, Paloneva J, Gentile M, Hakola P, Hemelsoet D, Ridha B, Kopra O, Julkunen I et al (2007) Transcript profiles of dendritic cells of PLOSL patients link demyelinating CNS disorders with abnormalities in pathways of actin bundling and immune response. J Mol Med 85:971–983PubMedCrossRefGoogle Scholar
  24. 24.
    Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT et al (2000) Gene Ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25:25–29PubMedCrossRefGoogle Scholar
  25. 25.
    Hubbard TJ, Aken BL, Beal K, Ballester B, Caccamo M, Chen Y, Clarke L, Coates G, Cunningham F, Cutts T et al (2007) Ensembl 2007. Nucleic Acids Res 35:D610–D617PubMedCrossRefGoogle Scholar
  26. 26.
    Lehtonen A, Ahlfors H, Veckman V, Miettinen M, Lahesmaa R, Julkunen I (2007) Gene expression profiling during differentiation of human monocytes to macrophages or dendritic cells. J Leukoc Biol 82:710–720PubMedCrossRefGoogle Scholar
  27. 27.
    Geijtenbeek TB, Torensma R, van Vliet SJ, van Duijnhoven GC, Adema GJ, van Kooyk Y, Figdor CG (2000) Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100:575–585PubMedCrossRefGoogle Scholar
  28. 28.
    Cambi A, Gijzen K, de Vries JM, Torensma R, Joosten B, Adema GJ, Netea MG, Kullberg BJ, Romani L, Figdor CG (2003) The C-type lectin DC-SIGN (CD209) is an antigen-uptake receptor for Candida albicans on dendritic cells. Eur J Immunol 33:532–538PubMedCrossRefGoogle Scholar
  29. 29.
    Goodridge HS, Simmons RM, Underhill DM (2007) Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells. J Immunol 178:3107–3115PubMedGoogle Scholar
  30. 30.
    Donini M, Zenaro E, Tamassia N, Dusi S (2007) NADPH oxidase of human dendritic cells: role in Candida albicans killing and regulation by interferons, dectin-1 and CD206. Eur J Immunol 37:1194–1203PubMedCrossRefGoogle Scholar
  31. 31.
    Kieran M, Blank V, Logeat F, Vandekerckhove J, Lottspeich F, Le Bail O, Urban MB, Kourilsky P, Baeuerle PA, Israel A (1990) The DNA binding subunit of NF-kappa B is identical to factor KBF1 and homologous to the rel oncogene product. Cell 62:1007–1018PubMedCrossRefGoogle Scholar
  32. 32.
    Chaussabel D, Semnani RT, McDowell MA, Sacks D, Sher A, Nutman TB (2003) Unique gene expression profiles of human macrophages and dendritic cells to phylogenetically distinct parasites. Blood 102:672–681PubMedCrossRefGoogle Scholar
  33. 33.
    Suciu-Foca N, Manavalan JS, Scotto L, Kim-Schulze S, Galluzzo S, Naiyer AJ, Fan J, Vlad G, Cortesini R (2005) Molecular characterization of allospecific T suppressor and tolerogenic dendritic cells: review. Int Immunopharmacol 5:7–11PubMedCrossRefGoogle Scholar
  34. 34.
    Sanchez-Madrid F, Krensky AM, Ware CF, Robbins E, Strominger JL, Burakoff SJ, Springer TA (1982) Three distinct antigens associated with human T-lymphocyte-mediated cytolysis: LFA-1, LFA-2, and LFA-3. Proc Natl Acad Sci USA 79:7489–7493PubMedCrossRefGoogle Scholar
  35. 35.
    Das H, Sugita M, Brenner MB (2004) Mechanisms of Vdelta1 gammadelta T cell activation by microbial components. J Immunol 172:6578–6586PubMedGoogle Scholar
  36. 36.
    Nagafuchi S, Umene K, Yamanaka F, Oohashi S, Shindo M, Kurisaki H, Kudoh J, Shimizu N, Hara T, Harada M (2007) Recurrent herpes simplex virus infection in a patient with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy associated with L29P and IVS9-1G>C compound heterozygous autoimmune regulator gene mutations. J Intern Med 261:605–610PubMedCrossRefGoogle Scholar
  37. 37.
    Varga G, Balkow S, Wild MK, Stadtbaeumer A, Krummen M, Rothoeft T, Higuchi T, Beissert S, Wethmar K, Scharffetter-Kochanek K et al (2007) Active MAC-1 (CD11b/CD18) on DCs inhibits full T-cell activation. Blood 109:661–669PubMedCrossRefGoogle Scholar
  38. 38.
    Grossman WJ, Verbsky JW, Barchet W, Colonna M, Atkinson JP, Ley TJ (2004) Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21:589–601PubMedCrossRefGoogle Scholar
  39. 39.
    Wethmar K, Helmus Y, Luhn K, Jones C, Laskowska A, Varga G, Grabbe S, Lyck R, Engelhardt B, Bixel MG et al (2006) Migration of immature mouse DC across resting endothelium is mediated by ICAM-2 but independent of beta2-integrins and murine DC-SIGN homologues. Eur J Immunol 36:2781–2794PubMedCrossRefGoogle Scholar
  40. 40.
    Hubert P, Jacobs N, Caberg JH, Boniver J, Delvenne P (2007) The cross-talk between dendritic and regulatory T cells: good or evil? J Leukoc Biol 82:781–794PubMedCrossRefGoogle Scholar
  41. 41.
    Angelini F, Del Duca E, Piccinini S, Pacciani V, Rossi P, Manca Bitti ML (2005) Altered phenotype and function of dendritic cells in children with type 1 diabetes. Clin Exp Immunol 142:341–346PubMedCrossRefGoogle Scholar
  42. 42.
    Trucco M, Giannoukakis N (2007) Immunoregulatory dendritic cells to prevent and reverse new-onset type 1 diabetes mellitus. Expert Opin Biol Ther 7:951–963PubMedCrossRefGoogle Scholar
  43. 43.
    Monrad S, Kaplan MJ (2007) Dendritic cells and the immunopathogenesis of systemic lupus erythematosus. Immunol Res 37:135–145PubMedCrossRefGoogle Scholar
  44. 44.
    Laborde EA, Vanzulli S, Beigier-Bompadre M, Isturiz MA, Ruggiero RA, Fourcade MG, Catalan Pellet AC, Sozzani S, Vulcano M (2007) Immune complexes inhibit differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol 179:673–681PubMedGoogle Scholar
  45. 45.
    Johnnidis JB, Venanzi ES, Taxamn DJ, Ting JP, Benoist CO, Mathis DJ (2005) Chromosomal clustering of genes controlled by the aire transcription factor. Proc Natl Acad Sci USA 102(20):7233–7238PubMedCrossRefGoogle Scholar
  46. 46.
    Anderson MS, Venanzi ES, Chen Z, Berzins SP, Benoist C, Mathis D (2005) The cellular mechanism of aire control of T cell tolerance. Immunity 23(2):227–239PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Nora Pöntynen
    • 1
  • Mari Strengell
    • 2
  • Niko Sillanpää
    • 3
  • Juha Saharinen
    • 1
    • 4
  • Ismo Ulmanen
    • 1
  • Ilkka Julkunen
    • 2
  • Leena Peltonen
    • 1
    • 5
    • 6
    • 7
  1. 1.National Public Health Institute and FIMMInstitute for Molecular Medicine Finland, BiomedicumHelsinkiFinland
  2. 2.Department of Viral Diseases and ImmunologyNational Public Health InstituteHelsinkiFinland
  3. 3.Department of Pathology, Institute of Medical Technology, Tampere University HospitalUniversity of TampereTampereFinland
  4. 4.Genome Informatics UnitBiomedicumHelsinkiFinland
  5. 5.Department of Medical GeneticsUniversity of HelsinkiHelsinkiFinland
  6. 6.Wellcome Trust Sanger InstituteCambridgeUK
  7. 7.The Broad InstituteCambridgeUSA

Personalised recommendations