Original Article

Journal of Molecular Medicine

, Volume 86, Issue 10, pp 1139-1152

Critical immunological pathways are downregulated in APECED patient dendritic cells

  • Nora PöntynenAffiliated withNational Public Health Institute and FIMM, Institute for Molecular Medicine Finland, Biomedicum Email author 
  • , Mari StrengellAffiliated withDepartment of Viral Diseases and Immunology, National Public Health Institute
  • , Niko SillanpääAffiliated withDepartment of Pathology, Institute of Medical Technology, Tampere University Hospital, University of Tampere
  • , Juha SaharinenAffiliated withNational Public Health Institute and FIMM, Institute for Molecular Medicine Finland, BiomedicumGenome Informatics Unit, Biomedicum
  • , Ismo UlmanenAffiliated withNational Public Health Institute and FIMM, Institute for Molecular Medicine Finland, Biomedicum
  • , Ilkka JulkunenAffiliated withDepartment of Viral Diseases and Immunology, National Public Health Institute
  • , Leena PeltonenAffiliated withNational Public Health Institute and FIMM, Institute for Molecular Medicine Finland, BiomedicumDepartment of Medical Genetics, University of HelsinkiWellcome Trust Sanger InstituteThe Broad Institute

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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