Journal of Molecular Medicine

, 86:1139

Critical immunological pathways are downregulated in APECED patient dendritic cells

Authors

    • National Public Health Institute and FIMMInstitute for Molecular Medicine Finland, Biomedicum
  • Mari Strengell
    • Department of Viral Diseases and ImmunologyNational Public Health Institute
  • Niko Sillanpää
    • Department of Pathology, Institute of Medical Technology, Tampere University HospitalUniversity of Tampere
  • Juha Saharinen
    • National Public Health Institute and FIMMInstitute for Molecular Medicine Finland, Biomedicum
    • Genome Informatics UnitBiomedicum
  • Ismo Ulmanen
    • National Public Health Institute and FIMMInstitute for Molecular Medicine Finland, Biomedicum
  • Ilkka Julkunen
    • Department of Viral Diseases and ImmunologyNational Public Health Institute
  • Leena Peltonen
    • National Public Health Institute and FIMMInstitute for Molecular Medicine Finland, Biomedicum
    • Department of Medical GeneticsUniversity of Helsinki
    • Wellcome Trust Sanger Institute
    • The Broad Institute
Original Article

DOI: 10.1007/s00109-008-0374-7

Cite this article as:
Pöntynen, N., Strengell, M., Sillanpää, N. et al. J Mol Med (2008) 86: 1139. doi:10.1007/s00109-008-0374-7

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

AIREAPS1Dendritic cellTranscript profile

Supplementary material

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

Copyright information

© Springer-Verlag 2008