Critical immunological pathways are downregulated in APECED patient dendritic cells

Nora Pöntynen, Mari Strengell, Niko Sillanpää, Juha Saharinen, Ismo Ulmanen, Ilkka Julkunen, Leena Peltonen

    Research output: Contribution to journalArticleScientificpeer-review

    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.
    Original languageEnglish
    JournalJournal of Molecular Medicine
    Volume86
    Issue number10
    Pages (from-to)1139-1152
    Number of pages14
    ISSN0946-2716
    DOIs
    Publication statusPublished - 2008
    MoE publication typeA1 Journal article-refereed

    Fields of Science

    • 311 Basic medicine
    • 312 Clinical medicine
    • 318 Medical biotechnology
    • 217 Medical engineering
    • 118 Biological sciences

    Cite this

    Pöntynen, N., Strengell, M., Sillanpää, N., Saharinen, J., Ulmanen, I., Julkunen, I., & Peltonen, L. (2008). Critical immunological pathways are downregulated in APECED patient dendritic cells. Journal of Molecular Medicine, 86(10), 1139-1152. https://doi.org/10.1007/s00109-008-0374-7