title: Critical immunological pathways are downregulated in APECED patient dendritic cells.
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.
authors.affiliation: National Public Health Institute and FIMM, Institute for Molecular Medicine Finland, Biomedicum, Helsinki, Finland. nora.pontynen@ktl.fi
authors.forename: Nora
authors.initials: N
authors.lastname: Pöntynen
authors.forename: Mari
authors.initials: M
authors.lastname: Strengell
authors.forename: Niko
authors.initials: N
authors.lastname: Sillanpää
authors.forename: Juha
authors.initials: J
authors.lastname: Saharinen
authors.forename: Ismo
authors.initials: I
authors.lastname: Ulmanen
authors.forename: Ilkka
authors.initials: I
authors.lastname: Julkunen
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D000328:Adult; D002176:Candida albicans / Q000254:growth & development; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism* / Q000382:microbiology / Q000821:virology; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016884:Polyendocrinopathies, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029082:Sendai virus / Q000254:growth & development; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014158:Transcription, Genetic; D000096927:AIRE Protein
chemical_list: D016207:Cytokines; D014157:Transcription Factors; D000096927:AIRE Protein