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 © Springer-Verlag 2008 Correspondence to: Nora Pöntynen. Electronic supplementary material The online version of this article (doi:10.1007/s00109-008-0374-7) contains supplementary material, which is available to authorized users. Conflict of interest statement Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts 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 patientderived 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.

Anticommensal Responses Are Associated with Regulatory T Cell Defect in Autoimmune Polyendocrinopathy–Candidiasis–Ectodermal Dystrophy Patients

“…Extrathymic Aire-expressing cells have been shown to contribute to immune tolerance in secondary lymphoid organs (6) and both dendritic and NKT cell abnormalities have been reported in APECED (6,12,13,38). All of these cells have also been implicated in the regulation of intestinal immunity, so disruption of their function might promote loss of tolerance to commensal Ags.…”

“…Several studies have reported defects in the number or function of regulatory T cells (Treg) (8)(9)(10)(11), and dendritic cells have been shown to be abnormal (12,13). Practically all patients have neutralizing Abs against type I IFNs (14), which are often the earliest manifestation of the disease, and autoantibodies targeting other cytokines are also found, of which anti-IL-17 and -IL-22 Abs have been linked to impaired defense against Candida (2,15,16).…”

Autoimmune regulator (AIRE) contributes to Dectin-1–induced TNF-α production and complexes with caspase recruitment domain–containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1

“…Patients had the following AIRE mutations: (1) 205-208dupCACG, (2) 994del [13], (1) Asp70fsX148, (2) R257X, (1) compound heterozygote, 16 and (1) 967_979del14bp. PBMCs were isolated within 48 hours of blood being drawn.…”

“…Monocytic cells from patients with APECED syndrome are known to have an abnormal response to Candida species antigens, as measured by cytokine production and protein phosphorylation. 12,13 However, a direct mechanistic role for AIRE in this innate response has not been evaluated. Because AIRE contains its own CARD domain 14 and subcellular localization studies of fluorescent AIRE have demonstrated its presence in the cytosol, 15 we hypothesized that AIRE might function specifically in the Dectin-1 response to Candida species within the cell cytoplasm.…”

Autoimmune polyendocrine syndrome type 1: case report and review of literature

“…Indeed, researchers have noted abnormalities in peripheral DC function in APECED patients (47), although defects were generally modest, and sometimes contradictory (48).…”