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

• Published in: Journal of allergy and clinical immunology Vol. 129; no. 2; pp. 464 - 472.e3
• Main Authors: Pedroza, Luis A., PhD, Kumar, Vipul, MS, Sanborn, Keri B., PhD, Mace, Emily M., PhD, Niinikoski, Harri, MD, PhD, Nadeau, Kari, MD, PhD, de Moraes Vasconcelos, Dewton, MD, PhD, Perez, Elena, MD, PhD, Jyonouchi, Soma, MD, Jyonouchi, Harumi, MD, Banerjee, Pinaki P., PhD, Ruuskanen, Olli, MD, PhD, Condino-Neto, Antonio, MD, PhD, Orange, Jordan S., MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01-02-2012; Elsevier
• Subjects: AIRE Protein; Allergy and Immunology; beta-Glucans - pharmacology; Biological and medical sciences; Candida; CARD Signaling Adaptor Proteins - immunology; Cell Line; chronic mucocutaneous candidiasis; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immunity, Innate; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; innate immunity; Intracellular Signaling Peptides and Proteins - immunology; Lectins, C-Type - immunology; Leukocytes, Mononuclear - immunology; Medical sciences; Microscopy, Confocal; monocytes; Polyendocrinopathies, Autoimmune - immunology; Primary immunodeficiency; Protein-Tyrosine Kinases - immunology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Syk Kinase; Transcription Factors - genetics; Transcription Factors - immunology; Transduction, Genetic; Tumor Necrosis Factor-alpha - immunology; AIRE; FACS; Autoimmune regulator; chronic mucocutaneous candidiasis; innate immunity; shRNA; CMC; Wheat germ agglutinin; TLR; APECED; Toll-like receptor; 4′,6-Diamidino-2-phenylindole; monocytes; Syk; PMA; CARD9; Caspase recruitment domain–containing protein 9; DAPI; Primary immunodeficiency; WGA; Fluorescence-activated cell sorting; Spleen tyrosine kinase; Short hairpin RNA; Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy; Phorbol 12-myristate 13-acetate; Candidiasis; Mycosis; C type lectin receptor; Natural immunity; Biosynthesis; Recruitment; Immunology; Primary; Mucocutaneous; Tyrosine protein kinase Syk; Protein-tyrosine kinase; Tumor necrosis factor α; Immunopathology; Dectin 1; Monocyte; Enzyme; Transferases; Cytokine; Immune deficiency; Infection; Chronic
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2011.08.027

Background Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome is a complex immunologic disease caused by mutation of the autoimmune regulator (AIRE) gene. Autoimmunity in patients with APECED syndrome has been shown to result from deficiency of AIRE function in transcriptional regulation of thymic peripheral tissue antigens, which leads to defective T-cell negative selection. Candidal susceptibility in patients with APECED syndrome is thought to result from aberrant adaptive immunity. Objective To determine whether AIRE could function in anticandidal innate immune signaling, we investigated an extrathymic role for AIRE in the immune recognition of β-glucan through the Dectin-1 pathway, which is required for defense against Candida species. Methods Innate immune signaling through the Dectin-1 pathway was assessed in both PBMCs from patients with APECED syndrome and a monocytic cell line. Subcellular localization of AIRE was assessed by using confocal microscopy. Results PBMCs from patients with APECED syndrome had reduced TNF-α responses after Dectin-1 ligation but in part used a Raf-1–mediated pathway to preserve function. In the THP-1 human monocytic cell line, reducing AIRE expression resulted in significantly decreased TNF-α release after Dectin-1 ligation. AIRE formed a transient complex with the known Dectin-1 pathway components phosphorylated spleen tyrosine kinase and caspase recruitment domain–containing protein 9 after receptor ligation and localized with Dectin-1 at the cell membrane. Conclusion AIRE can participate in the Dectin-1 signaling pathway, indicating a novel extrathymic role for AIRE and a defect that likely contributes to fungal susceptibility in patients with APECED syndrome.