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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:129

Article

Pedroza, Luis A.^1,2,3  Kumar, Vipul¹  Sanborn, Keri B.^1,4  Mace, Emily M.¹  Niinikoski, Harri⁵  Nadeau, Kari⁶  Vasconcelos, Dewton de Moraes⁷  Perez, Elena⁸  Jyonouchi, Soma¹  Jyonouchi, Harumi⁹  Banerjee, Pinaki P.¹  Ruuskanen, Olli⁵  Condino-Neto, Antonio³  Orange, Jordan S.^1,4 

[1] Childrens Hosp Philadelphia, Dept Pediat, Div Immunol, Philadelphia, PA 19104 USA

[2] Univ Estadual Campinas, Sch Med, Ctr Investigat Pediat, Sao Paulo, Brazil

[3] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, BR-05508 Sao Paulo, Brazil

[4] Univ Penn, Immunol Grad Grp, Sch Med, Philadelphia, PA 19104 USA

[5] Turku Univ Hosp, Div Immunol & Allergy, FIN-20520 Turku, Finland

[6] Stanford Univ, Sch Med, Div Immunol & Allergy, Stanford, CA 94305 USA

[7] Univ Sao Paulo, Sch Med, Lab Dermatol & Immunodeficiency LIM56, BR-05508 Sao Paulo, Brazil

[8] Univ S Florida, Sch Med, Dept Pediat, Div Allergy & Immunol, Tampa, FL 33620 USA

[9] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Pediat, Div Allergy Immunol & Infect Dis, Newark, NJ 07103 USA

关键词: Primary immunodeficiency;    innate immunity;    chronic mucocutaneous candidiasis;    monocytes;   

DOI  :  10.1016/j.jaci.2011.08.027

来源: Elsevier

【 摘 要 】

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 beta-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-alpha 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-a 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. (J Allergy Clin Immunol 2012;129:464-72.)

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