Autoimmune regulator (AIRE) contributes to Dectin-1–induced TNF-⍺ production and complexes with caspase recruitment domain–containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1 - 03/02/12
, Vipul Kumar, MS b, , Keri B. Sanborn, PhD b, d, Emily M. Mace, PhD b, Harri Niinikoski, MD, PhD e, Kari Nadeau, MD, PhD f, Dewton de Moraes Vasconcelos, MD, PhD g, Elena Perez, MD, PhD h, Soma Jyonouchi, MD b, Harumi Jyonouchi, MD i, Pinaki P. Banerjee, PhD b, Olli Ruuskanen, MD, PhD e, Antonio Condino-Neto, MD, PhD c, ‡, Jordan S. Orange, MD, PhD b, d, ‡, ⁎ 
Corresponding author: Jordan S. Orange, MD, PhD, Children’s Hospital of Philadelphia, 3615 Civic Ctr Blvd, ARC 907A, Philadelphia, PA 19104.Abstract |
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-⍺ 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-⍺ 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.
Le texte complet de cet article est disponible en PDF.Key words : Primary immunodeficiency, innate immunity, chronic mucocutaneous candidiasis, monocytes
Abbreviations used : AIRE, APECED, CARD9, CMC, DAPI, FACS, PMA, shRNA, Syk, TLR, WGA
Plan
| Supported by Children’s Hospital of Philadelphia and the Jeffrey Modell Diagnostic Center (J.S.O.), the Vagelos Scholars program in the Molecular Life Sciences of the University of Pennsylvania (V.K.), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazil; L.A.P.), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) grant 09/51747-3 for (L.A.P. and A.C.-N.), FAPESP grant 99/07399-7 (D.d.M.V.), and Conselho Nacional de Desenvolvimento Científico e Tecnológico grant 501332/2010-3 (A.C.-N.). |
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| Disclosure of potential conflict of interest: E. Perez is a consultant for Baxter and CSL Behring; is a chair for the American Academy of Allergy, Asthma & Immunology (AAAAI) Primary Immunodeficiency Committee; is an AAAAI Web reviewer; and is a member of the Clinical Immunology Society Finance Committee. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 129 - N° 2
P. 464 - février 2012 Retour au numéro
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