Samantha Shafer1, Yikun Yao1, William Comrie1, Sarah Cook1, Yu Zhang1, Gözde Yesil2, Elif Karakoç-Aydiner3, Safa Baris3, Haluk Cokugras4, Sezin Aydemir4, Ayca Kiykim4, Ahmet Ozen3, Michael Lenardo5. 1. Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. 2. Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul, Turkey. 3. Marmara University, School of Medicine, Department of Pediatrics, Division of Allergy and Immunology, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic Center for Primary Immunodeficiency Diseases, Istanbul, Turkey; Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey. 4. Cerrahpasa Medical Faculty, Istanbul University-Cerrahpasa, Pediatric Allergy and Immunology, Istanbul, Turkey. 5. Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: LENARDO@NIH.GOV.
Abstract
BACKGROUND: TRAF3 interacting protein 2 (TRAF3IP2) (Act1) is an adapter protein that interacts with IL-17R via its similar expression to fibroblast growth factor genes and IL-17R domain and coordinates 2 separate proinflammatory pathways following IL-17 cytokine stimulation. OBJECTIVE: We sought to elucidate the immunologic consequences of TRAF3IP2 homozygous mutations to improve treatments for immunodeficiency patients with chronic mucocutaneous candidiasis. METHODS: We describe 2 patients presenting with chronic mucocutaneous candidiasis who harbor biallelic nonsense mutations in TRAF3IP2. The cellular and molecular features of this genetic defect were assessed using in vitro cytokine assays and protein analysis. RESULTS: We show that the homozygous mutation causes complete loss of protein expression. We also show that the absence of TRAF3IP2 was associated with a defective response to combined IL-2/IL-25 (IL-17E) stimulation. CONCLUSIONS: Failure to initiate normal signaling downstream of IL-17R engagement likely contributes to the patients' recurrent fungal infections. These findings add to our molecular understanding of genetic defects affecting this critical pathway of antifungal immunity. Published by Elsevier Inc.
BACKGROUND: TRAF3 interacting protein 2 (TRAF3IP2) (Act1) is an adapter protein that interacts with IL-17R via its similar expression to fibroblast growth factor genes and IL-17R domain and coordinates 2 separate proinflammatory pathways following IL-17 cytokine stimulation. OBJECTIVE: We sought to elucidate the immunologic consequences of TRAF3IP2 homozygous mutations to improve treatments for immunodeficiency patients with chronic mucocutaneous candidiasis. METHODS: We describe 2 patients presenting with chronic mucocutaneous candidiasis who harbor biallelic nonsense mutations in TRAF3IP2. The cellular and molecular features of this genetic defect were assessed using in vitro cytokine assays and protein analysis. RESULTS: We show that the homozygous mutation causes complete loss of protein expression. We also show that the absence of TRAF3IP2 was associated with a defective response to combined IL-2/IL-25 (IL-17E) stimulation. CONCLUSIONS: Failure to initiate normal signaling downstream of IL-17R engagement likely contributes to the patients' recurrent fungal infections. These findings add to our molecular understanding of genetic defects affecting this critical pathway of antifungal immunity. Published by Elsevier Inc.
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