Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6
| Autor: | Safa Baris, Mehdi Benamar, Qian Chen, Mehmet Cihangir Catak, Mónica Martínez-Blanco, Muyun Wang, Jason Fong, Michel J. Massaad, Asena Pinar Sefer, Altan Kara, Royala Babayeva, Sevgi Bilgic Eltan, Ayse Deniz Yucelten, Emine Bozkurtlar, Leyla Cinel, Elif Karakoc-Aydiner, Yumei Zheng, Hao Wu, Ahmet Ozen, Klaus Schmitz-Abe, Talal A. Chatila |
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| Přispěvatelé: | BARIŞ S., Benamar M., Chen Q., Catak M. C., Martínez-Blanco M., Wang M., Fong J., Massaad M. J., Sefer A. P., Kara A., et al. |
| Rok vydání: | 2023 |
| Předmět: |
Immunology
Life Sciences (LIFE) Sağlık Bilimleri gain-of-function mutation Clinical Medicine (MED) Yaşam Bilimleri Health Sciences ALERJİ Immunology and Allergy Klinik Tıp (MED) primary atopic disorders Jakinibs STAT6 Janus kinase inhibitors Klinik Tıp İmmünoloji Temel Bilimler Life Sciences Inborn errors of immunity CLINICAL MEDICINE Tıp ALLERGY Yaşam Bilimleri (LIFE) Medicine İmmünoloji ve Alerji Natural Sciences |
| Zdroj: | Journal of Allergy and Clinical Immunology. |
| ISSN: | 0091-6749 |
| DOI: | 10.1016/j.jaci.2023.01.023 |
| Popis: | Background: Inborn errors of immunity have been implicated in causing immune dysregulation, including allergic diseases. STAT6 is a key regulator of allergic responses. Objectives: This study sought to characterize a novel gain-of-function STAT6 mutation identified in a child with severe allergic manifestations. Methods: Whole-exome and targeted gene sequencing, lymphocyte characterization, and molecular and functional analyses of mutated STAT6 were performed. Results: This study reports a child with a missense mutation in the DNA binding domain of STAT6 (c.1114G>A, p.E372K) who presented with severe atopic dermatitis, eosinophilia, and elevated IgE. Naive lymphocytes from the affected patient displayed increased TH2- and suppressed TH1- and TH17-cell responses. The mutation augmented both basal and cytokine-induced STAT6 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reversed STAT6 hyperresponsiveness to IL-4, normalized TH1 and TH17 cells, suppressed the eosinophilia, and improved the patient\"s atopic dermatitis. Conclusions: This study identified a novel inborn error of immunity due to a STAT6 gain-of-function mutation that gave rise to severe allergic dysregulation. Janus kinase inhibitor therapy could represent an effective targeted treatment for this disorder. |
| Databáze: | OpenAIRE |
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