The Journal of allergy and clinical immunology · 2023
Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Baris Safa, Benamar Mehdi, Chen Qian, Catak Mehmet Cihangir, Martínez-Blanco Mónica, Wang Muyun, Fong Jason, Massaad Michel J, Sefer Asena Pinar, Kara Altan, Babayeva Royala, Eltan Sevgi Bilgic, Yucelten Ayse Deniz, Bozkurtlar Emine, Cinel Leyla, Karakoc-Aydiner Elif, Zheng Yumei, Wu Hao, Ozen Ahmet, Schmitz-Abe Klaus, Chatila Talal A
Аннотация
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.
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.