Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6

被引:40
作者
Baris, Safa [1 ,4 ,5 ]
Benamar, Mehdi [6 ,9 ]
Chen, Qian [6 ,9 ]
Catak, Mehmet Cihangir [1 ,4 ,5 ]
Martinez-Blanco, Monica [6 ,9 ]
Wang, Muyun [6 ,9 ]
Fong, Jason [6 ,9 ]
Massaad, Michel J. [11 ,12 ]
Sefer, Asena Pinar [1 ,4 ,5 ]
Kara, Altan [13 ]
Babayeva, Royala [1 ,4 ,5 ]
Eltan, Sevgi Bilgic [1 ,4 ,5 ]
Yucelten, Ayse Deniz [2 ]
Bozkurtlar, Emine [3 ]
Cinel, Leyla [3 ]
Karakoc-Aydiner, Elif [1 ,4 ,5 ]
Zheng, Yumei [7 ,10 ]
Wu, Hao [7 ,10 ]
Ozen, Ahmet [1 ,4 ,5 ]
Schmitz-Abe, Klaus [6 ,8 ,9 ]
Chatila, Talal A. [6 ,9 ,14 ]
机构
[1] Marmara Univ, Sch Med, Div Pediat Allergy & Immunol, Istanbul, Turkiye
[2] Marmara Univ, Sch Med, Dept Dermatol, Istanbul, Turkiye
[3] Marmara Univ, Sch Med, Dept Pathol, Istanbul, Turkiye
[4] Istanbul Jeffrey Modell Diagnost & Res Ctr Primary, Istanbul, Turkiye
[5] Isil Berat Barlan Ctr Translat Med, Istanbul, Turkiye
[6] Boston Childrens Hosp, Div Immunol, Boston, MA USA
[7] Boston Childrens Hosp, Program Cellular & Mol Med, Boston, MA USA
[8] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA USA
[9] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA
[10] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA
[11] Amer Univ Beirut, Dept Expt Pathol Immunol & Microbiol, Beirut, Lebanon
[12] Amer Univ Beirut, Med Ctr, Dept Pediat & Adolescent Med, Beirut, Lebanon
[13] Gene Engn & Biotechnol Inst, TUBITAK Marmara Res Ctr, Gebze, Turkiye
[14] Harvard Med Sch, Boston Childrens Hosp, Dept Pediat, Div Immunol, Boston, MA 02115 USA
基金
美国国家卫生研究院;
关键词
Inborn errors of immunity; primary atopic disorders; STAT6; gain-of-function mutation; Janus kinase inhibitors; Jakinibs; T-HELPER-CELLS; COMBINED IMMUNODEFICIENCY; ATOPIC DISORDERS; INBORN-ERRORS; HUMAN-DISEASE; IL-4; IGE; INTERLEUKIN-4; RESPONSES; SUSCEPTIBILITY;
D O I
10.1016/j.jaci.2023.01.023
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
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. (J Allergy Clin Immunol 2023;152:182-94.)
引用
收藏
页码:182 / 194.e7
页数:20
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