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 T_H2- and suppressed T_H1- and T_H17-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 T_H1 and T_H17 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.

中文翻译：

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由于转录因子 STAT6 功能突变导致严重过敏失调

背景

先天性免疫缺陷可能导致免疫失调，包括过敏性疾病。STAT6是过敏反应的关键调节因子。

目标

本研究试图描述在患有严重过敏表现的儿童中发现的一种新的功能获得性 STAT6 突变的特征。

方法

对突变的 STAT6 进行了全外显子组和靶向基因测序、淋巴细胞表征以及分子和功能分析。

结果

本研究报告了一名 STAT6 DNA 结合域（c.1114G>A，p.E372K）存在错义突变的儿童，该儿童出现严重特应性皮炎、嗜酸性粒细胞增多和 IgE 升高。来自受影响患者的初始淋巴细胞表现出 T _H 2 细胞反应增加，而 T _H 1 和 T _H 17 细胞反应受到抑制。该突变增强了基础和细胞因子诱导的 STAT6 磷酸化，而不影响去磷酸化动力学。Janus 激酶 1/2 抑制剂鲁索替尼治疗逆转了 STAT6 对 IL-4 的高反应性，使 T _H 1 和 T _H 17 细胞正常化，抑制了嗜酸性粒细胞增多，并改善了患者的特应性皮炎。

结论

这项研究发现了一种新的先天性免疫缺陷，该缺陷是由于 STAT6 功能获得性突变引起的，该突变会导致严重的过敏性失调。Janus 激酶抑制剂疗法可能代表这种疾病的有效靶向治疗。