Department of Health Sciences, University of Florence, Florence, Italy; Immunology Unit, Department of Pediatrics, Meyer Children's Hospital, Florence, Florence, Italy.
Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany.
J Allergy Clin Immunol. 2022 Nov;150(5):1237-1241.e3. doi: 10.1016/j.jaci.2022.06.007. Epub 2022 Jun 21.
Germline mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for 2 distinct human diseases: autosomal-dominant hyper-IgE syndrome (AD-HIES) caused by STAT3 loss-of-function mutations and STAT3 gain-of-function disease. So far, these entities have been regarded as antithetic, with AD-HIES mainly associated with characteristic infections and a connective tissue phenotype and STAT3 gain-of-function characterized by lymphoproliferation and poly-autoimmunity. The R335W substitution in the DNA-binding domain of STAT3 was initially described in 2 patients with typical AD-HIES, but paradoxically, recent functional analysis demonstrated a gain-of-function effect of this variant.
A patient with Sjögren syndrome and features of AD-HIES with this mutation is described and the molecular consequences are further characterized.
This study provides a clinical and immunological description of the patient. STAT phosphorylation in primary patient cells was studied and A4 cells transfected with the patient allele were used to study phosphorylation kinetics, transcriptional activity, and target-gene induction.
The hybrid clinical features of the patient were associated with normal T17 cells. Enhanced and prolonged STAT3 phosphorylation, an increased STAT3 driven luciferase reporter activity upon IL-6 stimulation, but reduced IL-6-induced SOCS3 production were all observed.
The germline R335W-STAT3 variant displays a mixed behavior in vitro that mainly shows gain-of-function, but also loss-of-function features. This is matched by an ambiguous clinical and immunological phenotype that dismantles the classical antithetic dualism of gain- versus loss-of-function. Germline STAT3 mutation-related disease represents a pathological spectrum with the p.R335W associated phenotype locating between the 2 recognized clinical disease patterns.
信号转导子和转录激活子 3（STAT3）的种系突变负责 2 种不同的人类疾病：由 STAT3 功能丧失突变引起的常染色体显性高免疫球蛋白 E 综合征（AD-HIES）和 STAT3 功能获得性疾病。到目前为止，这些实体一直被认为是对立的，AD-HIES 主要与特征性感染和结缔组织表型相关，而 STAT3 功能获得性疾病的特征是淋巴增生和多自身免疫。STAT3 DNA 结合域中的 R335W 取代最初在 2 例典型 AD-HIES 患者中描述，但矛盾的是，最近的功能分析表明该变体具有功能获得效应。
描述了一例具有 Sjögren 综合征和 AD-HIES 特征的患者，并进一步分析了该突变的分子后果。
本研究提供了患者的临床和免疫学描述。研究了原代患者细胞中 STAT 磷酸化情况，并使用转染了患者等位基因的 A4 细胞研究了磷酸化动力学、转录活性和靶基因诱导。
患者的混合临床特征与正常 T17 细胞有关。观察到增强和延长的 STAT3 磷酸化、IL-6 刺激时 STAT3 驱动的荧光素酶报告基因活性增加，但 IL-6 诱导的 SOCS3 产生减少。
种系 R335W-STAT3 变体在体外表现出混合行为，主要表现为功能获得，但也表现出功能丧失特征。这与不明确的临床和免疫学表型相匹配，打破了功能获得与功能丧失的经典对偶性。种系 STAT3 突变相关疾病代表一种病理谱，p.R335W 相关表型位于 2 种公认的临床疾病模式之间。
