A patient-based murine model recapitulates human STAT3 gain-of-function syndrome

IF 4.5 3区 医学 Q2 IMMUNOLOGY Clinical immunology Pub Date : 2024-07-15 DOI:10.1016/j.clim.2024.110312
Kornvalee Meesilpavikkai , Zijun Zhou , Kasiphak Kaikaew , Suphattra Phakham , Peter J. van der Spek , Sigrid Swagemakers , Deon J. Venter , Maaike de Bie , Benjamin Schrijver , Christopher Schliehe , Fabian Kaiser , Virgil A.S.H. Dalm , P. Martin van Hagen , Nattiya Hirankarn , Hanna IJspeert , Willem A. Dik
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Abstract

STAT3 gain-of-function (GOF) variants results in a heterogeneous clinical syndrome characterized by early onset immunodeficiency, multi-organ autoimmunity, and lymphoproliferation. While 191 documented cases with STAT3 GOF variants have been reported, the impact of individual variants on immune regulation and the broad clinical spectrum remains unclear. We developed a Stat3p.L387R mouse model, mirroring a variant identified in a family exhibiting common STAT3 GOF symptoms, and rare phenotypes including pulmonary hypertension and retinal vasculitis. In vitro experiments revealed increased STAT3 phosphorylation, nuclear migration, and DNA binding of the variant. Our Stat3p.L387R model displayed similar traits from previous Stat3GOF strains, such as splenomegaly and lymphadenopathy. Notably, Stat3p.L387R/+ mice exhibited heightened embryonic lethality compared to prior Stat3GOF/+ models and ocular abnormalities were observed. This research underscores the variant-specific pathology in Stat3p.L387R/+ mice, highlighting the ability to recapitulate human STAT3 GOF syndrome in patient-specific transgenic murine models. Additionally, such models could facilitate tailored treatment development.

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基于患者的小鼠模型再现了人类 STAT3 功能增益综合征。
STAT3 功能增益(GOF)变异导致了一种以早发免疫缺陷、多器官自身免疫和淋巴细胞增殖为特征的异质性临床综合征。虽然已有 191 例 STAT3 GOF 变体病例的记录,但单个变体对免疫调节和广泛临床范围的影响仍不清楚。我们建立了一个Stat3p.L387R小鼠模型,该模型反映了在一个家族中发现的变体,该家族表现出常见的STAT3 GOF症状,以及包括肺动脉高压和视网膜血管炎在内的罕见表型。体外实验显示,该变异体的 STAT3 磷酸化、核迁移和 DNA 结合均有所增加。我们的Stat3p.L387R模型显示出与以前的Stat3GOF菌株相似的特征,如脾肿大和淋巴结病。值得注意的是,与之前的Stat3GOF/+模型相比,Stat3p.L387R/+小鼠表现出更高的胚胎致死率,并且观察到眼部异常。这项研究强调了Stat3p.L387R/+小鼠的变异特异性病理,突出了在患者特异性转基因小鼠模型中再现人类STAT3 GOF综合征的能力。此外,这种模型还有助于开发有针对性的治疗方法。
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来源期刊
Clinical immunology
Clinical immunology 医学-免疫学
CiteScore
12.30
自引率
1.20%
发文量
212
审稿时长
34 days
期刊介绍: Clinical Immunology publishes original research delving into the molecular and cellular foundations of immunological diseases. Additionally, the journal includes reviews covering timely subjects in basic immunology, along with case reports and letters to the editor.
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