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

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

  • Clin Immunol. 2024 Jul 15:266:110312. doi: 10.1016/j.clim.2024.110312.
Kornvalee Meesilpavikkai 1,  Zijun Zhou 2,  Kasiphak Kaikaew 3,  Suphattra Phakham 4,  Peter J van der Spek 5,  Sigrid Swagemakers 5,  Deon J Venter 6,  Maaike de Bie 7,  Benjamin Schrijver 2,  Christopher Schliehe 8,  Fabian Kaiser 8,  Virgil A S H Dalm 9,  P Martin van Hagen 10,  Nattiya Hirankarn 11,  Hanna IJspeert 7,  Willem A Dik 12
Affiliations

Affiliations

  • 1 Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
  • 2 Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Division of Allergy & Clinical Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • 3 Center of Excellence in Alternative and Complementary Medicine of Gastrointestinal and Liver Diseases, Department of Physiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
  • 4 Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
  • 5 Department of Pathology and Clinical Bioinformatics, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • 6 Department of Pathology, Mater Health Services, Brisbane, Queensland, Australia.
  • 7 Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • 8 Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • 9 Department of Internal Medicine, Division of Allergy & Clinical Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands.
  • 10 Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Division of Allergy & Clinical Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: p.m.vanhagen@erasmusmc.nl.
  • 11 Center of Excellence in Immunology and Immune-mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Electronic address: Nattiya.h@chula.ac.th.
  • 12 Laboratory Medical Immunology, Department of Immunology, Erasmus University Medical Center, Rotterdam, the Netherlands. Electronic address: w.dik@erasmusmc.nl.
PMID: 39019339 DOI: 10.1016/j.clim.2024.110312
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.

Keywords

Autoimmunity; Immune regulatory disorders; Immunodeficiency; Patient-specific variants; STAT3 GOF syndrome; Transgenic mouse model.

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