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Dominant-Negative Versus Gain-of-Function STAT3 Defects: A Systematic Review on Epidemiological, Clinical, Immunological, and Molecular Aspects

Lookup NU author(s): Dr Christo TsilifisORCiD, Professor Andrew GenneryORCiD

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Abstract

© 2025 American Academy of Allergy, Asthma & Immunology. Background: Germline signal transducer and activator of transcription 3 (STAT3) mutations cause 2 distinct syndromes with predominant infectious or autoimmune phenotype. Objective: The objective of this study is to compile literature reports on gain-of-function (GOF) and dominant-negative (DN) mutations in the STAT3. Methods: We searched 3 main databases including PubMed, Scopus, and Web of Science from 1990 to 2023. All full-text articles and major reviews were manually searched for additional studies. Results: A total of 490 patients were reported in 107 articles including 265 patients with DN-STAT3 and 225 patients with GOF-STAT3 mutations. Major clinical differences between STAT3-DN and STAT3-GOF patients were observed in rates of infectious complication (98.2% vs 85.4%, P <. 001), pneumonia (67.3% vs 52.1%, P =. 006), sinusitis (17.5% vs 2.1%, P <. 001), otitis (27.7% vs 5.2%, P <. 001), abscess (52.7% vs 17.7%, P <. 001), dermatologic manifestation (88.3% vs 58.4%, P <. 001), atopic disorders (66.4% vs 40.2%, P <. 001), interstitial lung disease (0.7% vs 17.7%, P <. 001), dental/gingival disorders (38.5% vs 11.7%, P <. 001), and endocrinopathies (0.9% vs 16.5%, P <. 001), respectively. Most patients had normal counts of lymphocyte subsets, with the exceptions of higher CD3+ T cells and lower natural killer cells in STAT3-DN patients, and lower CD4+ T cells in STAT3-GOF patients. Most STAT3-DN patients had either normal or high serum concentrations of IgG, IgA, and IgM with almost universal raised serum IgE. Most STAT3-GOF patients had a low level of IgG, but normal levels of IgA, IgM, and IgE. Conclusions: Patients with STAT3-DN had recurrent dermatological and pulmonary infections, eczema, elevated IgE, and eosinophilia, whereas patients with STAT3-GOF had early-onset polyautoimmunity and frequently require immunosuppressive therapy.

Publication metadata

Author(s): Hajialigol A, Azizi G, Seifi Alan M, Soltani A, Arabian Z, Tamiji M, Tsilifis C, Gennery AR, Jamee M

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology: In Practice

Year: 2025

Volume: 13

Issue: 6

Pages: 1440-1448

Print publication date: 01/06/2025

Online publication date: 15/04/2025

Acceptance date: 07/04/2025

ISSN (print): 2213-2198

ISSN (electronic): 2213-2201

Publisher: Elsevier BV

URL: https://doi.org/10.1016/j.jaip.2025.04.014

DOI: 10.1016/j.jaip.2025.04.014

PubMed id: 40246075

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