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● Signal transducer and activator of transcription 1 gain-of-function (STAT1-GOF) mutations mediate extensive infections and autoimmunity.
● Over 125 STAT1-GOF mutations have been reported in at least 660 patients worldwide.
● STAT1-GOF promotes distinct immune cell proliferation in infected and non-infected states.
● Gender and mutation location are potentially related to the clinical phenotype of STAT1-GOF patients.
Inborn errors of the signal transducer and activator of transcription 1 (STAT1) result in four types of immunodeficiency disease with varying degrees of impaired STAT1 function: autosomal recessive (AR) complete STAT1 deficiency, AR partial STAT1 deficiency, autosomal dominant (AD) STAT1 deficiency, and AD STAT1 gain-of-function (STAT1-GOF). Of which, the STAT1-GOF mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections, especially chronic mucocutaneous candidiasis (CMC) and Talaromyces marneffei infection and predisposition to humoral autoimmunity. STAT1-GOF mutations lead to enhanced phosphorylation of STAT1 (pSTAT1), delayed dephosphorylation, and impaired nuclear dephosphorylation. As a result, the development of T helper (Th) 17 cells is impaired, limiting the production of interleukin (IL)-17, which plays an important role in antifungal immunity. Additionally, mutations can also cause a decrease in the proportion of CD4+, CD8+, and natural killer (NK) cells. Recent research demonstrated that in the absence of overt infection, STAT-GOF mice can disrupt naïve CD4+ T cell homeostasis and promote expansion and differentiation of abnormal T-follicular helper/T-helper 1-like (Tfh/Th1-like) T cells and germinal center-like (GC-like) B cells, and thus reminds us of the complex molecular mechanism of autoimmune disease with/without fungal infection, which may further involve specific clinical treatment including antifungal and anti-autoimmunity therapies. In addition, sex and location of mutation were also associated with the clinical phenotype. Individuals with DNA binding domain (DBD) mutations had a higher prevalence of autoimmunity and aberrant B cell activation. Disrupted CD4+ T cell homeostasis occurred sooner and more robustly in females, highlighting the importance of specific treatment to normalize STAT1 expression and restore immune tolerance in patients with STAT1-GOF syndrome. Herein, we provide a comprehensive review of STAT1-GOF aiming to further clarify the regulatory mechanism of cellular and humoral immune deficiency in patients with fungal infection with or without autoimmunity.
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