| Autor: |
Largent, Andrea D., Lambert, Katharina, Chiang, Kristy, Shumlak, Natali, Liggitt, Denny, Oukka, Mohammed, Torgerson, Troy R., Buckner, Jane H., Allenspach, Eric J., Rawlings, David J., Jackson, Shaun W. |
| Zdroj: |
Science Translational Medicine; 7/5/2023, Vol. 15 Issue 703, p1-16, 16p |
| Abstrakt: |
Heterozygous signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections and predisposition to humoral autoimmunity. To gain insights into immune characteristics of STAT1-driven inflammation, we performed deep immunophenotyping of pediatric patients with STAT1 GOF syndrome and age-matched controls. Affected individuals exhibited dysregulated CD4+ T cell and B cell activation, including expansion of TH1-skewed CXCR3+ populations that correlated with serum autoantibody titers. To dissect underlying immune mechanisms, we generated Stat1 GOF transgenic mice (Stat1GOF mice) and confirmed the development of spontaneous humoral autoimmunity that recapitulated the human phenotype. Despite clinical resemblance to human regulatory T cell (Treg) deficiency, Stat1GOF mice and humans with STAT1 GOF syndrome exhibited normal Treg development and function. In contrast, STAT1 GOF autoimmunity was characterized by adaptive immune activation driven by dysregulated STAT1-dependent signals downstream of the type 1 and type 2 interferon (IFN) receptors. However, in contrast to the prevailing type 1 IFN-centric model for STAT1 GOF autoimmunity, Stat1GOF mice lacking the type 1 IFN receptor were only partially protected from STAT1-driven systemic inflammation, whereas loss of type 2 IFN (IFN-γ) signals abrogated autoimmunity. Last, germline STAT1 GOF alleles are thought to enhance transcriptional activity by increasing total STAT1 protein, but the underlying biochemical mechanisms have not been defined. We showed that IFN-γ receptor deletion normalized total STAT1 expression across immune lineages, highlighting IFN-γ as the critical driver of feedforward STAT1 elevation in STAT1 GOF syndrome. Editor's summary: Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations lead to immune dysregulation and predispose affected individuals to humoral autoimmunity, but the underlying mechanisms are not fully understood. Here, Largent and colleagues performed deep immunophenotyping of pediatric patients with STAT1 GOF syndrome, finding expansion of TH1-skewed CXCR3-positive cell populations that correlated with serum autoantibody titers. A Stat1 GOF transgenic mouse model developed spontaneous autoimmunity characterized by absence of Treg dysfunction and by adaptive immune activation driven by type 2 interferon signaling. Further, deletion of the interferon-γ receptor normalized STAT1-dependent inflammation, suggesting that agents that block interferon-γ signaling may constitute a potential treatment for patients with STAT1 GOF syndrome. —Melissa Norton [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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