Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations

Tabellini, Giovanna; Vairo, Donatella; Scomodon, Omar; Tamassia, Nicola; Ferraro, Rosalba Monica; Patrizi, Ornella; Gasperini, Sara; Soresina, Annarosa; Giardino, Giuliana; Pignata, Claudio; Lougaris, Vassilios; Plebani, Alessandro; Dotta, Laura; Cassatella, Marco A.; Parolini, Silvia; Badolato, Raffaele

doi:10.1016/j.jaci.2016.10.051

Cited by 50 publications

(58 citation statements)

References 42 publications

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“…Consistent with previous reports (23), we found that pSTAT1 induction peaked 15 min after IFN-γ stimulation and started to decline toward baseline at 30 min after stimulation in all 13 healthy donor monocytes (Figure 1A). Similar kinetics of pSTAT1 induction peak and decline were observed in all eight APECED patients (Figure 1A).…”

Section: Resultssupporting

confidence: 92%

“…The defect in STAT1 levels post-IFN-γ stimulation that we observed in our APECED patients is modest relative to the complete absence of STAT1 phosphorylation following IFN-γ stimulation in patients with IFN-γ receptor deficiency [(23); Figure 1A]. Therefore, significant residual STAT1 signaling is functional in APECED patients to prevent the development of mycobacterial infections in these patients.…”

Section: Discussionmentioning

confidence: 70%

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Autoimmune Regulator Deficiency Results in a Decrease in STAT1 Levels in Human Monocytes

et al. 2017

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare primary immunodeficiency disorder typically caused by biallelic autoimmune regulator (AIRE) mutations that manifests with chronic mucocutaneous candidiasis (CMC) and autoimmunity. Patients with STAT1 gain-of-function (GOF) mutations also develop CMC and autoimmunity; they exhibit increased STAT1 protein levels at baseline and STAT1 phosphorylation (pSTAT1) upon interferon (IFN)-γ stimulation relative to healthy controls. AIRE interacts functionally with a protein that directly regulates STAT1, namely protein inhibitor of activated STAT1, which inhibits STAT1 activation. Given the common clinical features between patients with AIRE and STAT1 GOF mutations, we sought to determine whether APECED patients also exhibit increased levels of STAT1 protein and phosphorylation in CD14+ monocytes. We obtained peripheral blood mononuclear cells from 8 APECED patients and 13 healthy controls and assessed the levels of STAT1 protein and STAT1 tyrosine phosphorylation at rest and following IFN-γ stimulation, as well as the levels of STAT1 mRNA. The mean STAT1 protein levels in CD14+ monocytes exhibited a ~20% significant decrease in APECED patients both at rest and after IFN-γ stimulation relative to that of healthy donors. Similarly, the mean peak value of IFN-γ-induced pSTAT1 level was ~20% significantly lower in APECED patients compared to that in healthy controls. The decrease in STAT1 and peak pSTAT1 in APECED patients was not accompanied by decreased STAT1 mRNA or anti-IFN-γ autoantibodies; instead, it correlated with the presence of autoantibodies to type I IFN and decreased AIRE−/− monocyte surface expression of IFN-γ receptor 2. Our data show that, in contrast to patients with STAT1 GOF mutations, APECED patients show a moderate but consistent and significant decrease in total STAT1 protein levels, associated with lower peak levels of pSTAT1 molecules after IFN-γ stimulation.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 70%

Autoimmune Regulator Deficiency Results in a Decrease in STAT1 Levels in Human Monocytes

et al. 2017

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“…Of the tested patients in the same cohort, 19% had lymphopenia, 28% CD4 lymphopenia, 16% CD8 lymphopenia, 19% low B cells, 49% low memory B cells, 25% low NK cells, 82% low CD3 + IL-17 + or CD4 + IL-17 + cells, 32% low T cell proliferation, 38% low IgG2, and 50% low IgG4 [5]. Tabellini et al demonstrated impaired NK cell function in GOF mutations [12]. In our cohort, 1 patient had low CD3 + , CD4 + , and CD8 + cells.…”

Section: Discussionmentioning

confidence: 99%

Risks of Ruxolitinib in STAT1 Gain-of-Function-Associated Severe Fungal Disease

Zimmerman

Rösler²,

Zerbe

et al. 2017

Open Forum Infectious Diseases

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“…and Interleukin-17 immunity, 5 and abnormal function of natural killer cells. 6 Here, we report on a patient with a de novo missense mutation in STAT1 (NM_007315.3, MIM #600555, c.1398C>G, p.Ser466Arg) within the DNA-binding domain, and recently described to cause combined immunodeficiency with CMCD and defective Th1 and Th17 responses. 7 We further characterize the functional impact of this missense change and document its association with a peculiar phenotype resembling an interferonopathy.…”

Section: Introductionmentioning

confidence: 91%

The activating p.Ser466Arg change in STAT1 causes a peculiar phenotype with features of interferonopathies

et al. 2019

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Signal Transducer and Activator of Transcription 1 (STAT1) is a DNA‐binding signal transducer that regulates transcription of specific genes in response to IFNγ and IFNα/β stimulation. Loss‐of‐function mutations impairing STAT1 activity are known to confer susceptibility to intracellular bacterial and viral diseases. Conversely, the few known activating mutations of STAT1 allow predisposition to chronic mucocutaneous candidiasis disease, and occur in patients with combined immunodeficiency and defective Th1 and Th17 responses. Here, we report on a de novo gain‐of‐function (GoF) STAT1 mutation (c.1398C>G, p.Ser466Arg) identified by exome sequencing in an individual with brain calcification, arthritis, recurrent pericarditis, leukopenia, thrombocytopenia and low C3 levels, a phenotype resembling an interferonopathy. The Ser466Arg change affects a highly conserved residue located in the DNA binding domain of the protein and the amino acid substitution was documented to have an activating role both in vitro and in vivo. Altogether, clinical features and functional studies are compatible with hyperactivation of the Interferon pathways, highlighting a role of STAT1 GoF mutation in clinical phenotypes fitting interferonopathies.

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Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations

Cited by 50 publications

References 42 publications

Autoimmune Regulator Deficiency Results in a Decrease in STAT1 Levels in Human Monocytes

Autoimmune Regulator Deficiency Results in a Decrease in STAT1 Levels in Human Monocytes

Risks of Ruxolitinib in STAT1 Gain-of-Function-Associated Severe Fungal Disease

The activating p.Ser466Arg change in STAT1 causes a peculiar phenotype with features of interferonopathies

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