Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations

Vargas-Hernández, Alexander; Mace, Emily M.; Zimmerman, Ofer; Zerbe, Christa S.; Freeman, Alexandra F.; Rosenzweig, Sergio D.; Leiding, Jennifer W.; Torgerson, Troy R.; Altman, Matthew C.; Schussler, Edith; Cunningham‐Rundles, Charlotte; Chinn, Iván K.; Carisey, Alexandre F.; Hanson, I. Celine; Rider, Nicholas L.; Holland, Steven M.; Orange, Jordan S.; Forbes, Lisa R.

doi:10.1016/j.jaci.2017.08.040

Cited by 82 publications

(79 citation statements)

References 65 publications

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“…NK cells from these patients are poorly functional and additionally have altered phenotype and homeostasis. Similarly to those seen in PASLI disease patients, these cells seem to be immature, with an increase in the CD56 bright subset and decreased expression of CD16, perforin, and KIR . However, again it is unclear whether this phenotype represents a true halt in terminal maturation, or whether this is more reflective of impaired homeostasis or regulation of specific receptors.…”

Section: Primary Immune Deficiencies With Nk Cell Featuresmentioning

confidence: 90%

“…Perhaps unsurprisingly, patients with STAT5B mutations have profoundly impaired NK cell development, with few NK cells in the periphery and accompanying poor NK cell function . NK cell phenotype and function are also affected in patients with gain‐of‐function mutations in STAT1, or loss‐of‐function mutations in STAT3 . In the case of STAT3 mutations, which lead to hyper‐IgE syndrome, poor NK cell function can be attributed to decreased expression of the activating receptor NKG2D on peripheral blood NK cells .…”

Section: Primary Immune Deficiencies With Nk Cell Featuresmentioning

confidence: 99%

“…In the case of STAT3 mutations, which lead to hyper‐IgE syndrome, poor NK cell function can be attributed to decreased expression of the activating receptor NKG2D on peripheral blood NK cells . In addition, deregulated STAT signaling may impair NK cell function or homeostasis through downstream signaling, as is the case in NK cells from patients with STAT1‐GOF mutations . NK cells from these patients are poorly functional and additionally have altered phenotype and homeostasis.…”

Section: Primary Immune Deficiencies With Nk Cell Featuresmentioning

confidence: 99%

“…Finally, JAK1 and JAK3 are important adapters that mediate STAT signaling, and treatment of STAT1‐GOF patients with the JAK inhibitor ruxolitinib improves NK cell function and phenotype . Patients with JAK3 mutations generally present with T − B + NK − SCID, demonstrating that JAK3 function is non‐redundant for IL‐15‐mediated signaling supporting NK cell development .…”

Section: Primary Immune Deficiencies With Nk Cell Featuresmentioning

confidence: 99%

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Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

Mace

Orange

2018

Immunological Reviews

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133

107

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Human NK cells are innate immune effectors that play a critical roles in the control of viral infection and malignancy. The importance of their homeostasis and function can be demonstrated by the study of patients with primary immunodeficiencies (PID), which are part of the family of diseases known as inborn defects of immunity. While NK cells are affected in many PIDs in ways that may contribute to a patient’s clinical phenotype, a small number of PIDs have an NK cell abnormality as their major immunological defect. These PIDs can be collectively referred to as NK cell deficiency disorders (NKD), and include effects upon NK cell numbers, subsets and/or functions. The clinical impact of NKD can be severe including fatal viral infection, with particular susceptibility to herpesviral infections, such as cytomegalovirus, varicella zoster virus and Epstein-Barr virus. While NKD is rare, studies of these diseases are important for defining specific requirements for human NK cell development and homeostasis. New themes in NK cell biology are emerging through the study of both known and novel NKD, particularly those affecting cell cycle and DNA damage repair, as well as broader PIDs having substantive impact upon NK cells. In addition, the discovery of NKD that affect other innate lymphoid cell (ILC) subsets opens new doors for better understanding the relationship between conventional NK cells and other ILC subsets. Here we describe the biology underlying human NKD, particularly in the context of new insights into innate immune cell function, including a discussion of recently described NKD with accompanying effects on ILC subsets. Given the impact of these disorders upon human immunity with a common focus upon NK cells, the unifying message of a critical role for NK cells in human host defense singularly emerges.

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Section: Primary Immune Deficiencies With Nk Cell Featuresmentioning

confidence: 90%

Section: Primary Immune Deficiencies With Nk Cell Featuresmentioning

confidence: 99%

Section: Primary Immune Deficiencies With Nk Cell Featuresmentioning

confidence: 99%

Section: Primary Immune Deficiencies With Nk Cell Featuresmentioning

confidence: 99%

See 2 more Smart Citations

Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

Mace

Orange

2018

Immunological Reviews

Self Cite

133

107

View full text Add to dashboard Cite

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“…The clinical (brain calcification, arthritis, recurrent pericarditis) and laboratory (leukopenia, thrombocytopenia, low C3 levels) features observed in the present patient, which are typical of interferonopathies, together with the collected biochemical and functional information on the Ser466Arg change, suggest that the disorder associated to upregulated STAT1 function is to be considered as a subgroup of interferonopathies. In this respect, there have been some reports of patients with STAT1 GoF mutations who appeared to have benefited from treatment with Janus Kinase (JAK) inhibitors with improvement of immunological abnormalities, cytopenias and mucocutaneous candidiasis . Further studies with JAK inhibitors are needed to provide the rationale for this targeted therapeutic approache …”

Section: Resultsmentioning

confidence: 99%

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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Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

et al. 2019

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STAT1 gain‐of‐function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1‐dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN‐α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN‐α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon‐stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon‐related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

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Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations

Abstract: Properly regulated STAT1 signaling is critical for NK cell maturation and function. Modulation of increased STAT1 phosphorylation with ruxolitinib is an important option for therapeutic intervention in patients with STAT1 GOF mutations.

Cited by 82 publications

References 65 publications

Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

Emerging insights into human health and NK cell biology from the study of NK cell deficiencies

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

Interferon signature in patients with STAT1 gain‐of‐function mutation is epigenetically determined

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