Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56bright subset

Mace, Emily M.; Hsu, Amy P.; Monaco-Shawver, Linda; Makedonas, George; Rosen, Joshua B.; Dropulic, Lesia; Cohen, Jeffrey I.; Frenkel, Eugene P.; Bagwell, John C.; Sullivan, John L.; Biron, Christine A.; Spalding, Christine; Zerbe, Christa S.; Uzel, Gülbû; Holland, Steven M.; Orange, Jordan S.

doi:10.1182/blood-2012-09-453969

Cited by 211 publications

(213 citation statements)

References 34 publications

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“…Genetic lesions causing susceptibility to EBV infection in primary immunodeficiency patients have pointed to compromised NK cell responses (Biron et al, 1989). However, all so far identified mutations affect other immune compartments (Mace et al, 2013), and NK cell depletion did not alter MHV-68 infection (Usherwood et al, 2005). In order to determine the role of NK cells during primary EBV infection, NK cell depletion prior to EBV infection was recently analyzed in huNSG mice (Chijioke et al, 2013 …”

Section: Innate Immune Responses To Ebv In His Micementioning

confidence: 99%

Animal models of Epstein Barr virus infection

Chatterjee

Leung

Münz

2014

Journal of Immunological Methods

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Epstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV-related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing. AbstractEpstein Barr virus (EBV) was the first human tumor virus to be identified. Despite 50 years of research on this oncogenic virus, no therapeutic or prophylactic vaccine is available against this pathogen. In part, the development of such a vaccine is hampered by the lack of in vivo models for EBV infection and immune control. However, with the advent of mice with reconstituted human immune system components (HIS mice), certain aspects of EBV associated diseases and immune responses can be modeled in vivo. In this review, we will discuss the insights that can be gained from these experiments, and how immune system components can be manipulated to interrogate their function during EBV infection. Finally, we will compare EBV immunobiology in HIS mice to infection by EBV-related viruses in monkeys, and we will outline the strengths and weaknesses of these two in vivo models of EBV infection. Both of these models show great promise as a platform for preclinical EBV vaccine testing. Chatterjee et al. 3

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Section: Innate Immune Responses To Ebv In His Micementioning

confidence: 99%

Animal models of Epstein Barr virus infection

Chatterjee

Leung

Münz

2014

Journal of Immunological Methods

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“…In all familial cases, the trait was inherited in an autosomal dominant fashion. A succession of follow-up reports established new cases and recalled a fascinating series of historical precedents by retrospective diagnosis (Kaur et al, 1972;Robinson et al, 1983;Biron et al, 1989;Ballas et al, 1990;Couderc et al, 1992;Horwitz et al, 1996;Wendland et al, 2000;Khanjari et al, 2003;Witzke et al, 2004;Bodor et al, 2012;Holme et al, 2012;Ishida et al, 2012;Kazenwadel et al, 2012;Camargo et al, 2013;Mace et al, 2013;Mutsaers et al, 2013;Niimi et al, 2013;Pasquet et al, 2013;Chou et al, 2014;Gao et al, 2014;West et al, 2014). The first we are aware of was a report in this journal in 1972, describing an Icelandic family with MDS/AML in association with trisomy 8 and PelgerHuet abnormality (Kaur et al, 1972), subsequently traced two generations later to a GATA2 T354M mutation (Dickinson et al, 2014).…”

Section: Clinical Syndromes Associated With Gata2 Mutationmentioning

confidence: 99%

“…NK-mediated restriction of virally infected or dysplastic targets is impaired, weakening immunosurveillance of papillomatosis and other malignant transformations. The most obvious and consistent feature is loss of the CD56 bright population of immature NK cells, analogous to transitional B cells (Mace et al, 2013;Dickinson et al, 2014). Remaining NK cells appear skewed toward a more mature phenotype with loss of NKG2A (KLRC1) and CD62L (SELL) and increased expression of killer cell immunoglobulin-like receptors (KIRs) (Dickinson et al, 2014).…”

Section: Nk Cellsmentioning

confidence: 99%

“…Other familial cases of AML with immunodeficiency and pulmonary dysfunction have also since been tracked to GATA2 mutation (Robinson et al, 1983;Horwitz et al, 1996). The original case of human NK deficiency is now known to be a GATA2 phenotype (Biron et al, 1989;Mace et al, 2013). GATA2 mutation has also been identified in paediatric neutropenia and aplastic anaemia (Pasquet et al, 2013).…”

Section: Clinical Syndromes Associated With Gata2 Mutationmentioning

confidence: 99%

“…The original report of human NK deficiency was a case of GATA2 mutation and other primary NK deficiency in humans is actually very rare (Biron et al, 1989;Mace et al, 2013). NK-mediated restriction of virally infected or dysplastic targets is impaired, weakening immunosurveillance of papillomatosis and other malignant transformations.…”

Section: Nk Cellsmentioning

confidence: 99%

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Haematopoietic and immune defects associated with GATA2 mutation

Collin

2018

Pathology

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SummaryHeterozygous familial or sporadic GATA2 mutations cause a multifaceted disorder, encompassing susceptibility to infection, pulmonary dysfunction, autoimmunity, lymphoedema and malignancy. Although often healthy in childhood, carriers of defective GATA2 alleles develop progressive loss of mononuclear cells (dendritic cells, monocytes, B and Natural Killer lymphocytes), elevated FLT3 ligand, and a 90% risk of clinical complications, including progression to myelodysplastic syndrome (MDS) by 60 years of age. Premature death may occur from childhood due to infection, pulmonary dysfunction, solid malignancy and MDS/acute myeloid leukaemia. GATA2 mutations include frameshifts, amino acid substitutions, insertions and deletions scattered throughout the gene but concentrated in the region encoding the two zinc finger domains. Mutations appear to cause haplo-insufficiency, which is known to impair haematopoietic stem cell survival in animal models. Management includes genetic counselling, prevention of infection, cancer surveillance, haematopoietic monitoring and, ultimately, stem cell transplantation upon the development of MDS or another lifethreatening complication.

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Natural selection for killer receptors and their MHC class I ligands: In pursuit of gene pairs that fit well in tandem

Brown

Gamache

Nash

et al. 2018

Journal of Leukocyte Biology

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Our understanding of the genetic basis of host resistance to viral infection and disease has progressed significantly over the last century. Numerous genes coding for modifiers of immune functions have been identified, which impact a variety of critical cellular processes, including signaling via lymphocyte receptors and their ligands, signal transduction, cytokine signaling, production and release of cytotoxic effectors, transcriptional regulation, and proliferation. Genome‐wide association studies implicate an important role for both highly polymorphic NK cell receptors and their MHC class I ligands in modifying host resistance. These findings indicate NK cells are critical mediators of viral control with considerable potential to affect morbidity and mortality outcomes. They further suggest that both stimulatory and inhibitory NK receptor polymorphisms alter NK cell sensing of MHC I ligands on viral targets, which influences how NK cells respond to infection. In many cases, however, the underlying causes associated with host outcomes remain elusive. Herein, we discuss several modes of NK cell sensing of MHC I and MHC I‐like molecules on viral targets, and the role of genetic diversity in this evolutionarily dynamic process. We further suggest that natural selection for paired NK receptors with opposing function, but shared MHC I ligands may give rise to rare, but highly effective MHC I‐dependent modes of NK cell sensing of viral targets.

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Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56bright subset

Abstract: Key Points Mutations in GATA2 are a cause of human NK cell deficiency. GATA2 is required for human NK cell maturation, specifically maintenance of the CD56bright subset.

Cited by 211 publications

References 34 publications

Animal models of Epstein Barr virus infection

Animal models of Epstein Barr virus infection

Haematopoietic and immune defects associated with GATA2 mutation

Natural selection for killer receptors and their MHC class I ligands: In pursuit of gene pairs that fit well in tandem

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