Biallelic mutations in IRF8 impair human NK cell maturation and function

Mace, Emily M.; Bigley, Venetia; Gunesch, Justin T.; Chinn, Iván K.; Angelo, Laura S.; Care, Matthew A.; Maisuria, Sheetal; Keller, Michael D.; Togi, Sumihito; Watkin, Levi B.; LaRosa, David F.; Jhangiani, Shalini N.; Muzny, Donna M.; Stray-Pedersen, Asbjørg; Akdemir, Zeynep Coban; Smith, Jansen B.; Hernandez-Sanabria, Mayra; Le, Duy T.; Hogg, Graham D.; Cao, Tram N.; Freud, Aharon G.; Szymanski, Eva P.; Savic, Sinisa; Collin, Matthew; Cant, Andrew J.; Gibbs, Richard A.; Holland, Steven M.; Caligiuri, Michael A.; Ozato, Keiko; Paust, Silke; Doody, Gina M.; Lupski, James R.; Orange, Jordan S.

doi:10.1172/jci86276

Cited by 87 publications

(89 citation statements)

References 78 publications

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“…IRF8 deficiency in mice is characterized by absence of monocytes, DCs, NK cells, and a lack of IL-12 and IFNγ production (28,29) . Similarly, IRF8 mutations identified to date in humans cause a spectrum of immune cell phenotypes (25,30–32) . The homozygous K108E variant in the DNA-binding domain leads to severe immunodeficiency, characterized by complete lack of monocytes, DCs, IL-12, IFN-γ and TNF-α production (25,30) .…”

Section: Discussionmentioning

confidence: 99%

“…The compound heterozygous mutations R83C/R291Q lead to complex immunodeficiency syndrome caused by DC and monocyte deficiency (31) . The biallelic A201V/P224L mutation within the IAD domain leads to NK cell deficiency with decreased NK cell number and CD56 dim subset, which is also observed in Irf8 −/− mice but not in Irf8 +/− mice (32) . In contrast to the K108E mutation, the A201V/P224L variant is able to normally activate IRF1- and PU.1-dependent transcription, which is manifested by a subtle DC deficiency and normal production of IFN- γ and TNF-α.…”

Section: Discussionmentioning

confidence: 99%

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Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption

Thumbigere‐Math

Foster

Bachu

et al. 2019

Journal of Bone and Mineral Research

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This is the first study to report a novel mutation in the interferon regulatory factor 8 gene (IRF8G388S) associated with Multiple Idiopathic Tooth Root Resorption, a form of periodontal disease. The IRF8G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. Functional assays demonstrated that the IRF8G388S mutant promoted osteoclastogenesis and failed to inhibit NFATc1-dependent transcriptional activation when compared to IRF8WT control. Further, similar to subjects with heterozygous IRF8G388S mutation, Irf8+/− mice exhibited increased osteoclast activity in the mandibular alveolar bone surrounding molar teeth. Immunohistochemistry illustrated increased NFATc1 expression in the dentoalveolar region of Irf8−/− and Irf8+/− mice when compared to Irf8+/+ controls. Genome-wide analyses revealed that IRF8 constitutively bound to regulatory regions of several thousand genes in osteoclast precursors, and genetic aberration of IRF8 significantly enhanced many osteoclast-specific transcripts. Collectively, this study delineates the critical role of IRF8 in defining osteoclast lineage and osteoclast transcriptional program, which may help in better understanding of various osteoclast-mediated disorders, including periodontal disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption

Thumbigere‐Math

Foster

Bachu

et al. 2019

Journal of Bone and Mineral Research

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“…The fourth child was unaffected. Whole exome sequencing and analysis identified biallelic variants in the IRF association domain (IAD) of IRF8 that segregated appropriately within the family and were novel and damaging . Additional families were identified, including a child with homozygous variants in IRF8 and disseminated BCG disease, and a second child with compound heterozygous mutations and recurrent respiratory infections …”

Section: Classical Nkd (Cnkd)mentioning

confidence: 99%

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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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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“…Strikingly, a similar block in terminal maturation is also observed in mice with homozygous, but not heterozygous Irf8 mutations. IRF8 deficiency as a result of both homozygous and heterozygous mutation can lead to DC deficiency (67, 68), although DC subsets in the proband reported here were only minimally affected (66). While mutation and gene dosage effects may be at play, the NK cell phenotype was conserved between all patients with biallelic IRF8 mutations studied but was not identified in any individuals with heterozygous IRF8 mutation.…”

Section: Classical Nkdmentioning

confidence: 78%

“…The longitudinal study of a surviving affected sibling shows a distinctive, stable NK cell phenotype, with decreased NK cell function and increased CD56 bright NK cells relative to the CD56 dim subset (66). This phenotype is conserved in other patients with biallelic IRF8 mutation and is NK cell intrinsic.…”

Section: Classical Nkdmentioning

confidence: 99%

Genetic Causes of Human NK Cell Deficiency and Their Effect on NK Cell Subsets

Mace

Orange

2016

Front. Immunol.

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Human NK cells play critical roles in human host defense, particularly the control of viral infection and malignancy, and patients with congenital immunodeficiency affecting NK cell function or number can suffer from severe illness. The importance of NK cell function is particularly underscored in patients with primary immunodeficiency in which NK cells are the primary or sole affected population (NK cell deficiency, NKD). While NKD may lead to the absence of NK cells, we are also gaining an increasing appreciation of the effect that NKD may have on the generation of specific NK cell subsets. In turn, this leads to improved insights into the requirements for human NK cell subset generation, as well as their importance in immune homeostasis. The presence of inherently abnormally developed or functionally impaired NK cells, in particular, appears to be problematic in the way of interfering with normal human host defense and may be more impactful than low numbers of NK cells alone. Here, we review the known genetic causes of NKD and the insight that is derived by these into the requirements for human subset generation and, by extension, for NK cell-mediated immunity.

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Biallelic mutations in IRF8 impair human NK cell maturation and function

Cited by 87 publications

References 78 publications

Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption

Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption

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

Genetic Causes of Human NK Cell Deficiency and Their Effect on NK Cell Subsets

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