A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations

Hoyos-Bachiloglu, Rodrigo; Chou, Janet; Sodroski, Catherine; Beano, Abdallah; Bainter, Wayne; Angelova, Magdalena; Idrissi, Eman Al; Habazi, Murad K.; Alghamdi, Hamza Ali; Almanjomi, Fahd; Shehri, Mohamed Al; Elsidig, Nagi; Eldin, Morsi Alaa; Knipe, David M.; AlZahrani, Mofareh; Geha, Raif S.

doi:10.1172/jci93486

Cited by 53 publications

(54 citation statements)

References 24 publications

(38 reference statements)

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“…Since the discovery of its first genetic etiology in 1996, MSMD has been reported and a causal genetic lesion described in 501 individuals from 356 kindreds originating from 57 countries on five continents (Figure a). Over this period, the genetic dissection of MSMD in these patients has revealed this condition to be caused by inborn errors of interferon (IFN)‐γ immunity . These findings confirm that IFN‐γ, first described in 1965 as an antiviral IFN, is actually the macrophage‐activating factor, as shown in 1983 .…”

Section: Introductionsupporting

confidence: 61%

“…Since the last comprehensive review on MSMD in 2014, three new genetic disorders have been reported, caused by mutations of TYK2 and SPPL2A, (two novel genetic etiologies) and IFNGR2 (a novel allelic form). Moreover, new mutations associated with the other 18 disorders have also been reported . We also discuss here two recently reported syndromic forms of MSMD: AR RORγ/RORγT and Janus kinase (JAK)1 deficiencies .…”

Section: Introductionmentioning

confidence: 80%

“…Since 2014, 34 new disease‐causing mutations have been reported at six MSMD loci already discovered before this date, including IFNGR1, IFNGR2 , IL12RB1 , IL12B , STAT1 and NEMO . Interestingly, the two new hypomorphic NEMO mutations underlie mycobacterial diseases without anhidrotic ectodermal dysplasia .…”

Section: New Mutations At Known Msmd Locimentioning

confidence: 99%

“…A sizeable proportion of patients with MSMD also display invasive infections because of other intra‐macrophagic microorganisms, such as Salmonella , or mucocutaneous infections caused by Candida species . Other infectious diseases have also been reported, albeit more rarely . Acquired and inherited immunodeficiencies conferring a predisposition to mycobacterial diseases in the context of other infections must first be excluded, before a diagnosis of MSMD can be reached .…”

Section: Introductionmentioning

confidence: 99%

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Mendelian susceptibility to mycobacterial disease: 2014–2018 update

et al. 2018

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Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-c immunity. Since 1996, disease-causing mutations have been found in 11 genes, which, through allelic heterogeneity, underlie 21 different genetic disorders. We briefly review here progress in the study of molecular, cellular and clinical aspects of MSMD since the last comprehensive review published in 2014. Highlights include the discoveries of (1) a new genetic etiology, autosomal recessive signal peptide peptidase-like 2 A deficiency, (2) TYK2-deficient patients with a clinical phenotype of MSMD, (3) an allelic form of partial recessive IFN-cR2 deficiency, and (4) two forms of syndromic MSMD: RORc/RORcT and JAK1 deficiencies. These recent findings illustrate how genetic and immunological studies of MSMD can shed a unique light onto the mechanisms of protective immunity to mycobacteria in humans.

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Section: Introductionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 80%

Section: New Mutations At Known Msmd Locimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mendelian susceptibility to mycobacterial disease: 2014–2018 update

et al. 2018

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“…This notion was supported by a recent study on an individual who harbors digenic homozygous deficiencies in IFNAR1 (loss of a stop codon led to an extended protein with a hypomorphic response to the cytokine) and the IFN-g receptor (limited expression and no signaling) and, as a result, experiences disseminated mycobacteria, Streptococcus viridans bacteremia, and exceptionally high CMV viremia. Notably, and unlike the loss-of-function IFNAR2 sibling described above (64), this patient does not suffer from complications following MMR vaccination (66), probably because the patient's IFN-I responsiveness, although hypomorphic, is sufficient to control infection and/or demonstrates the compensatory capability of IFN-l.…”

Section: The Upper Limit: Type I Interferonopathiesmentioning

confidence: 73%

The Goldilocks Zone of Type I IFNs: Lessons from Human Genetics

Taft

Bogunovic

2018

The Journal of Immunology

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Type I IFNs (IFN-Is) are powerful cytokines. They provide remarkable protection against viral infections, but their indiscriminate production causes severe self-inflicted damage that can be lethal, particularly in early development. In humans, inappropriately high IFN-I levels caused by defects in the regulatory mechanisms that control IFN-I production and response result in clinical conditions known as type I interferonopathies. In essence, type I interferonopathies define the upper limit of safe, IFN-related inflammation in vivo. Conversely, the loss of IFN-I responsiveness increases susceptibility to viral infections, but, surprisingly, most affected individuals survive despite these inborn errors of immunity. These findings suggest that too much IFN-I early in life is toxic, but that insensitivity to IFN-I is perhaps not the death sentence it was initially thought to be. Human genetic analyses have suggested that seemingly insignificant levels of IFN-regulated gene activity may be sufficient for most of the antiviral defenses used by humans in natura.

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Structural integrity with functional plasticity: what type I IFN receptor polymorphisms reveal

Weerd

Vivian

Lim

et al. 2020

Journal of Leukocyte Biology

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The type I IFNs activate an array of signaling pathways, which are initiated after IFNs bind their cognate receptors, IFNα/β receptor (IFNAR)1 and IFNAR2. These signals contribute to many aspects of human health including defense against pathogens, cancer immunosurveillance, and regulation of inflammation. How these cytokines interact with their receptors influences the quality of these signals. As such, the integrity of receptor structure is pivotal to maintaining human health and the response to immune stimuli. This review brings together genome wide association studies and clinical reports describing the association of nonsynonymous IFNAR1 and IFNAR2 polymorphisms with clinical disease, including altered susceptibility to viral and bacterial pathogens, autoimmune diseases, cancer, and adverse reactions to live‐attenuated vaccines. We describe the amino acid substitutions or truncations induced by these polymorphisms and, using the knowledge of IFNAR conformational changes, IFNAR‐IFN interfaces and overall structure‐function relationship of the signaling complexes, we hypothesize the effect of these polymorphisms on receptor structure. That these predicted changes to IFNAR structure are associated with clinical manifestations of human disease, highlights the importance of IFNAR structural integrity to maintaining functional quality of these receptor‐mediated responses. Type I IFNs are pivotal to innate immune responses and ultimately, to human health. Understanding the consequences of altered structure on the actions of these clinically significant cell receptors provides important information on the roles of IFNARs in health and disease.

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A digenic human immunodeficiency characterized by IFNAR1 and IFNGR2 mutations

Cited by 53 publications

References 24 publications

Mendelian susceptibility to mycobacterial disease: 2014–2018 update

Mendelian susceptibility to mycobacterial disease: 2014–2018 update

The Goldilocks Zone of Type I IFNs: Lessons from Human Genetics

Structural integrity with functional plasticity: what type I IFN receptor polymorphisms reveal

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