Phagocyte nicotinamide adenine dinucleotide phosphate oxidase activity in patients with inherited IFN-γR1 or IFN-γR2 deficiency

Conti, Francesca; Aragão-Filho, Walmir Cutrim; Prando, Carolina; Deswarte, Caroline; Hubeau, Marjorie; Newburger, Peter E.; Casanova, Jean‐Laurent; Bustamante, Jacinta; Condino‐Neto, Antônio

doi:10.1016/j.jaci.2014.11.004

Cited by 11 publications

(12 citation statements)

References 9 publications

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“…These particular mutations were shown to abolish the respiratory burst function in monocyte‐derived macrophages (MDMs), when these cells were activated with BCG, PPD (purified protein derived from M.tb ), or IFN‐γ. By contrast to what had been observed for CGD patients, neutrophils, monocytes, and monocyte‐derived dendritic cells (MDDCs) from these patients had a normal respiratory burst, as estimated by measurements of superoxide and hydrogen peroxide production . Interestingly, the impaired function of NADPH in MDM was found to be correlated with the impaired expression of gp91 phox in these cells .…”

Section: X‐linked Recessive Gp91phox Deficiencycontrasting

confidence: 59%

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood

Boisson–Dupuis

Bustamante

El-Baghdadi

et al. 2015

Immunological Reviews

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195

165

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Summary Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb) and a few related mycobacteria, is a devastating disease, killing more than a million individuals per year worldwide. However, its pathogenesis remains largely elusive, as only a small proportion of infected individuals develop clinical disease either during primary infection or during reactivation from latency or secondary infection. Subacute, hematogenous, and extrapulmonary disease tends to be more frequent in infants, children, and teenagers than in adults. Life-threatening primary TB of childhood can result from known acquired or inherited immunodeficiencies, although the vast majority of cases remain unexplained. We review here the conditions conferring a predisposition to childhood clinical diseases caused by mycobacteria, including not only M.tb but also weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria. Infections with weakly virulent mycobacteria are much rarer than TB, but the inherited and acquired immunodeficiencies underlying these infections are much better known. Their study has also provided genetic and immunological insights into childhood TB, as illustrated by the discovery of single-gene inborn errors of IFN-γ immunity underlying severe cases of TB. Novel findings are expected from ongoing and future human genetic studies of childhood TB in countries that combine a high proportion of consanguineous marriages, a high incidence of TB, and an excellent clinical care, such as Iran, Morocco, and Turkey.

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Section: X‐linked Recessive Gp91phox Deficiencycontrasting

confidence: 59%

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood

Boisson–Dupuis

Bustamante

El-Baghdadi

et al. 2015

Immunological Reviews

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195

165

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“…Interestingly, our studies of monocytes, MDMs, and MDDCs suggest that these cell types are not dependent on p40 phox for PMA-induced NADPH oxidase activity. This situation contrasts with that for MSMD-causing gp91 phox mutations, which disrupt NADPH oxidase activity in MDMs but not in other phagocytes (neutrophils, monocytes, and MDDCs) (25,41). The conservation of NADPH oxidase activity may explain the milder infectious phenotype of p40 phox -deficient patients than of patients with classic CGD, including the absence of invasive bacterial and fungal infections.…”

Section: Discussionmentioning

confidence: 86%

“…Monocytes from 6 patients (P12, P15, P16, P19, P20, and P22) responded similarly to cells from healthy controls (Supplemental Figure 5B). We further investigated the NADPH oxidase activity of MDMs, as previously described (25,41). MDMs from healthy controls, P12, P20, and P22 had normal or low levels of H 2 O 2 after stimulation, depending on the stimulus, whereas MDMs from a patient with classic CGD released no H 2 O 2 ( Figure 5A).…”

Section: Introductionmentioning

confidence: 97%

Inherited p40phox deficiency differs from classic chronic granulomatous disease

Geer¹,

Nieto-Patlán²,

Kuhns³

et al. 2018

Journal of Clinical Investigation

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108

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Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40 phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40 phox -deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMAinduced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40 phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD. phox -deficient patient is compound heterozygous for a premature stop codon and a missense mutation in the PX domain that compromises binding to PI(3)P, which results in the impairment of neutrophil phagocytosis-induced oxidase activity (26). As in classic CGD neutrophils, intracellular oxidant production after stimulation with serum-opsonized zymosan (SOZ), IgG beads, or serumopsonized Staphylococcus aureus is impaired in the patient's neutrophils, and S. aureus killing is also defective (20,26,30). However, in this patient, unlike in classic CGD patients, the production of O 2 -by neutrophils in response to stimulation with PMA or formyl-methionyl-leucyl-phenylalanine (fMLF) is normal (26). The killing of S. aureus by neutrophils is also impaired in p40 phox deficiency and classic CGD are largely unknown. Here, we describe the characteristics of 24 patients from 12 families in 8 countries with biallelic mutations of NCF4. The Journal of Clinical Investigation R E S E A R C H A R T I C L E

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“…Indeed, when macrophages were activated with BCG, PPD (purified protein derivate from M. tuberculosis ), or IFN-γ and triggered with phorbol ester, the respiratory burst was completely abolished. By contrast to what has been observed for CGD patients, neutrophils monocytes and monocytes-derived dendritic cells (MDCs) from patients with XR2-MSMD had a normal respiratory burst, as shown by measurements of superoxide and hydrogen peroxide production in response to phorbol ester induction and physiological stimuli [22, 302]. The specific impact of these mutations on MDMs and EBV-B is dependent on the levels of gp91 phox protein and flavocytochrome b 558 and correlated with the defect in NADPH oxidase activity [22].…”

Section: X-linked Recessive Cybb Deficiencymentioning

confidence: 99%

Mendelian susceptibility to mycobacterial disease: Genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

Bustamante

Boisson–Dupuis

Abel

et al. 2014

Seminars in Immunology

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609

655

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Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests. MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis, and more rarely to infections with other intramacrophagic bacteria, fungi, or parasites, and even, perhaps, a few viruses. Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, CYBB) genes have been discovered. The high level of allelic heterogeneity has already led to the definition of 18 different disorders. The nine gene products are physiologically related, as all are involved in IFN-γ-dependent immunity. These disorders impair the production of (IL12B, IL12RB1, IRF8, ISG15, NEMO) or the response to (IFNGR1, IFNGR2, STAT1, IRF8, CYBB) IFN-γ. These defects account for only about half the known MSMD cases. Patients with MSMD-causing genetic defects may display other infectious diseases, or even remain asymptomatic. Most of these inborn errors do not show complete clinical penetrance for the case-definition phenotype of MSMD. We review here the genetic, immunological, and clinical features of patients with inborn errors of IFN-γ-dependent immunity.

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Phagocyte nicotinamide adenine dinucleotide phosphate oxidase activity in patients with inherited IFN-γR1 or IFN-γR2 deficiency

Cited by 11 publications

References 9 publications

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood

Inherited and acquired immunodeficiencies underlying tuberculosis in childhood

Inherited p40phox deficiency differs from classic chronic granulomatous disease

Mendelian susceptibility to mycobacterial disease: Genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

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