Dataset Information

Inherited p40phox deficiency differs from classic chronic granulomatous disease.

ABSTRACT: Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-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 PMA-induced 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 p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.

SUBMITTER: van de Geer A

PROVIDER: S-EPMC6118590 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Inherited p40phox deficiency differs from classic chronic granulomatous disease.

van de Geer Annemarie A Nieto-Patlán Alejandro A Kuhns Douglas B DB Tool Anton Tj AT Arias Andrés A AA Bouaziz Matthieu M de Boer Martin M Franco José Luis JL Gazendam Roel P RP van Hamme John L JL van Houdt Michel M van Leeuwen Karin K Verkuijlen Paul Jh PJ van den Berg Timo K TK Alzate Juan F JF Arango-Franco Carlos A CA Batura Vritika V Bernasconi Andrea R AR Boardman Barbara B Booth Claire C Burns Siobhan O SO Cabarcas Felipe F Bensussan Nadine Cerf NC Charbit-Henrion Fabienne F Corveleyn Anniek A Deswarte Caroline C Azcoiti María Esnaola ME Foell Dirk D Gallin John I JI Garcés Carlos C Guedes Margarida M Hinze Claas H CH Holland Steven M SM Hughes Stephen M SM Ibañez Patricio P Malech Harry L HL Meyts Isabelle I Moncada-Velez Marcela M Moriya Kunihiko K Neves Esmeralda E Oleastro Matias M Perez Laura L Rattina Vimel V Oleaga-Quintas Carmen C Warner Neil N Muise Aleixo M AM López Jeanet Serafín JS Trindade Eunice E Vasconcelos Julia J Vermeire Séverine S Wittkowski Helmut H Worth Austen A Abel Laurent L Dinauer Mary C MC Arkwright Peter D PD Roos Dirk D Casanova Jean-Laurent JL Kuijpers Taco W TW Bustamante Jacinta J

The Journal of clinical investigation 20180806 9

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-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 muta ...[more]

PMID: 29969437

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Project description:This study will determine if the drug infliximab is safe for treating inflammatory bowel disease (IBD) in patients with chronic granulomatous disease (CGD). IBD is an inflammation or irritation of the gut that leads to symptoms such as diarrhea, bloating and stomach cramps. CGD is an inherited disease affecting white blood cells called neutrophils in which patients are susceptible to repeated bacterial and fungal infections. They also have a higher incidence of some autoimmune diseases, such as IBD. Infliximab is approved to treat Crohn’s disease, an IBD similar to that seen in patients with CGD. Patients 10 years of age and older with CGD and IBD may be eligible for this study. Candidates are screened with a medical history, physical examination, blood and urine tests, electrocardiogram (EKG), tuberculosis skin test (PPD skin testing), and stool test for the presence of infections. Additional tests may be done, including colonoscopy (procedure using a flexible tube through the rectum to examine the lining of the gut) and imaging studies such as an x-ray, chest CT scan (test using a special x-ray machine), MRI (test using a magnetic field and radio waves), and barium studies (study using a drinkable solution of barium to help enhance the x-ray pictures of the gut). Participants are divided into patients with IBD symptoms (Group 1) and patients without IBD symptoms (Group 2) for the following procedures: Group 1 Patients are evaluated every 6 months with a medical history and physical examination for signs and symptoms of IBD. Patients who are taking moderate to high doses of steroid medications have their medication slowly lowered (tapered) and are evaluated every 3 months for a total of 2 years. Patients in this group who start to develop IBD symptoms are moved to Group 2 for treatment with infliximab (see below). Group 2 Patients in Group 2 receive infliximab infusions at 2-week intervals for three doses. The drug is given over a 2-hour period through a catheter placed in a vein. Patients are evaluated with a medical history, physical exam, and blood tests the day of each dose. One week after the last dose, they have another evaluation, including a colonoscopy. Patients who respond well to infliximab may continue to receive the drug every 2 months for a total of 1 year, with evaluations at every dosing visit. At the end of the first year of receiving infliximab, all patients have follow-up evaluations every 6 months for a total of 2 years. Group 3 Subjects who volunteer to undergo colonoscopy and research biopsies that serve as controls for evaluation of the patient gut samples.

Project description:BackgroundPatients with chronic granulomatous disease (CGD) experience immunodeficiency because of defects in the phagocyte NADPH oxidase and the concomitant reduction in reactive oxygen intermediates. This may result in a reduction in atherosclerotic injury.Methods and resultsWe prospectively assessed the prevalence of cardiovascular risk factors, biomarkers of inflammation and neutrophil activation, and the presence of magnetic resonance imaging and computed tomography quantified subclinical atherosclerosis in the carotid and coronary arteries of 41 patients with CGD and 25 healthy controls in the same age range. Univariable and multivariable associations among risk factors, inflammatory markers, and atherosclerosis burden were assessed. Patients with CGD had significant elevations in traditional risk factors and inflammatory markers compared with control subjects, including hypertension, high-sensitivity C-reactive protein, oxidized low-density lipoprotein, and low high-density lipoprotein. Despite this, patients with CGD had a 22% lower internal carotid artery wall volume compared with control subjects (361.3±76.4 mm(3) versus 463.5±104.7 mm(3); P<0.001). This difference was comparable in p47(phox)- and gp91(phox)-deficient subtypes of CGD and independent of risk factors in multivariate regression analysis. In contrast, the prevalence of coronary arterial calcification was similar between patients with CGD and control subjects (14.6%, CGD; 6.3%, controls; P=0.39).ConclusionsThe observation by magnetic resonance imaging and computerized tomography of reduced carotid but not coronary artery atherosclerosis in patients with CGD despite the high prevalence of traditional risk factors raises questions about the role of NADPH oxidase in the pathogenesis of clinically significant atherosclerosis. Additional high-resolution studies in multiple vascular beds are required to address the therapeutic potential of NADPH oxidase inhibition in cardiovascular diseases.Clinical trial registration urlhttp://www.clinicaltrials.gov. Unique identifier: NCT01063309.

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Inherited p40phox deficiency differs from classic chronic granulomatous disease.

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Inherited p40phox deficiency differs from classic chronic granulomatous disease.

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