The p47phox mouse knock-out model of chronic granulomatous disease.

Chronic granulomatous disease (CGD) is caused by a congenital defect in phagocyte reduced nicotinamide dinucleotide phosphate (NADPH) oxidase production of superoxide and related species. It is characterized by recurrent life-threatening bacterial and fungal infections and tissue granuloma formation. We have created a mouse model of CGD by targeted disruption of p47phox, one of the genes in which mutations cause human CGD. Identical to the case in human CGD, leukocytes from p47phox-/- mice produced no superoxide and killed staphylococci ineffectively. p47phox-/- mice developed lethal infections and granulomatous inflammation similar to those encountered in human CGD patients. This model mirrors human CGD and confirms a critical role for the phagocyte NADPH oxidase in mammalian host defense.

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Reconstitution of bactericidal activity in chronic granulomatous disease cells by glucose-oxidase–containing liposomes

Blood ◽

10.1182/blood.v98.10.3097 ◽

2001 ◽

Vol 98 (10) ◽

pp. 3097-3105 ◽

Cited By ~ 19

Author(s):

Claudia E. Gerber ◽

Gernot Bruchelt ◽

Ulrike B. Falk ◽

Andrea Kimpfler ◽

Oliver Hauschild ◽

...

Keyword(s):

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Glucose Oxidase ◽

Whole Blood ◽

Fungal Infections ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Confocal Laser ◽

Granulomatous Disease ◽

Life Threatening

Abstract Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency characterized by phagocytes devoid of a functioning nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The failure of CGD phagocytes to produce reactive oxygen species (ROS) results in a marked increase in the susceptibility of affected patients to life-threatening bacterial and fungal infections. This study investigated whether loading of CGD phagocytes with glucose oxidase (GO)–containing liposomes (GOLs) could restore cellular production of bactericidal ROS (eg, H2O2 and HOCl) in vitro. Results indicate that GO encapsulated in liposomes enabled NADPH oxidase-deficient phagocytes to use H2O2 for the production of highly bactericidal HOCl. The intracellular colocalization of bacteria and liposomes (or liposome-derived ferritin) was demonstrated by confocal laser microscopy and electron microscopy. After uptake of GOLs (approximately 0.2 U/mL at 1 mM total lipid concentration, size approximately 180 nm), CGD granulocytes produced HOCl levels comparable to those of normal phagocytes. Remarkably, after treatment with GOLs, CGD phagocytes killed Staphylococcus aureus as efficiently as normal granulocytes. Moreover, treated cells retained sufficient motility toward chemotactic stimuli as measured by chemotaxis assay. Side effects were evaluated by measuring the H2O2 concentrations and the production of methemoglobin in whole blood. These studies revealed that H2O2 produced by GOLs was degraded immediately by the antioxidative capacity of whole blood. Elevated methemoglobin levels were observed only after application of extremely high amounts of GOLs (2 U/mL). In summary, the application of negatively charged GOLs might provide a novel effective approach in the treatment of patients with CGD at high risk for life-threatening infections.

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Staphylococcus aureus, phagocyte NADPH oxidase and chronic granulomatous disease

FEMS Microbiology Reviews ◽

10.1093/femsre/fuw042 ◽

2016 ◽

pp. fuw042 ◽

Cited By ~ 17

Author(s):

Helene Buvelot ◽

Klara M. Posfay-Barbe ◽

Patrick Linder ◽

Jacques Schrenzel ◽

Karl-Heinz Krause

Keyword(s):

Staphylococcus Aureus ◽

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Granulomatous Disease ◽

Phagocyte Nadph Oxidase

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Topics in Chronic Granulomatous Disease

PEDIATRICS ◽

10.1542/peds.88.1.183 ◽

1991 ◽

Vol 88 (1) ◽

pp. 183-185

Author(s):

SHIGENOBU UMEKI

Keyword(s):

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Host Defense ◽

Superoxide Anion ◽

Fungal Infections ◽

Regulatory Elements ◽

Granulomatous Disease ◽

Phagocytic Cells ◽

Oxidase System ◽

Membrane Bound

To the Editor.— Such phagocytic cells as neutrophils and macrophages are crucial elements in the host defense against bacterial [See table in the PDF file] and fungal infections. Microbicidal activity depends to a large extent on NADPH oxidase system, which can be activated by stimuli (bacteria, fungi) and which generates the superoxide anion and other highly reactive forms of reduced oxygen.1,2 The neutrophil NADPH oxidase system is composed functionally of membrane-bound catalytic components (which consist of at least two constituents, the low potential cytochrome b5583-5 and flavoprotein5) and soluble cytosolic components6,7 which participate as either catalytic or regulatory elements.

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Unusual late presentation of X-linked chronic granulomatous disease in an adult female with a somatic mosaic for a novel mutation in CYBB

Blood ◽

10.1182/blood-2004-02-0675 ◽

2005 ◽

Vol 105 (1) ◽

pp. 61-66 ◽

Cited By ~ 58

Author(s):

Baruch Wolach ◽

Yitshak Scharf ◽

Ronit Gavrieli ◽

Martin de Boer ◽

Dirk Roos

Keyword(s):

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

X Chromosome ◽

Clinical Symptoms ◽

Novel Mutation ◽

Late Presentation ◽

Granulomatous Disease ◽

Phagocyte Nadph Oxidase ◽

Mucosal Cells ◽

General Defect

Abstract Most patients with chronic granulomatous disease (CGD) have mutations in the X-linked CYBB gene that encodes gp91phox, a component of the phagocyte NADPH oxidase. The resulting X-linked form of CGD is usually manifested in boys. Rarely, X-CGD is encountered in female carriers with extreme expression of the mutated gene. Here, we report on a woman with a novel mutation in CYBB (CCG[90-92] → GGT), predicting Tyr30Arg31 → stop, Val in gp91phox, who presented with clinical symptoms at the age of 66. The mutation was present in heterozygous form in genomic DNA from her leukocytes but was fully expressed in mRNA from these cells, indicating that in her leukocytes the X chromosome carrying the nonmutated CYBB allele had been inactivated. Indeed, only 0.4% to 2% of her neutrophils showed NADPH oxidase activity. This extreme skewing of her X-chromosome inactivation was not found in her cheek mucosal cells and is thus not due to a general defect in gene methylation on one X chromosome. Moreover, the CYBB mutation was not present in the DNA from her cheek cells and was barely detectable in the DNA from her memory T lymphocytes. Thus, this patient shows a somatic mosaic for the CYBB mutation, which probably originated during her lifetime in her bone marrow.

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An Uncommon Feature of Chronic Granulomatous Disease in a Neonate

Case Reports in Infectious Diseases ◽

10.1155/2016/5943783 ◽

2016 ◽

Vol 2016 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Razieh Afrough ◽

Sayyed Shahabeddin Mohseni ◽

Setareh Sagheb

Keyword(s):

Mortality Rate ◽

Chronic Granulomatous Disease ◽

High Mortality ◽

Neonatal Period ◽

Fungal Infections ◽

Granuloma Formation ◽

Granulomatous Disease ◽

Life Threatening

Chronic Granulomatous Disease (CGD) represents recurrent life-threatening bacterial and fungal infections and granuloma formation with a high mortality rate. CGD’s sign and symptoms usually appear in infancy and children before the age of five; therefore, its presentation in neonatal period with some uncommon features may be easily overlooked. Here we describe a case of CGD in a 24-day-old boy, presenting with a diffuse purulent vesiculopustular rash and multiple osteomyelitis.

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Case Report: Secondary Hemophagocytic Lymphohistiocytosis With Disseminated Infection in Chronic Granulomatous Disease—A Serious Cause of Mortality

Frontiers in Immunology ◽

10.3389/fimmu.2020.581475 ◽

2020 ◽

Vol 11 ◽

Author(s):

Jacqueline D. Squire ◽

Stephanie N. Vazquez ◽

Angela Chan ◽

Michele E. Smith ◽

Deepak Chellapandian ◽

...

Keyword(s):

Immune Deficiency ◽

Chronic Granulomatous Disease ◽

Hemophagocytic Lymphohistiocytosis ◽

Fungal Infections ◽

Primary Immune Deficiency ◽

Granulomatous Disease ◽

Simultaneous Treatment ◽

Hematopoietic Stem ◽

Increased Risk ◽

Life Threatening

Chronic granulomatous disease (CGD) is a primary immune deficiency due to defects in phagocyte respiratory burst leading to severe and life-threatening infections. Patients with CGD also suffer from disorders of inflammation and immune dysregulation including colitis and granulomatous lung disease, among others. Additionally, patients with CGD may be at increased risk of systemic inflammatory disorders such as hemophagocytic lymphohistiocytosis (HLH). The presentation of HLH often overlaps with symptoms of systemic inflammatory response syndrome (SIRS) or sepsis and therefore can be difficult to identify, especially in patients with a primary immune deficiency in which incidence of infection is increased. Thorough evaluation and empiric treatment for bacterial and fungal infections is necessary as HLH in CGD is almost always secondary to infection. Simultaneous treatment of infection with anti-microbials and inflammation with immunosuppression may be needed to blunt the hyperinflammatory response in secondary HLH. Herein, we present a series of X-linked CGD patients who developed HLH secondary to or with concurrent disseminated CGD-related infection. In two patients, CGD was a known diagnosis prior to development of HLH and in the other two CGD was diagnosed as part of the evaluation for HLH. Concurrent infection and HLH were fatal in three; one case was successfully treated, ultimately receiving hematopoietic stem cell transplantation. The current literature on presentation, diagnosis, and treatment of HLH in CGD is reviewed.

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Retroviral Gene Therapy for X-Linked Chronic Granulomatous Disease: Results from Phase I/II Trial.

Blood ◽

10.1182/blood.v112.11.2349.2349 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2349-2349 ◽

Cited By ~ 2

Author(s):

Joong Gon Kim ◽

Hyo Seop Ahn ◽

Hyoung Jin Kang ◽

Sujeong Kim ◽

Youngtae Hong ◽

...

Keyword(s):

Gene Therapy ◽

Nadph Oxidase ◽

Phase I ◽

Chronic Granulomatous Disease ◽

Viral Vectors ◽

Conditioning Regimen ◽

Transduction Efficiency ◽

Granulomatous Disease ◽

Gene Therapy Trial ◽

Life Threatening

Abstract X-linked chronic granulomatous disease (X-CGD) is an inherited immunodeficiency disease caused by a defect in the gp91phox gene encoding one of the subunits of the NADPH oxidase complex. NADPH oxidase plays an important role in eradicating the pathogen engulfed by the phagocytes. Therefore, CGD patients suffer from recurring life-threatening infection by bacteria or fungi, and die before 30 in most cases. In an effort to treat this life-threatening disease, we initiated a phase I/II gene therapy trial in 2007. Two X-CGD patients were enrolled in the trial. The retroviral vector used for gene delivery was the MLV-based MT vector containing gp91 phox cDNA (Yu et al., Gene Ther2000; 7: 797, Hong et al., J Gene Med2004; 6: 724). Viral vectors have been produced from PG13 packaging cells in compliance with GMP. The clinical protocol was approved by the Korean FDA. G-CSF mobilized peripheral blood CD34+ cells were obtained from patients, and transduced in retronectin-coated gas-permeable bags containing SCGM media supplemented with SCF, FLT3L, TPO, and IL-3. The transduction efficiency was 10.5% for patient #1 and 28.5% for patient #2 when assessed by gp91 FACS analysis. Before receiving transduced cells, patients were treated with a conditioning regimen consisting of busulfan (3.2 mg/kg/day for 2 days) and fludarabine (40 mg/m2/day for 3 days). No adverse effects were observed from the use of busulfan and fludarabine. The percentage of superoxide-producing cells, as determined by DHR assay, was 6.4% and 14.5% at day 17, and decreased to less than 0.1% (after 1 year) and 0.4% (after 7 months). Thus far, abnormal cell expansion has not been observed.

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Histopathological features of patients with chronic granulomatous disease

LymphoSign Journal ◽

10.14785/lymphosign-2019-0009 ◽

2019 ◽

Vol 6 (3) ◽

pp. 107-112

Author(s):

Paria Kashani ◽

Haiying Chen

Keyword(s):

Nadph Oxidase ◽

Chronic Granulomatous Disease ◽

Primary Immunodeficiency ◽

Tissue Injury ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Granulomatous Inflammation ◽

Severe Infection ◽

Granulomatous Disease ◽

Histopathological Features ◽

Paediatric Cohort

Introduction: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Affected patients suffer recurrent life-threatening infections due to phagocyte dysfunction and dysregulation of the immune system. Histopathological assessment is important to help identify the extent and severity of infection and tissue injury. Aim: We present pathological findings in 5 patients with CGD who were followed at our centre. Methods: Patient information was reviewed retrospectively in accordance with local institutional guidelines. All patients had confirmed diagnosis of CGD with mutation in one of the 5 subunits of the NADPH oxidase. Results: Histopathological features of the gastrointestinal tract, liver, and spleen are noted, and include the presence of granulomatous inflammation and pigmented macrophages. Discussion: It is essential for clinicians to keep primary immunodeficiency as one of the differential diagnoses in patients with severe infection or inflammation, whether in the absence or presence of granuloma formation. The detection of PAS-positive macrophages, diffuse granulomatous inflammation, and hepatic abscesses should raise strong suspicion of CGD. Statement of novelty: We describe the histopathological findings of a paediatric cohort of patients with CGD.

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