Topics in Chronic Granulomatous Disease

PEDIATRICS ◽  
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.

Gene Therapy for X-Linked Chronic Granulomatous Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 409-409
Author(s):  
Marion G. Ott ◽  
Stefan Stein ◽  
Ulrike Koehl ◽  
Andrea Schilz ◽  
Klaus Kuhlcke ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Fungal Infections ◽  
Selective Advantage ◽  
Gene Replacement ◽  
Transduction Efficiency ◽  
Granulomatous Disease ◽  
Phagocytic Cells ◽  
Cd34 Cells ◽  
Genes Encoding

Abstract Chronic Granulomatous Disease (CGD) is a primary immunodeficiency in which phagocytic cells of affected patients have impaired antimicrobial activity due to a defect in the production of reactive oxygen species (ROS). CGD is caused by mutations in any one of four genes encoding for the subunits of the NADPH oxidase complex. CGD is an ideal target for a gene replacement therapy, since females carriers of CGD with as low as 5-10% NADPH oxidase activity are healthy. Based on our preclinical work, we initiated a Phase I/II trial in January 2004. Two X-CGD patients, 26 and 25 years old, were recruited based on their long history of recurrent and life-threatening bacterial and fungal infections. G-CSF mobilized CD34+ cells were transduced with a monocistronic gp91phox retroviral vector. The transduction efficiency was 45% for Pat.1 and 40% for Pat. 2. The number of CD34+ cells reinfused was 1.2x10e7 per kg for Pat.1 and 0.9x10e7 per kg for Pat. 2. Before reinfusion, the patients were conditioned with liposomal busulphan given i.v. at a dose of 4 mg/kg at two consecutive days, starting at day -3. The treatment was well tolerated and no adverse effects have been observed. Neutrophil counts declined to less than 100 cells per μl at day 15 post reinfusion in both patients and recovered to more than 500 cells per μl at day 30 for Pat. 1 and day 20 for Pat. 2. A significant fraction of gene marked cells has been detected in peripheral blood of both patients since day +21. Similarly, therapeutically relevant levels of ROS production have been observed. In conclusion, the protocol we have used allows for stable engraftment of gene transduced hematopoietic cells under conditions in which gene corrected cells lack a selective advantage over non-corrected cells.

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

1995 ◽  
Vol 182 (3) ◽  
pp. 751-758 ◽  
Author(s):  
S H Jackson ◽  
J I Gallin ◽  
S M Holland
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Fungal Infections ◽  
Critical Role ◽  
Granulomatous Inflammation ◽  
Mammalian Host ◽  
Granulomatous Disease ◽  
Knock Out ◽  
Phagocyte Nadph Oxidase ◽  
Life Threatening

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.

scholarly journals Altered expression of neutrophil peripheral benzodiazepine receptor in X-linked chronic granulomatous disease

Blood ◽  
1990 ◽  
Vol 76 (1) ◽  
pp. 184-188
Author(s):  
F Zavala ◽  
F Veber ◽  
B Descamps-Latscha
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Host Defense ◽  
Covalent Binding ◽  
Benzodiazepine Receptor ◽  
Mononuclear Phagocytes ◽  
Human Neutrophils ◽  
Granulomatous Disease ◽  
Peripheral Benzodiazepine Receptor ◽  
Cytochrome B558

This study was aimed at determining whether the peripheral benzodiazepine receptor (PBZDR), which is abundantly expressed on mononuclear phagocytes, is involved in host defense mechanisms depending on phagocyte membrane-associated NADPH-oxidase complex. Analysis by reversible and covalent binding of PBZDR expression on human neutrophils shows that it is modulated during NADPH-oxidase activation with phorbol 12-myristate 13-acetate. Based on a series of 17 patients with chronic granulomatous disease (CGD), results show that PBZDR expression is dramatically impaired in X-linked CGD, an inherited disorder due to a mutation on the gene coding for cytochrome b558 NADPH- oxidase component, whereas it is unaffected in autosomal recessive CGD where cytochrome b558 is normally expressed, suggesting a link between PBZDR and cytochrome b558 expressions. PBZDR can be assigned by covalent binding to an 18-Kd membrane protein. These results suggest that the neutrophil PBZDR, which can accommodate the widely prescribed anxiolytic drug Valium (diazepam), is involved in host defense against pathogens, a function that could be affected by neuroimmune interactions.

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

Blood ◽  
2001 ◽  
Vol 98 (10) ◽  
pp. 3097-3105 ◽  
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.

scholarly journals A mutation located at the 5' splice junction sequence of intron 3 in the p67phox gene causes the lack of p67phox mRNA in a patient with chronic granulomatous disease

Blood ◽  
1995 ◽  
Vol 85 (1) ◽  
pp. 242-249 ◽  
Author(s):  
LC Tanugi-Cholley ◽  
JP Issartel ◽  
J Lunardi ◽  
F Freycon ◽  
F Morel ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Splice Junction ◽  
Granulomatous Disease ◽  
Free System ◽  
Junction Sequence ◽  
Functional Defect ◽  
A Cell ◽  
Membrane Bound ◽  
Main Components

Chronic granulomatous disease (CGD) is due to a functional defect of the O2(-)-generating NADPH oxidase of neutrophils. Mutations resulting in CGD have been shown to occur in only four genes, thus identifying the main components of the oxidase complex, namely the two subunits of a membrane-bound cytochrome b and two cytosolic factors of activation of 67 kD (p67phox) and 47 kD (p47phox). The present study deals with the biochemical and genetic analysis of the defect in a patient suffering from a p67phox-deficient form of CGD. The p67phox deficiency was ascertained by immunochemistry and the ability of recombinant p67phox to restore NADPH oxidase activity using a cell-free system of oxidase activation. The cellular extracts from the proband contained no p67phox protein and no p67phox mRNA when assayed by Western and Northern blot analysis. However, reverse transcription of mRNA and subsequent cDNA amplification by polymerase chain reaction using specific p67phox primers showed that trace amounts of a p67phox mRNA deleted for exon 3 were synthesized in the patient immortalized B lymphocytes. Sequence analysis of the genomic DNA showed a T-to-C transition at position +2 of intron 3. This point mutation in the consensus 5′ splice site of the intron 3 was probably responsible for lack of accumulation of mRNA and also for the skipping of exon 3 detected in the few mRNA molecules that escaped cellular degradation.

Genetic Variants of Chronic Granulomatous Disease: Prevalence of Deficiencies of Two Cytosolic Components of the NADPH Oxidase System

1989 ◽  
Vol 321 (10) ◽  
pp. 647-652 ◽  
Author(s):  
Robert A. Clark ◽  
Harry L. Malech ◽  
John Gallin ◽  
Hiroyuki Nunoi ◽  
Bryan D. Volpp ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Genetic Variants ◽  
Disease Prevalence ◽  
Granulomatous Disease ◽  
Oxidase System

scholarly journals p40phox, a third cytosolic component of the activation complex of the NADPH oxidase to contain src homology 3 domains

1993 ◽  
Vol 296 (3) ◽  
pp. 557-561 ◽  
Author(s):  
F B Wientjes ◽  
J J Hsuan ◽  
N F Totty ◽  
A W Segal
Keyword(s):  
Nadph Oxidase ◽  
Sequence Similarity ◽  
Granulomatous Disease ◽  
Phagocytic Cells ◽  
Src Homology 3 ◽  
N Terminus ◽  
Phagocyte Oxidase ◽  
Src Homology ◽  
Membrane Bound ◽  
Flavocytochrome B

The NADPH oxidase generates superoxide in phagocytic cells. It is important for immunity and its deficiency leads to chronic granulomatous disease (CGD). It consists of a membrane-bound flavocytochrome b that lies dormant until activated by the translocation to the plasma membrane of cytosolic proteins, p47phox (phox for phagocyte oxidase), p67phox and p21rac, a small GTP-binding protein. We show here that a novel component, p40phox, forms an activation complex with p47phox and p67phox with which it translocates to the membrane to associate with the flavocytochrome b. cDNA cloning and amino acid analysis revealed that p40phox has an src homology 3 (SH3) domain and a large region of sequence similarity with the N-terminus of p47phox. The primary association of p40phox appears to be with p67phox, and it is present in reduced amounts in patients with CGD lacking p67phox.

scholarly journals Altered expression of neutrophil peripheral benzodiazepine receptor in X-linked chronic granulomatous disease

Blood ◽  
1990 ◽  
Vol 76 (1) ◽  
pp. 184-188 ◽  
Author(s):  
F Zavala ◽  
F Veber ◽  
B Descamps-Latscha
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Host Defense ◽  
Covalent Binding ◽  
Benzodiazepine Receptor ◽  
Mononuclear Phagocytes ◽  
Human Neutrophils ◽  
Granulomatous Disease ◽  
Peripheral Benzodiazepine Receptor ◽  
Cytochrome B558

Abstract This study was aimed at determining whether the peripheral benzodiazepine receptor (PBZDR), which is abundantly expressed on mononuclear phagocytes, is involved in host defense mechanisms depending on phagocyte membrane-associated NADPH-oxidase complex. Analysis by reversible and covalent binding of PBZDR expression on human neutrophils shows that it is modulated during NADPH-oxidase activation with phorbol 12-myristate 13-acetate. Based on a series of 17 patients with chronic granulomatous disease (CGD), results show that PBZDR expression is dramatically impaired in X-linked CGD, an inherited disorder due to a mutation on the gene coding for cytochrome b558 NADPH- oxidase component, whereas it is unaffected in autosomal recessive CGD where cytochrome b558 is normally expressed, suggesting a link between PBZDR and cytochrome b558 expressions. PBZDR can be assigned by covalent binding to an 18-Kd membrane protein. These results suggest that the neutrophil PBZDR, which can accommodate the widely prescribed anxiolytic drug Valium (diazepam), is involved in host defense against pathogens, a function that could be affected by neuroimmune interactions.

scholarly journals Pulmonary manifestations in adult patients with chronic granulomatous disease

2015 ◽  
Vol 45 (6) ◽  
pp. 1613-1623 ◽  
Author(s):  
Hélène Salvator ◽  
Nizar Mahlaoui ◽  
Emilie Catherinot ◽  
Elisabeth Rivaud ◽  
Benoit Pilmis ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Fungal Infections ◽  
Medical Data ◽  
Adult Patients ◽  
Granulomatous Disease ◽  
Phagocytic Cells ◽  
Infectious Risk ◽  
Respiratory Events ◽  
Pulmonary Manifestations ◽  
National Cohort

Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by failure of superoxide production in phagocytic cells. The disease is characterised by recurrent infections and inflammatory events, frequently affecting the lungs. Improvement of life expectancy now allows most patients to reach adulthood. We aimed to describe the pattern of pulmonary manifestations occurring during adulthood in CGD patients.This was a retrospective study of the French national cohort of adult patients (≥16 years old) with CGD.Medical data were obtained for 67 adult patients. Pulmonary manifestations affected two-thirds of adult patients. Their incidence was significantly higher than in childhood (mean annual rate 0.22 versus 0.07, p=0.01). Infectious risk persisted despite anti-infectious prophylaxis. Invasive fungal infections were frequent (0.11 per year per patient) and asymptomatic in 37% of the cases. They often required lung biopsy for diagnosis (10 out of 30). Noninfectious respiratory events concerned 28% of adult patients, frequently associated with a concomitant fungal infection (40%). They were more frequent in patients with the X-linked form of CGD. Immune-modulator therapies were required in most cases (70%).Respiratory manifestations are major complications of CGD in adulthood. Noninfectious pulmonary manifestations are as deleterious as infectious pneumonia. A specific respiratory monitoring is necessary.

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