The enzymatic basis for production by human neutrophils

1982 ◽  
Vol 60 (11) ◽  
pp. 1353-1358 ◽  
Author(s):  
Bernard M. Babior
Keyword(s):  
Electron Transfer ◽  
Chronic Granulomatous Disease ◽  
Human Neutrophils ◽  
Granulomatous Disease ◽  
Direct Route ◽  
Text Production ◽  
Membrane Bound ◽  
New Form

[Formula: see text] production is the first step in the generation of a group of powerful microbicidal oxidants by neutrophils. The production of [Formula: see text] is catalyzed by a membrane-bound, NADPH-preferring flavoprotein oxidase, a conclusion supported by much evidence including the discovery of a new form of chronic granulomatous disease caused by a mutation affecting that oxidase directly. Also involved in the [Formula: see text]-forming reaction is a b-type cytochrome; the role of this cytochrome is as yet undefined, though it does not appear to be on the direct route of electron transfer between NADPH and oxygen. It has been postulated that quinones too participate in the [Formula: see text]-forming reaction, but further work is necessary to define their role more fully.

scholarly journals Estrogen binding by leukocytes during phagocytosis,.

1977 ◽  
Vol 145 (4) ◽  
pp. 983-998 ◽  
Author(s):  
S J Klebanoff
Keyword(s):  
Chronic Granulomatous Disease ◽  
Reaction Mechanisms ◽  
Dehydrogenase Deficiency ◽  
Cell Types ◽  
Neutrophil Function ◽  
Granulomatous Disease ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Estrogen Binding ◽  
Two Populations

Estradiol binds covalently to normal leukocytes during phagocytosis. The binding involves three cell types, neutrophils, eosinophils, and monocytes and at least two reaction mechanisms, one involving the peroxidase of neutrophils and monocytes (myeloperoxidase [MPO]) and possibly the eosinophil peroxidase, and the second involving catalase. Binding is markedly reduced when leukocytes from patients with chronic granulomatous disease (CGD), severe leukocytic glucose 6-phosphate dehydrogenase deficiency, and familial lipochrome histiocytosis are employed and two populations of neutrophils, one which binds estradiol and one which does not, can be demonstrated in the blood of a CGD carrier. Leukocytes from patients with hereditary MPO deficiency also bind estradiol poorly although the defect is not as severe as in CGD. These findings are discussed in relation to the inactivation of estrogens during infection and the possible role of estrogens in neutrophil function.

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.

Role of oxygen intermediates in cytotoxicity: Studies in chronic granulomatous disease

Inflammation ◽  
1993 ◽  
Vol 17 (1) ◽  
pp. 77-92 ◽  
Author(s):  
Robert L. Roberts ◽  
Bonnie J. Ank ◽  
Michael W. Fanger ◽  
Li Shen ◽  
E. Richard Stiehm
Keyword(s):  
Chronic Granulomatous Disease ◽  
Granulomatous Disease ◽  
Oxygen Intermediates ◽  
Cytotoxicity Studies

scholarly journals Cytosolic free calcium changes induced by chemotactic peptide in neutrophils from patients with chronic granulomatous disease

Blood ◽  
1984 ◽  
Vol 63 (1) ◽  
pp. 231-233 ◽  
Author(s):  
PD Lew ◽  
C Wollheim ◽  
RA Seger ◽  
T Pozzan
Keyword(s):  
Chronic Granulomatous Disease ◽  
Calcium Concentration ◽  
Cytosolic Calcium ◽  
Human Neutrophils ◽  
Free Calcium ◽  
Granulomatous Disease ◽  
Chemotactic Peptide ◽  
Intact Cells ◽  
Calcium Indicator ◽  
Free Calcium Concentration

Abstract Cytoplasmic free calcium concentration (Ca2+)i was measured in neutrophils from patients with the classical X-linked form of chronic granulomatous disease (CGD) by trapping the fluorescent calcium indicator Quin 2 in intact cells. CGD neutrophils do not produce superoxide and are only slightly depolarized upon stimulation by the chemotactic peptide. N-formyl-methionyl-leucyl-phenylalanine (FMLP). The resting levels, as well as (Ca2+)i changes induced by FMLP in CGD cells, were quantitatively and kinetically similar to those observed in normal cells. We conclude that the defect in CGD cells is distal to, or independent of, the changes in (Ca2+)i induced by FMLP stimulation and that normal membrane depolarization does not seem to be necessary for receptor-mediated rise in free cytosolic calcium in human neutrophils.

Further evaluation of luminol-enhanced luminescence in the diagnosis of disorders of leukocyte oxidative metabolism: role of myeloperoxidase.

1983 ◽  
Vol 29 (3) ◽  
pp. 513-515 ◽  
Author(s):  
M S Cohen ◽  
P S Shirley ◽  
L R DeChatelet
Keyword(s):  
Chronic Granulomatous Disease ◽  
Oxidative Metabolism ◽  
Clinical Consequence ◽  
Granulomatous Disease ◽  
Myeloperoxidase Deficiency ◽  
Luminescence Assay ◽  
Diagnostic Confusion ◽  
Enhanced Luminescence ◽  
Hereditary Nature

Abstract Chemiluminescence can be used to identify defects in the oxidative metabolism of granulocytes. This procedure has recently been adopted for use with microliter quantities of whole blood, appropriate for prenatal or neonatal study. Although the contribution of myeloperoxidase to the chemiluminescence assay has been noted, the possible diagnostic confusion between chronic granulomatous disease of childhood (which is rare and severe) and myeloperoxidase deficiency (which is common and of little clinical consequence) has not been stressed. We report a father and his infant daughter whose cells emitted no light in the luminol-enhanced luminescence assay; both patients are totally peroxidase deficient. These results emphasize the hereditary nature of myeloperoxidase deficiency, and the possibility for erroneous diagnosis of chronic granulomatous disease of childhood based on the luminol-enhanced luminescence test.

scholarly journals NADPH-binding component of the respiratory burst oxidase system: studies using neutrophil membranes from patients with chronic granulomatous disease lacking the beta-subunit of cytochrome b558.

1994 ◽  
Vol 179 (1) ◽  
pp. 291-297 ◽  
Author(s):  
S Tsunawaki ◽  
H Mizunari ◽  
H Namiki ◽  
T Kuratsuji
Keyword(s):  
Chronic Granulomatous Disease ◽  
Respiratory Burst ◽  
Beta Subunit ◽  
Human Neutrophils ◽  
Granulomatous Disease ◽  
Oxidase System ◽  
Cytochrome B558 ◽  
Respiratory Burst Oxidase ◽  
Stimulation Of ◽  
Binding Component

The NADPH-binding site of the respiratory burst oxidase system of neutrophils has been proposed to be either at a cytosolic component or at the beta-subunit of cytochrome b558. In this study, affinity labeling of resting and stimulated membranes, the latter having been assembled by all of the oxidase components from both membrane and cytosol, was carried out using [32P]NADPH dialdehyde (oNADPH). Stimulation of human neutrophils with PMA greatly increased O2(-)-generating activity and caused considerable translocation of the cytosolic components p47phox and p67phox. Nevertheless, PMA stimulation did not produce a labeled band which included positions at 47, 67, and approximately 32 kD. The most intense band reflected a molecular mass of 84 kD regardless of the state of activation, but a labeled band was never found near the beta-subunit (91 kD) of cytochrome b558. This 84-kD protein was further confirmed in neutrophils of 14 patients with gp91phox-deficient X-linked chronic granulomatous disease. These results indicate that the NADPH-binding component is not recruited from the cytosol, and also, that a membranous redox component besides cytochrome b558 must be involved in the NADPH oxidase system.

scholarly journals A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity

Blood ◽  
2009 ◽  
Vol 114 (15) ◽  
pp. 3309-3315 ◽  
Author(s):  
Juan D. Matute ◽  
Andres A. Arias ◽  
Nicola A. M. Wright ◽  
Iwona Wrobel ◽  
Christopher C. M. Waterhouse ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Chronic Granulomatous Disease ◽  
Oxidase Activity ◽  
Autosomal Recessive ◽  
Premature Stop Codon ◽  
Superoxide Production ◽  
Human Neutrophils ◽  
Granulomatous Disease ◽  
Recessive Mutations ◽  
Px Domain

Abstract Chronic granulomatous disease (CGD), an immunodeficiency with recurrent pyogenic infections and granulomatous inflammation, results from loss of phagocyte superoxide production by recessive mutations in any 1 of 4 genes encoding subunits of the phagocyte NADPH oxidase. These include gp91phox and p22phox, which form the membrane-integrated flavocytochrome b, and cytosolic subunits p47phox and p67phox. A fifth subunit, p40phox, plays an important role in phagocytosis-induced superoxide production via a phox homology (PX) domain that binds to phosphatidylinositol 3-phosphate (PtdIns(3)P). We report the first case of autosomal recessive mutations in NCF4, the gene encoding p40phox, in a boy who presented with granulomatous colitis. His neutrophils showed a substantial defect in intracellular superoxide production during phagocytosis, whereas extracellular release of superoxide elicited by phorbol ester or formyl-methionyl-leucyl-phenylalanine (fMLF) was unaffected. Genetic analysis of NCF4 showed compound heterozygosity for a frameshift mutation with premature stop codon and a missense mutation predicting a R105Q substitution in the PX domain. Parents and a sibling were healthy heterozygous carriers. p40phoxR105Q lacked binding to PtdIns(3)P and failed to reconstitute phagocytosis-induced oxidase activity in p40phox-deficient granulocytes, with premature loss of p40phoxR105Q from phagosomes. Thus, p40phox binding to PtdIns(3)P is essential for phagocytosis-induced oxidant production in human neutrophils and its absence can be associated with disease.

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.

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