The molecular and cellular pathology of Chronic Granulomatous Disease

Segal, Anthony W.

doi:10.1111/j.1365-2362.1988.tb01037.x

Cited by 38 publications

(26 citation statements)

References 83 publications

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“…Cytosolic components include proteins of 47 and 67 kD, both of which are recognized by a polyclonal polyspecific antiserum (B-1) prepared against partially purified PMN cytosol (23). Cytochrome b558 is generally absent from patients with classical X-linked CGD, whereas either p47 or p67 is missing from CGD patients with autosomal inheritance, normal cytochrome b558, and a cytosolic defect in the cell-free oxidase system (6,7,9,(20)(21)(22)(23)(24)(25)(26)(27).…”

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confidence: 99%

“…The membrane fractions from stimulated but not control PMN exhibited NADPH-dependent superoxide formation as previously described (1,(4)(5)(6)(7)(8) Densitometry indicated relative intensities (compared with the response to PMA 100 ng/ml set at 100%) for DMSO and the three increasing concentrations of PMA as follows: p47-7, 0, 100, and 21, respectively; p67-0, 0, 100, and 91, respectively. In parallel assays of the rate of superoxide formation 3 min after stimulation, relative rates (compared with the response to PMA 100 ng/ml set at 100%) for DMSO and the three increasing concentrations of PMA were 0, 0, 100, and 89, respectively.…”

Section: Legend)mentioning

confidence: 99%

“…The critical microbicidal role of the neutrophil respiratory burst is clearly illustrated by the severe problems with recurrent infections observed in patients with CGD (1-3, 6). The enzymatic system responsible for the burst has been characterized as a multicomponent oxidase that transports electrons from NADPH to oxygen (1)(2)(3)(4)(5)(6)(7)(8). The dormant oxidase in resting PMN is activated during phagocytosis or on exposure to various soluble mediators.…”

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confidence: 99%

“…The dormant oxidase in resting PMN is activated during phagocytosis or on exposure to various soluble mediators. Classically, the oxidase has been considered to be a membrane-bound enzyme system based on its segregation with membrane fractions of activated neutrophils (1,(4)(5)(6)(7)(8). However, an activatable cell-free oxidase system composed of subcellular organelles from resting cells has permitted a clear demonstration of roles for cytosolic as well as membrane components (10)(11)(12)(13)(14)(15).…”

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confidence: 99%

“…The oxidative burst is mediated by an activatable nicotinamide~adeniae dinucleotide phosphate (NADPH) oxidase present in normal PMN but nonfunctional in cells of patients 'with the inherited disorder chronic granulomatous disease (CGD)' (1)(2)(3)(4)(5)(6)(7)(8)(9). The NADPH oxidase system is composed of several discrete components, some residing in the membrane and'others in the cytosol (2,(8)(9)(10)(11)(12)(13)(14)(15).…”

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Two cytosolic components of the human neutrophil respiratory burst oxidase translocate to the plasma membrane during cell activation.

Clark¹,

Volpp²,

Leidal³

et al. 1990

J. Clin. Invest.

412

214

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The superoxide-forming respiratory burst oxidase of human neutrophils is composed of membrane-associated catalytic components and cytosolic constituents required for oxidase activation. This study concerns the hypothesis that cytosolic oxidase components translocate to a membrane fraction when neutrophils are stimulated and the oxidase is activated.A polyclonal antiserum that recognizes two discrete cytosolic oxidase components of 47 and 67 kD was used to probe transfer blots of electrophoresed membrane and cytosol fractions of resting and stimulated neutrophils. In contrast to their strictly cytosolic localization in unstimulated cells, both proteins were detected in membrane fractions of neutrophils activated by phorbol esters and other stimuli. This translocation event was a function of stimulus concentration as well as time and'temperature of exposure to the stimulus. It was inhibited by concentrations of N-ethylmaleimide that blocked superoxide formation but was unaffected by 2-deoxyglucose. There was a correlation between translocation of the cytosolic proteins and activation of the oxidase as determined by superoxide formation. Quantitative analyses suggested that 10% of total cellular p47 and p67 became membrane-associated during phorbol ester activation of the oxidase. Analysis of Percoll density gradient fractions indicated that the target membrane for translocation of both proteins was the plasua 'membrane rather than membranes of either specific or azurophilic granules. In the cell-free oxidase system arachidonate-dependent but membrane-independent precipitation of the cytosolic oxidase proteins was demonstrated. The data show that activation of the respiratory burst oxidase in stimulated human neutrophils is closely associated with translocation of the 47-and 67-kD cytosolic oxidase components to the plasma membrane. We suggest that this translocation event is important in oxidase activation. (J.

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confidence: 99%

Section: Legend)mentioning

confidence: 99%

Section: Legend)mentioning

confidence: 99%

Section: Legend)mentioning

confidence: 99%

mentioning

confidence: 99%

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Two cytosolic components of the human neutrophil respiratory burst oxidase translocate to the plasma membrane during cell activation.

Clark¹,

Volpp²,

Leidal³

et al. 1990

J. Clin. Invest.

412

214

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Phorbol myristate acetate-induced NADPH oxidase activity in human neutrophils: only half the story has been told

Lundqvist

Follin

Khalfan

et al. 1996

Journal of Leukocyte Biology

122

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The paradigm for activation of the neutrophil NADPH oxidase with the protein kinase C activator phorbol myristate acetate (PMA) states that the oxidase assembles the plasma membrane and that the metabolites generated are released extracellularly. This paradigm is challenged by the results presented. Most of the PMA-induced oxidase activity measured as chemiluminescence and dichlorofluorescein fluorescence was insensitive to scavengers of superoxide anion and hydrogen peroxide. This indicates that oxidase activity also takes place in a cellular compartment that the scavengers cannot reach. From the results obtained with granule-deficient HL-60 cells and cord blood neutrophils, we suggest that the scavenger-insensitive part of the NADPH oxidase activity in normal neutrophils resides in an intracellular compartment identical to or originating from granules. Our results also indicate that specific and azurophil granules have to be in very close contact to allow the generated oxygen metabolites to reach and react with myeloperoxidase.

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