A study of 25 patients with chronic granulomatous disease: A new classification by correlating respiratory burst, cytochrome b, and flavoprotein (original) (raw)
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Blood, 1983
A patient with an X-linked genetic disease resembling chronic granulomatous disease (CGD) but differing in several aspects from previously studied cases is described. The oxidase enzyme of the patient's granulocytes was normally activated, but had reduced activity as shown by an increased Michaelis constant and decreased maximum velocity of NADPH-dependent superoxide production. Cytochrome-b was undetectable in dithionite difference spectra. This CGD-like disease further implicates cytochrome-b as an important component of the microbicidal NADPH oxidase system and provides insight into its role in the enzyme complex.
The Journal of Infectious Diseases, 2003
Chronic granulomatous disease (CGD) is a rare congenital syndrome that results in severe, recurrent bacterial and fungal infections. The most common form is caused by defects in the CYBB gene, leading to the absence of gp91phox associated with totally abolished NADPH oxidase activity (X91 0 CGD). We report 3 brothers with atypical cases of X-linked CGD, characterized by low levels of expression of gp91phox (X91 Ϫ CGD). A point mutation (T-55C) identified in the CYBB gene's promoter region appears to prevent the full expression of this gene in neutrophils. This results in low levels of expression of gp91phox protein that are correlated with residual oxidase activity in the whole population of neutrophils. The total O 2 Ϫ production in these cells was ∼5% of normal. Despite this oxidase activity, the patients experienced severe and life-threatening infections. It was concluded that the O 2 Ϫ production in the neutrophils of these patients was not sufficient to protect them against infections, and this X91 Ϫ CGD phenotype must be considered to be a severe clinical form of CGD. Chronic granulomatous disease (CGD) is an immunodeficiency syndrome clinically characterized by severe, recurrent bacterial and fungal infections [1, 2]. CGD is a rare inherited disorder in which phagocytic cells are unable to kill engulfed microorganisms and is caused by a defect in the NADPH oxidase system [3-5]. This enzyme catalyzes the formation of superoxide anions, which are precursors of the generation of potent oxidants involved in the first step of phagocytic-cell microbicidal activity. The NADPH oxidase system consists of membrane-bound flavocytochrome b 558 (i.e., the redox center of the oxidase) and 3 cytosolic compo
European Journal of Clinical Investigation, 1992
Chronic Granulomatous Disease (CGD) manifests as a predisposition to infection as a result of defective function of the NADPH oxidase of phagocytic cells. Proteins identified as part of this system include two subunits of a cytochrome b (cytochrome b-245) and two cytosolic factors. The affected oxidase component was determined in 63 CGD patients from 57 families, by Western blotting of extracts of their neutrophils with antibodies to those proteins. 38 (67%) of the families were X-linked with a defect of the subunit of the cytochrome. 13 (23%) lacked p47-phox, 3 (5%) p67-phox, and 3 (5%) the a subunit of the cytochrome.
…, 1994
Chronic granulomatous disease (CGD) is characterized by the failure of phagocytic leukocytes to kill certain bacteria and fungi. This is caused by deficiencies in one of the components of NADPH oxidase, the enzyme in phagocytic leukocytes that generates superoxide. In a rare, autosomal recessive form of CGD, a 67-kD cytosolic component of NADPH oxidase (p67-phox) is missing. Until now, mutations in the gene coding for this protein have not been identified. We now report on a 1 0-year-old girl with lymph node and liver abscesses who was recognized as an A67' CGD patient by lack of NADPH oxidase activity in her granulocytes, a cytosolic defect in a cell-free oxidase system, and lack of immunoreactive material with an antiserum against the p67-phox protein. mRNA for this protein was present HRONIC GRANULOMATOUS disease (CGD) is a rare syndrome clinically characterized by recurrent, life-threatening pyogenic infections, with bacteria and fungi, of subcutaneous tissues, upper airways, lungs, bones, spleen, liver and lymph nodes.' This disease is caused by the inability of the patients' phagocytes (neutrophilic granulocytes, eosinophilic granulocytes, monocytes, and macrophages) to generate superoxide, a precursor of reactive oxygen metabolites essential for the killing of various microorganisms. In normal phagocytes, the enzyme NADPH oxidase starts to produce superoxide when the cells are activated, eg, by phagocytosis of microorganisms. This enzyme is composed of several subunits, some of which are localized in the plasma membrane and others (in resting cells) in the cytosol.* During phagocytosis, the cytosolic components translocate to the plasma membrane and integrate with the membrane-bound components into an enzymatically active complex. Defects in any of the four NADPH oxidase components cause inactivity of the enzyme, thus leading to CGD.3
Journal of Leukocyte Biology, 1992
Five male patients from four different families presented with a clinical record of chronic granulomatous disease (CGD): recurrent infections of the skin and/or respiratory tract with catalase-positive microorganisms, sometimes in combination with granulomata and/or abscesses in various organs. These patients differed from "classical" forms of the disease in that their neutrophils, although deficient in killing in vitro of Staphylococcus aureus, contained a decreased but measurable amount of cytochrome b358 (10-60% of normal on a heme basis), causing weak staining in the nitroblue tetrazolium dye test and a depressed respiratory burst after contact of the cells with fluid or particulate activators of the NADPH:02 oxidoreductase. In the cell-free activation system, the defect in the patients' cells was localized in the membrane fraction. In each of the four families, the cellular abnormalities showed an X-linked inheritance. Fusion experiments performed with the monocytes from these patients and those from patients with classical Xlinked, cytochrome b558-negative (Xb#{176}) or autosomal, cytochrome b558-positive (Ab) CGD showed complementation of NADPH:02 oxidoreductase activity in the latter but not in the former combination. Thus, the unusual CGD patients represent variant forms of XbO CGD, with mutations in the gene coding for the beta subunit of cytochrome b558 that do not cause complete loss of this protein.J. Leukoc. Biol. 51: 164-171; 1992.
Journal of Clinical Investigation, 1984
The NADPH-dependent 02-generating oxidase in subcellular fractions from the neutrophils ofthree male patients with chronic granulomatous disease was compared with the corresponding preparations from normal neutrophils. The oxidase from normal neutrophils contained flavin adenine dinucleotide in an -0.9:1 molar ratio with cytochrome b559. Each of the three chronic granulomatous disease patients had decreased amounts of the flavoprotein component of the oxidase fraction. The oxidase from two chronic granulomatous disease patients had undetectable amounts of cytochrome b559 whereas the third patient had a normal content of cytochrome b559, which was spectrally indistinguishable from the normal. The intrinsic cytochrome b559 in the oxidase fraction from stimulated neutrophils of the latter chronic granulomatous disease patient was not reduced by NADPH under anaerobic conditions, in distinction with the previously reported reduction of the normal cytochrome b559 under identical conditions. We conclude that the flavoprotein component of the oxidase may mediate transfer of electrons from NADPH to the cytochrome b559 in normal neutrophils, and that deficiency of this flavoprotein is associated with the chronic granulomatous disease phenotype in the three patients studied.