Combined abnormality of neutrophil chemotaxis and bactericidal activity in a child with chronic skin infections.
Explore the source record for details and available documents.
Blood Bactericidal Activity↗
Biomedical subjects
W D Biggar
Publications and source records attributed to W D Biggar.
A clinical study of young infants after small intestinal resection.
We prospectively studied 15 infants who, before 3 months of age, underwent resection of the small intestine-proximal in 3 infants, mid in 6, and distal in 6. Two died before one year of age. Many required prolonged parenteral nutrition, but by one year, 12 of the 13 survivors were on oral feedings only, and seven were above the third percentile for height and weight. Developmental delay occurred in the early postoperative period but diminished with time. There was compensatory adaptation of the remaining gut, shown by improving fat and B12 absorption and duodenal bile-salt concentrations. Bacterial contamination complicating end-to-side anastomoses occurred in two cases (P), gastric hyperacidity in four of 12 (1P, 3M), and hyperoxaluria in eight of 14 (1P, 5M, 2D). Studies of immune competence revealed normal cellular immune function (11/11), transient hypogammaglobulinemia (3/14), hypocomplementemia (1/12), and serum autoantibodies (3/10). Thus, massive resection of the small intestine did not preclude spontaneous improvement in absorptive function, growth, and development.
Child Development↗
Enhancement of human neutrophil bactericidal activity by chemotactic factors.
Neutrophils are important effector cells in the defense against microorganisms. They migrate into infected sites and then phagocytose and kill bacteria. Chemotactic factors may be important for initiating neutrophil migration. We investigated whether chemotactic factors might also influence an event subsequent to chemotaxis, namely bacterial killing. It was found that preincubation (20 min at 37 degrees C) of human leukocytes with chemotactic substances such as zymosan-activated serum, a C5a-containing fraction of zymosan-activated serum, N-formyl methionyl phenylalanine or N-formyl methionyl-leucine-phenylalanine, enhanced leukocyte killing of Staphylococcus aureus, Escherichia coli, and Streptococcus faecalis in a dose-dependent fashion. The concentration of chemotactic factor required to enhance killing was similar to that required to induce neutrophil chemotaxis. In addition, zymosan-activated serum, C5a fraction, and the two N-formyl methionyl peptides increased the hexose monophosphate shunt activity of resting and phagocytosing neutrophils by two- to threefold. In contrast, bacterial killing by sodium azide-treated neutrophils and neutrophils from a patient with chronic granulomatous disease was not increased by any chemotactic factor. These findings suggest that chemotactic factors stimulate neutrophil oxygen-dependent microbicidal pathways. These observations illustrate another important contribution of biologically active molecules to effector cell function and host defense.
Blood Bactericidal Activity↗
Effect of cyclic adenosine 3',5'-monophosphate antagonists on endotoxin-induced inhibition of human neutrophil chemotaxis.
We reported previously that Escherichia coli endotoxin inhibited human neutrophil chemotaxis toward C5a. This effect of endotoxin was antagonized by anti-inflammatory steroids. We now report that dibutyryl cyclic adenosine 3',5'-monophosphate, prostaglandin E1, isoproterenol, and cholera toxin also antagonize the suppression of chemotaxis by endotoxin. Each compound inhibited the effect of endotoxin in a dose-dependent fashion. To be effective, each compound except cholera toxin had to be present at the time of endotoxin challenge. Furthermore, propranolol blocked the protective effect of isoproterenol against endotoxin but not the protective effect of dibutyrl cyclic adenosine 3',5'-monophosphate or prostaglandin E1. Dibutyryl cyclic guanosine 3',5'-monophosphate, adenosine 5'-monophosphate, phenylephrine, prostaglandin F2 alpha, and carbachol did not modify the suppression of chemotaxis by endotoxin. Anti-inflammatory steroids and dibutyryl cyclic adenosine 3',5'-monophosphate are thought to stabilize phospholipids in certain cell membranes. This phospholipid-stabilizing action may contribute, at least in part, to the protective effect against endotoxin-mediated suppression of neutrophil chemotaxis.
Bucladesine↗
A new form of nucleoside phosphorylase deficiency in two brothers with defective T-cell function.
Two brothers, age 9 and 11, respectively, have marked deficiency of nucleoside phosphorylase associated with defective T-cell function and normal B-cell function. Unlike the previously described five patients with this syndrome, each of these children has sufficient NP catalytic activity in their red blood cells (below 1% of the normal level) to be visualized after electrophoresis and staining for the enzyme. Their healthy sibling has normal NP activity and a normal isozyme pattern. The nonconsanguineous parents have about half-normal NP activity, but their electrophoretic patterns differ from each other's and from those of their affected children. These findings are consistent with genetic heterogeneity at the NP structural gene locus, resulting in compound heterozygosity for two different abnormal alleles.
Child↗
Hydrogen peroxide release by rat alveolar macrophages: comparison with blood neutrophils.
Hydrogen peroxide release was examined using biochemical and cytochemical techniques in rat alveolar macrophages, at rest and during phagocytosis, and compared with rat blood neutrophils. Using biochemical techniques, alveolar macrophages released small amounts of hydrogen peroxide at rest, and no increase was observed after challenge with opsonized and nonopsonized zymosan particles at several particle-cell ratios (1:1 to 1:1,000). Neutrophils released similar quantities of hydrogen peroxide at rest but showed a 12-fold increase in hydrogen peroxide release following exposure to opsonized zymosan particles. Using cytochemical techniques to localize sites of hydrogen peroxide release, resting neutrophils showed little deposition of reaction product at the cell surface and occasional deposits in endocytotic vesicles. After exposure to latex particles, a dense reaction product was observed between the particle and the cell membrane, indicating significant increases in hydrogen peroxide release at the sites of particle contact with the neutrophil. The resting macrophage displayed a light, uniform precipitation of cerium over the cell surface and lining intracellular channels and endocytotic vesicles and vacuoles. Following particle exposure, there was no significant difference in the density or distribution of reaction product. These findings, together with previous studies of oxidative metabolism, suggest that alveolar macrophages do not release increased quantities of hydrogen peroxide during phagocytosis. In contrast to neutrophils, oxidative-dependent metabolic pathways may not be of primary importance for microbial killing by alveolar macrophages.
Animals↗
Effect of phorbol myristate acetate on cellular metabolism and lysozyme release from alveolar macrophages and polymorphonuclear leukocytes.
Phorbol myristate acetate stimulated oxidative metabolism in alveolar macrophages and blood neutrophils. This compound also stimulated lysozyme release from neutrophils but not from alveolar macrophages. These findings suggest that the regulation of lysozyme release from alveolar macrophages is different than for polymorphonuclear leukocytes.
Animals↗
Partial purine nucleoside phosphorylase deficiency. Studies of lymphocyte function.
Immune function in two brothers with a deficiency of purine nucleoside phosphorylase was evaluated in vivo and in vitro. Both patients had a history of recurrent infections and profound lymphopenia. Studies of cell-mediated immunity revealed an absence of delayed cutaneous reactivity to a number of antigens, including dinitrochlorobenzene, and significantly reduced lymphocyte proliferative responses to nonspecific mitogens, specific antigen, and allogeneic cells. E-rosetting cells were present but reduced in number (20.0% and 31.5%). Serum immunoglobulin levels, percentages of circulating immunoglobulin-and C3-receptor-bearing B cells, as well as the ability to produce antibody in response to specific antigen in vivo were normal. Moreover, studies of the in vitro induction of specific IgM antibody delineated the presence of T-helper and T-regulator cells. The normal induction of bone marrow precursor T-cell maturation by human thymic epithelium-conditioned medium or thymosin suggested that the initial stages of T-cell generation were intact in these patients. Attempts to reconstitute the in vitro proliferative response with a variety of reagents, including purine nucleoside phosphorylase itself, were unsuccessful. Selective impairment of certain aspects of T-cell function in these patients and a less severe clinical picture than previously described may be explained by the presence of a partial deficiency of nucleoside phosphorylase activity and incomplete block of purine catabolism.
Antibody Formation↗
Effect of methylprednisolone and polymyxin B sulfate on endotoxin-induced inhibition of human neutrophil chemotaxis.
Explore the source record for details and available documents.
Chemotaxis, Leukocyte↗
Neutrophil chemotaxis in two patients with recurrent staphylococcal skin infections and hyperimmunoglobulin E.
Explore the source record for details and available documents.
Adolescent↗
Inhibition of the biologic effects of endotoxin on neutrophils by polymyxin B sulfate.
Polymyxin B sulfate diminished the endotoxin-mediated release of human blood neutrophil lysosomal enzymes. Similarly, this antibiotic reduced the endotoxin-induced increase in the neutrophil hexose monophosphate pathway activity as measured by the release of 14CO2 from [l-14C]glucose. Although these effects were seen with therapeutically attainable levels of polymyxin B sulfate, they could not be demonstrated when the cell-endotoxin interaction preceded treatment with polymyxin B sulfate.
Endotoxins↗
The morbidity and mortality of splenectomy in childhood.
One hundred and eighty-two patients undergoing splenectomy in infancy and childhood were followed for periods of 2 to 15 years. Serious infections occurred in 11 patients (6%) with death in 6 (3.3%). In 10 patients the infection was sepsis, and in all but one patient the infection occurred within 2 years of splenectomy. Among children over 2 years of age the risk of infection was still appreciable except when the spleen was removed incidentally or for traumatic rupture. Splenectomy for thalassemia and portal hypertension resulted in an increased risk of serious infections when compared with removal of the spleen for hereditary spherocytosis, idiopathic thrombocytopenic purpura, trauma, or for technical reasons in the course of another operation. Post-splenectomy infections tended to follow a characteristic pattern. The infecting organism was predominantly pneumococcus, the course was fulminating and the mortality high.
Adolescent↗
Influence of serum-derived chemotactic factors and bacterial products on human neutrophil chemotaxis.
The chemotaxis of neutrophils has been shown to be modulated by serum factors, tissue factors, bacterial products, and a host of other substances. In vivo, these factors may act in concert with each other to modify neutrophil movement. We examined the effect of aggregated gamma globulin-activated serum (AS), bacterial factors, and endotoxin either alone or in combination with each other, on human neutrophil chemotaxis. Exposure of neutrophils to AS resulted in deactivation to AS but not to Escherichial coli or Staphylococcus epidermis culture filtrate. Exposure of neutrophils to S. epidermis or E. coli CF or E. coli endotoxin resulted in deactivation to AS or C5a but not to E. coli or S. epidermis culture filtrate. Addition of endotoxin to AS or C5a resulted in inhibition of chemotaxis by untreated neutrophils toward this combination as compared with AS alone. These results suggest that separate mechanisms may be involved when serum or bacterial chemotactic factors initiate human neutrophil chemotaxis. Furthermore, the potent but specific inhibitory effect of endotoxin on chemotaxis toward AS may be of clinical significance.
Blood↗
Role of lysozyme in the microbicidal activity of rat alveolar macrophages.
Lysozyme release from alveolar macrophages is stimulated by exposure to particles, such as latex and zymosan, and to bacteria. Rat alveolar marcophages contain 10-fold-greater intracellualr concentrations of lysozyme and release more lysozyme after stimulation than rat blood neutrophils. During 30 min of incubation in vitro, alveolar macrophages kill more than 99% of Micrococcus lysodeikticus in the incubation mixture, whereas neutrophils kill approximately 50% of the bacteria. The bactericidal capacity of alveolar macrophages for M. lysodeikticus exceeds that of neutrophils at all bacteria-to-cell ratios tested. This bacterial killing by alveolar macrophages is inhibited when specific rabbit antirat lysozyme serum is added to the incubation mixture. Electron microscopy studies indicate that bacterial killing occurs extracellularly. Initial degradation of bacteria occurs within 5 min, and lysis is complete by 25 to 30 min. Phagocytosis of lysed bacteria is maximum after 25 to 30 min. The greater quantities of lysozyme, both intracellularly and released into the extracellular environment by alveolar macrophages, suggest that this factor may be a mechanism by which alveolar macrophages contribute to pulmonary defense.
Animals↗
Purine nucleoside phosphorylase deficiency. Evidence for molecular heterogeneity in two families with enzyme-deficient members.
Purine-nucleoside phosphorylase (NP) deficiency is associated with severely defective thymus-derived (T)-cell and normally functioning bone marrow-derived (B)-cell immunity. In this study, two unrelated families with a total of three NP deficient members were investigated. High pressure liquid chromatography of the plasma of the three patients showed inosine levels greater than 66 muM. This nucleoside was absent from the plasma of their parents and control samples.NP was purified from normal human erythrocytes by affinity chromatography and an antiserum prepared in rabbits was used to study the NP variants in the two families. In family M the patient had no detectable erythrocyte NP activity and no detectable immunological-reacting material (irm) to the NP antibody. The parents, who are second cousins, had less than one-half of normal enzyme activity and approximately 14% irm attributable to a variant protein. Their electrophoretic patterns revealed a series of isozymes with slower than normal migration. In family B the patients had 0.5% residual enzyme activity and about one-half normal irm. Their electrophoretic pattern showed faintly staining bands which migrated faster than normal NP. The mother of the patients had one-half normal enzyme activity, 11% irm attributable to her variant protein, and a normal electrophoretic pattern. The father had less than one-half normal enzyme activity, equal amounts of normal and variant irm, and an electrophoretic pattern that showed increased activity of the more rapidly migrating isozyme bands.The combined use of immunological and electrophoretic techniques has shown the presence of three separate mutations; one in family M and two in family B associated with severely defective T-cell function.
Adult↗
Chronic granulomatous disease in an adult male: A proposed X-linked defect.
A 25-year old patient with chronic granulomatous disease of somewhat unusual history is described. The diagnosis of CGD was based on increased susceptibility to infection, granulomatous appearance of tissues, and diminished bactericidal and metabolic response of leukocytes during phagocytosis: the clinical and cellular features considered phenotypic of CGD. A 16-year-old female sibling had bactericidal and metabolic abnormalities of leukocyte function similar to those of the patient's leukocytes. Leukocytes from another sister, 26 years of age, were intermediate in bactericidal capacity. Two populations of leukocytes were identified by a histochemical test of NBT reduction. Both normal and abnormal polymorphonuclear leukocytes were present in the leukocyte population of the two sisters. Leukocytes from the patient's mother and maternal grandmother were normal by all methods tested. These findings are taken as evidence of a germ-line mutation in the chromosomal gene causing CGD, with transmission of the genetic defect from the mother to the son.
Adult↗
Bactericidal mechanisms in rabbit alveolar macrophages: evidence against peroxidase and hydrogen peroxide bactericidal mechanisms.
The role of peroxidase-mediated bacterial killing by rabbit alveolar macrophages was examined. During 3 h of incubation in vitro, alveolar macrophages ingested and killed greater than 88% of the Streptococcus faecalis, Proteus mirabilis, or Streptococcus pneumoniae present in the incubation mixture. Preincubation of alveolar macrophages with inhibitors of catalase, 3-amino-1,2,4-triazole or sodium nitrite, did not alter their bactericidal potential. Iodination of ingested zymosan particles, a peroxidase-dependent and hydrogen peroxide-dependent reaction, was not observed, in spite of vigorous phagocytosis by alveolar macrophages. Furthermore, iodination by alveolar macrophages was not significantly increased when peroxidase-coated zymosan particles were ingested. The results suggest that hydrogen peroxide may not be available to the phagocytic vacuole for microbial killing. Since tetrazolium dye reduction reflects the activity of an oxidase responsible for stimulated oxygen consumption by polymorphonuclear leukocytes, this reaction was also measured. Rabbit alveolar macrophages incubated with latex particles did not exhibit an increased dye reduction compared with resting cells. The absence of significant stimulation of tetrazolium dye reduction indicates that the oxidase reaction does not occur in the proximity of the phagocytic vacuole of alveolar macrophages.
Animals↗
Peroxidase activity of alveolar macrophages.
Peroxidase activity was studied in alveolar macrophages and compared to the peroxidase activity in polymorphonuclear leukocytes using cytochemical techniques. A dense reaction product for peroxidase was observed in the primary lysosomes of polymorphonuclear leukocytes, but no significant peroxidase or peroxidative enzymes could be detected in rabbit alveolar macrophages. Furthermore, following vigorous phagocytosis of zymosan particles by alveolar macrophages in vitro, no peroxidase could be detected in association with the phagocytic vacuole. Exogenous horseradish peroxidase was ingested readily by alveolar macrophages so that abundant reaction product was demonstrated in pinocytotic vesicles and phagocytic vacuoles. The uptake of exogenous peroxidase by pinocytosis appeared to be more vigorous in alveolar macrophages than in polymorphonuclear leukocytes. These studies demonstrate that alveolar macrophages do not contain significant quantities of peroxidase and suggest that, it contrast to polymorphonuclear leukocytes, peroxidative metabolism does not contribute in a major way to microbial killing by alveolar macrophages.
Animals↗