cyclic-gmp and Phagocyte-Bactericidal-Dysfunction

Topics: Actins; Agammaglobulinemia; Ascorbic Acid; Ataxia Telangiectasia; Blood Transfusion; Cell Adhesion; Cell Membrane; Chemotaxis; Cyclic GMP; Dysgammaglobulinemia; Exocrine Pancreatic Insufficiency; Female; Humans; IgA Deficiency; Immunoglobulin E; Levamisole; Male; Maternal-Fetal Exchange; Membrane Proteins; Microtubules; Myosins; Neutropenia; Phagocyte Bactericidal Dysfunction; Phagocytes; Pregnancy

In this review I have attempted to explain the processes of chemotaxis, phagocytosis, oxidant generation, and lysosomal degranulation in normal and genetically abnormal human PMN. In my view these leukocyte functions are most importantly dependent on the integrity of three cellular components: the plasma membrane, the submembranous microfilaments, and the cytoplasmic microtubules. These components are often discussed in isolation, and the biochemical and pharmacological aspects of their function are analyzed separately here. However, PMN motile and bactericidal activities require the interdependent functioning of membranes, microtubules, and microfilaments. I have therefore tried to provide an integrated view of cytoskeleton-membrane organization and function in human PMN. I have particularly emphasized dynamic aspects of the cytoskeleton and membranes, eg, the induction of microtubule assembly and membrane enzyme activation by surface ligands and the reorganization of microfilaments in response to the same ligands. With this background established, I have selected for discussion a series of diseases in which abnormalities of chemotaxis, phagocytosis, lysosomal degranulation, and/or oxidant generation can be explained directly or indirectly by abnormalities in dynamic properties of PMN membranes, microtubules, or microfilaments. I emphasize that even preliminary insight into the basis of these disorders has sometimes been sufficient to suggest useful clinical approaches to the management of patients. In several of these neutrophil abnormalities, ie, neutrophil actin dysfunction, Chédiak-Higashi syndrome, and its "antithesis" described by Gallin and co-workers, the cellular dysfunctions were well documented but the molecular basis was completely obscure prior to cell biologic analysis. Snyderman and Pike 159 and Chusid and co-workers 160 emphasized the existence of a large number of other neutrophil bactericidal abnormalities resulting from as yet unexplained cellular defects. Further analyses of the functional interactions between membranes and cytoskeletal components in neutrophils may not only clarify the molecular bases of the disorders described here but also may provide insight into the origins and proper therapeutic approach to other granulocyte dysfunctions.

Topics: Cell Membrane; Chemotaxis, Leukocyte; Cyclic AMP; Cyclic GMP; Cytoskeleton; Humans; Lysosomes; Microtubules; Neutrophils; Oxidoreductases; Phagocyte Bactericidal Dysfunction; Phagocytosis; Tubulin

Intensive laboratory investigation of patients with recurrent infections, and with infections with microbial species not usually considered to be pathogenic, have led to the identification of several defects in granulocyte function. The two functions of granulocytes which have received most attention in the past decade have been locomotion (especially response to chemotactic stimulation) and microbicidal activity. Defective granulocyte chemotaxis has been demonstrated in patients with clinical manifestations suggesting abnormalities related to vasoactive amines, i.e., patients with eczema and extreme IgE hyperimmunoglobulinemia. The depressed granulocyte chemotactic responsiveness found in these patients can be reproduced in vitro when histamine and beta adrenergic agents are incubated with control granulocytes. Since these compounds have been shown to increase levels of intracellular cyclic AMP in other cells, there appears to be an association between cyclic nucleotide metabolism and regulation of granulocyte locomotion. Defective granulocyte microbicidal activity is found in patients with chronic granulomatous disease and it has been shown that there is little increase in oxidative metabolism during phagocytosis by these cells. Methods for quantitating the oxidative metabolism of granulocytes and monocytes include oxygen uptake, reduction of nitroblue tetrazolium, formate oxidation, and chemiluminescence response during phagocytosis. Since products of oxygen metabolism, i.e., hydrogen peroxide, superoxide or singlet oxygen do not accumulate in granulocyte phagocytic vacuoles, intracellular microbes are not killed (except bacterial species that produce hydrogen peroxide). The biochemical basis for defective oxidative metabolism in granulocytes from patients with chronic granulomatous disease appears to be associated with abnormal nucleotide oxidase activity.

Topics: Blood Bactericidal Activity; Carbohydrate Metabolism, Inborn Errors; Cell Movement; Chediak-Higashi Syndrome; Chemotaxis, Leukocyte; Cyclic AMP; Cyclic GMP; Granulocytes; Granulomatous Disease, Chronic; Humans; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolases; Leukocytes; Luminescent Measurements; Mannose; Metabolism, Inborn Errors; NADH, NADPH Oxidoreductases; NADP; NADPH Oxidases; Nucleotides, Cyclic; Oxygen Consumption; Peroxidase; Phagocyte Bactericidal Dysfunction; Phagocytosis; Protein-Energy Malnutrition