Disorders of phagocyte function: biochemical aspects

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.