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The effect of infection by prototypes from the three major species of Leishmania on the oxidative burst of human mononuclear phagocytes in culture was examined. The presence of intracellular parasites of the three species, L.major, L.donovani and L.mexicana decreased hydrogen peroxide (H2O2) and superoxide anion (O2-) production. This was particularly apparent when infected cells were compared to control monocytes following treatment with IFN-gamma. Nitroblue tetrazolium (NBT) reduction by monocytes was also decreased in infected cells. This morphological analysis of infected monolayers clearly showed that infected monocytes were incapable of reducing the dye as compared to uninfected cells. Decrease in NBT positive cells and production of H2O2 and O2- was related to the degree of infection of the monocyte monolayers. These results suggest that the presence of intracellular Leishmania amastigotes in mononuclear phagocytes decreases the oxidative burst and may contribute to parasite survival. Failure of phagocytes from patients with chronic granulomatous disease to kill these intracellular parasites also emphasized the importance of the oxidative burst for this function. Nevertheless, the consistent increase in leishmaniacidal effect attained after IFN-gamma treatment of the monocyte monolayers indicates that other non-oxidative mechanisms induced by this cytokine are also important in the killing of these intracellular parasites.

We have studied and compared the effects of IgA and IgG immune complexes and concanavalin A (Con A) on human monocyte tumour necrosis factor (TNF) production. The presence of IgA-containing immune complexes in monocyte monolayers resulted in a dose-dependent increase of TNF production. Similar results were obtained with IgG-containing immune complexes and Con A. The presence of monomeric IgA or IgG did not increase TNF secretion. Both IgA and IgG immune complexes also increased monocyte interleukin-1 beta (IL-1 beta) production. Galactose inhibited the effect of IgA but not IgG immune complexes, while mannose inhibited the effect of Con A. Prednisolone abrogated TNF production, while indomethacin enhanced TNF production in all instances where cross-linking of plasma membrane receptors was achieved. These results indicate that activation of Fc alpha receptors (Fc alpha R), Fc gamma R or mannose receptors of the human monocyte plasma membrane by cross-linking results in increased TNF and IL-1 beta secretion. These findings may be of particular relevance in the pathogenesis of IgA immune complex-mediated disease.

We have studied the interaction of secretory immunoglobulin A (sIgA) derived from human breast milk with human monocytes. The presence of specific sIgA receptors on the monocyte membrane was confirmed by dose-dependent inhibition of E-sIgA rosette formation and by the binding of iodinated sIgA to monocyte monolayers. Binding was dependent on both the number of monocytes, as well as the amount of [125I]sIgA, and could be inhibited by unlabelled sIgA. Incubation of monocyte monolayers in the presence of increasing concentrations of secretory IgA and F(ab')2 anti-IgA resulted in a dose-dependent increase of the oxidative burst, as measured by H2O2 production. Neither sIgA or anti-IgA alone, nor incubation of IgG with anti-IgA, had any effect on the oxidative burst. These studies indicate that human monocytes have a receptor for sIgA and that specific activation of the monocytes occurs via these receptors.

The secretion of PGE2 from monocytes of newly diagnosed patients with Hodgkin's disease (HD) was compared to that of patients in remission, who were not receiving either chemotherapy or radiotherapy, and normal controls. We found that monocyte monolayers of some patients, both newly diagnosed and those in remission, secreted markedly elevated levels of PGE2. The lymphocyte proliferative response to PHA was increased to a similar extent in both newly diagnosed patients and those in remission when cultured in the presence of indomethacin. PGE2 concentrations in the medium of mononuclear cultures correlated with the lymphocyte proliferative response to PHA (P less than 0.05). However, no correlation of monocyte PGE2 production with decreased E rosette forming lymphocytes, anergy or clinical stage could be demonstrated. We suggest that PGE2 secretion by monocytes is indicative of an 'activated' state of these cells. It is, however, unlikely that PGE2 is the only molecular species responsible for the decreased cellular immune function in HD. 'Activated' monocytes may be part of the immune response in this disease and may be responsible for the decreased cellular immunity.

IgE was isolated from a patient with the hyper IgE, recurrent infection syndrome by immunoadsorption on sepharose bound goat anti-human IgE. Addition of this IgE to a monolayer culture of human monocytes resulted in a dose-dependent increase in PGE2 secretion. The addition of F(ab')2 fraction of goat anti-human IgE in the presence of sub-stimulating doses of IgE markedly increased PGE2 secretion; whereas addition of F(ab')2 fragment of irrelevant goat IgG had no effect. Similar activation of monocytes which could be enhanced by anti IgE was observed in the presence of the patient's serum. No such effect was seen in the presence of normal human serum. These results indicate that IgE may activate human monocytes and induce PGE secretion.

Ajax mice fed a diet with a reduced proportion of protein, cleared carbon more slowly, and produced less antibody of lower affinity, when immunized with human serum transferrin (HST) in saline than did normally fed controls. This finding is discussed in terms of the defective antibody response in protein-malnourished children, and the possible contribution such environmental factors may have on immunopathological and neoplastic effects of infection.

Leishmania organisms are obligate intracellular parasites of mammalian mononuclear phagocytes in vivo. In order to study the interactions of these parasites and mononuclear phagocytes, we have used a model of infection of Leishmania major in human monocytes in vitro. The presence of intracellular parasites did not alter the normal secretion of lysozyme or result in increased secretion of prostaglandin E2 (PGE2) or superoxide anion by the monocytes. Addition of concanavalin A (Con A), which binds to a specific membrane receptor, zymosan particles or endotoxin to infected monocyte monolayers, resulted in the expected increase in PGE2 secretion. In addition, the production of superoxide by infected monocytes treated with phorbol myristate acetate was not different from control uninfected cultures. Despite this evidence of biochemical activation, neither endotoxin, zymosan nor Con A had any parasiticidal effect on the intracellular parasites. In contrast, Con A-induced lymphokines from human mononuclear cells resulted in an increased killing of the intracellular amastigotes. These studies have shown that the induction of leishmaniacidal capacity of human monocytes is dependent on the type of stimulus used to induce activation.