Expression of fcyrilll, cr3 intracellular tumor necrosis factor-alpha and nitric oxide production by monocytes from children with plasmodium falciparum malaria
Ogonda, Adhiambo L.
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Malaria is a major cause of childhood morbidity and mortality in tiub-Saharan Africa. Most of the mortality is the result of severe Plasmodium falciparum (P. falciparum) disease complications such as severe malarial anemia (SMA) and cerebral malaria (CM). A clear understanding of the factors that play a role in the pathogenesis of severe P. falciparum malaria is essential for the development of effective prophylactic and therapeutic measures. Malaria infection leads to formation of immune complexes (ICs) that can interact with monocyte/macrophages by binding to their surface Fc gamma and complement receptors. The interaction of ICs with Fe gamma receptor III (FcyRIII, CD16) on monocytes/macrophages results in stimulation leading to production of nitric oxide (NO) and the cytokine tumor necrosis factor-alpha (TNF-(X) which ire important factors implicated in the development of severe malaria. FcyRIIIA can also mediate phagocytosis of antibody-coated infected and uninfected red cells which could contribute to the development of severe anaemia. However, phagocytosis of opsonized ICs via complement receptor 3 (CR3, Mac-1, CD I Ib/CD18) suppresses pro-inflammatory monocyte functions such as NO production. Therefore, the expression levels of these receptors on monocytes/macrophages may influence degree of stimulation and determine individuals' susceptibility to severe malaria. This study examined the expression of FcyRIII and CR3 on monocytes of children with severe malarial anaemia, cerebral malaria, and their age and gender-matched uncomplicated malaria controls by flow cytometr y. Whole blood was obtained from the patients during the acute illness and after recovery from illness and stained with directly conjugated antibodies against CD14, FcyRIII/CD16 and CR3/CD1 lb followed by red cell lysis. In addition, monocytes were stimulated with BSA-anti-BSA immune complexes to determine the effect on the intracellular expression of TNF-a and NO by monocytes. The expression of FcyRIII on total CD16+ mono~cyte population and on the CD14+CD16+ monocyte subpopulation was highest in SMA vases and correlated negatively with the haematocrit levels. The expression of CR3 w CD14+CD16+ and CD14++CD16+ monocytes sub-populations was lowest in SMA ases and correlated positively with the haematocrit levels. The ability to produce N in response to IC correlated positively with age and was higher in the SMA than in ( VI group (P= 0.013) but there were no differences between these severe malaria groups 'A i th their age matched controls. Intracellular TNF-a expression by CD14+CD16+ id CD14++CD16+ monocytes in response to IC stimulation correlated positively with their FcyRIII expression levels. The concentration of total monocytes and their subpopulations was significantly higher in SMA cases than in all the other clinical groups and correlated inversely with haematocrit levels. These findings suggest that CD14+CD16+ and CD14++CD16± monocytes may be more mature and responsive to activation in SMA cases than in CM cases. Over expression of FcyRIII on monocytes in response to P. falciparum infection may be an important contributing factor to the development of severe malarial anaemia.