The levels of CD16/Fc gamma receptor III A on CD14+CD16+ monocytes are higher in children with severe Plasmodium falciparum anemia than in children with cerebral or uncomplicated malaria

Abstract

Fc gamma receptor IIIA (CD16/FcRIIIA) on monocytes/macrophages may play an important role in the pathogenesis of severe malarial anemia (SMA) by promoting phagocytosis of IgG-coated uninfected red cells and by allowing the production of tumor necrosis factor alpha (TNF-) upon cross-linking by immune complexes (ICs). However, not much is known about the differential expression of this receptor on monocytes of children with severe malaria and uncomplicated malaria. Therefore, we investigated the expression of CD16/FcRIIIA on monocytes of children with SMA, cerebral malaria (CM), and their age-matched uncomplicated malaria controls by flow cytometry. Since CD14low (CD14) monocytes are considered more mature and macrophage-like than CD14high (CD14) monocytes, we also compared the level of expression of CD16/FcRIIIA according to the CD14 level and studied the relationship between CD16/FcRIIIA expression and intracellular TNF- production upon stimulation by ICs. CD16/FcRIIIA expression was the highest overall on CD14 CD16 monocytes of children with SMA at enrollment. At convalescence, SMA children were the only ones to show a significant decline in the same parameter. In contrast, there were no significant differences among groups in the expression of CD16/FcRIIIA on CD14 CD16 monocytes. A greater percentage of CD14 CD16 monocytes produced TNF- upon stimulation than any other monocyte subset, and the amount of intracellular TNF- correlated positively with CD16/FcRIIIA expression. Furthermore, there was an inverse correlation between hemoglobin levels and CD16/FcRIIIA expression in children with SMA and their controls. These data suggest that monocytes of children with SMA respond differently to Plasmodium falciparum infection by overexpressing CD16/FcRIIIA as they mature, which could enhance erythrophagocytosis and TNF- production. Severe malarial anemia (SMA) and cerebral malaria (CM) are two of the most serious manifestations of Plasmodium falciparum malaria and are important causes of childhood mortality and morbidity in sub-Saharan Africa. However, the pathogenesis of these complications remains unclear. A better understanding of the factors involved in the pathogenesis of severe malaria is essential for the identification of at-risk populations and the development of effective prophylactic and therapeutic measures. There is abundant evidence to suggest that destruction of uninfected red cells plays an important role in the development of SMA. Uninfected red cells of humans and mice infected with P. falciparum or rodent malaria have a reduced life span (26, 27, 48), and the life span is more reduced in patients with splenomegaly (26), a common finding in children with SMA. Uninfected erythrocytes can continue to be removed from circulation even following malaria treatment, suggesting that this phenomenon is not due to their continued invasion and rupture by parasites (27). A mathematical model suggested that