The Levels of CD16/Fcγ Receptor IIIA on CD14⁺CD16⁺Monocytes Are Higher in Children with SeverePlasmodium falciparumAnemia than in Children with Cerebral or Uncomplicated Malaria

Abstract

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.

Plasmodium falciparum Infection of Human Volunteers Activates Monocytes and CD16 + Dendritic Cells and Induces Upregulation of CD16 and CD1c Expression

“…Immune complexes are formed particularly during episodes of severe malaria, a condition associated with higher frequencies of CD16 ϩ monocytes (36). Moreover, following malaria infection, elevated CD16 expression on monocytes is associated with enhanced TNF production, as well as with a reduced hemoglobin level (36). This suggests that CD16 cross-linking by malaria-induced immune complexes can trigger inflammatory responses and erythrophagocytosis.…”

“…CD16 binds immune complexes, and the binding triggers effector functions such as phagocytosis and proinflammatory cytokine secretion (35). Immune complexes are formed particularly during episodes of severe malaria, a condition associated with higher frequencies of CD16 ϩ monocytes (36). Moreover, following malaria infection, elevated CD16 expression on monocytes is associated with enhanced TNF production, as well as with a reduced hemoglobin level (36).…”

Monocyte dysregulation and systemic inflammation during pediatric falciparum malaria

“…The two CD16 + subsets appear to have more activated, proinflammatory phenotypes (22)(23)(24). Increased proportions of circulating CD16 + intermediate and nonclassical monocytes have been associated with acute falciparum malaria (25)(26)(27). Evidence suggests that the CD16 + subpopulations have enhanced antiparasitic activity (26,28,29), though there are still significant gaps in our understanding of the functional roles of monocyte subpopulations during malaria.…”

“…Innate immune activation plays a crucial role in host protection as well as pathogenesis during malaria infection. Dynamic shifts in monocyte subpopulations occur during symptomatic malaria, and each monocyte subset is characterized by different stages of differentiation with distinct gene expression profiles, phenotypes, and physiologic functions (22,37 + subset in cases of both uncomplicated and severe malaria in children from western Kenya (27). The dynamics of circulating human monocyte subsets were recently studied using in vivo deuterium labeling, and experimental endotoxemia led to a transient but profound monocytopenia with restoration of circulating monocytes through release of classical monocytes from the bone marrow; classical monocytes were shown to give rise to intermediate and nonclassical Monocytes from children during acute malaria and 6 weeks following treatment are highly responsive to stimulation with TLR ligands.…”

Reduced Frequency of a CD14+CD16+Monocyte Subset with High Toll-Like Receptor 4 Expression in Cord Blood Compared to Adult Blood Contributes to Lipopolysaccharide Hyporesponsiveness in Newborns

“…The proportion of CD16 ϩ -expressing monocytes expands in a number of inflammatory conditions (reviewed in reference 20), ranging from arthritis (21), inflammatory bowel disease (22), atherosclerosis (23), and sepsis (24) to infections such as HIV (25)(26)(27) and malaria (28,29). Although TLR expression is known to differ among CD16 ϩ or CD16 Ϫ monocyte populations in peripheral blood (20), no study to date has documented any alteration of the monocyte subpopulations and the mechanisms underpinning changes in blood monocyte TLR in neonates versus adults.…”