EFFECTOR MECHANISMS AGAINST ASEXUAL ERYTHROCYTIC STAGES OF PLASMODIUM

Evidence for a role for macrophages/monocytes is largely based on in v itro not in vivo observations. Products of activated macrophages parti cularly tumor necrosis factor-alpha (TNF alpha) are implicated in the killing of parasites. Access of cytokines and other factors might be t hrough intracellular channels in the infected red blood cell. The cyto toxic elements in 'crisis' serum are uncertain but may include TNF, ga mma-interferon (IFN gamma), and lipid peroxidases. TNF alpha in excess , contributes to pathology. TNF, acting as a pyrogen and raising body temperature, may moderate parasite density by killing late asexual sta ges. Nitric oxide and other nitrogen intermediates, products of activa ted macrophages and a number of other cell types, have been demonstrat ed both in vitro and in vivo to have a protective role. Phagocytosis o f infected erythrocytes and merozoites, enhanced by the presence of im mune serum in some systems, has been reported. Killing of parasites by neutrophils is enhanced by immune serum and cytokines TNF alpha, IFN gamma and lymphotoxin. A role for natural killer cells has been sugges ted. Evidence for antibody-dependent cellular cytotoxicity (ADCC) is c ontroversial. Antibody-dependent cellular inhibitory activity (ADCI) ( blood monocytes plus immune IgG) has been described for P. falciparum. Evidence for an important role for complement is conflicting; an invo lvement in the protective activity of phagocytic cells is reported. An tibody isotypes have been relatively little studied. In murine systems IgG(2a) may have a role early in the protective immune response follo wed by IgG(1). In P. falciparum ADCI activity is mediated by IgG(1) an d IgG(3), two cytophilic isotypes. Antigenic variation by the asexual erythrocytic stages has been described for a number of malaria species and appears to serve as an immune evasion mechanism. One variant anti gen has been located on the surface of trophozoite/schizont-infected e rythrocytes and may be involved in cytoadherence. In P. falciparum in vitro and P. chabaudi in vivo antigenic switching may be at the rate o f 2% per generation.