Selected problems of malaria blood stage immunity.

Both antibody dependent and cell mediated mechanisms contribute to immunity in malaria. The parasites vary in sensitivity to antibody mediated inhibition due to underlying antigenic variation. When Plasmodium falciparum isolates are tested with antibodies from the donor originally harbouring the parasites or with those from other donors, growth inhibition is usually lowest in the autologous combinations. Parasites with decreased sensitivity are also generated in vitro by culturing them for prolonged periods in the presence of certain anti-plasmodial antibodies. When the antibodies are removed, a successive return of sensitivity develops. The decrease in sensitivity to inhibition may either be due to down-regulation of synthesis of the antigen or a selection of parasites with low antigen expression from the heterogeneous original populations. Both T lymphocytes carrying alpha/beta and gamma/delta antigen-receptors play a role in malaria immunity. However, although gamma/delta T cells may expand 40-fold or more in the peripheral immune system in acutely infected humans and also inhibit parasite growth in vitro and in vivo, their relative importance for protection or pathogenicity is presently unclear. Of the two major T cell subsets (CD4+, CD8+) carrying alpha/beta T cell receptors, the role of CD8+ T cells in blood stage infections appears to be limited. Instead, CD4+ T cells are of major importance. These cells comprise at least two functionally different subsets (Th1, Th2), distinguished on the basis of lymphokine secretion. In some rodent malaria models, Th1 cells producing primarily IL2 and IFN gamma give rise to protection in early infection while Th2 cells producing IL4 are essential for parasite clearance in late infection. In other mouse strains, the same parasites induce a strong Th2 response in early infection, resulting in a lethal course. CD4+ T cells of either Th1 or Th2 type also have regulatory functions in human P. falciparum malaria. Most humans living in areas of high endemicity have significantly elevated blood levels of IgE, reflecting a skewing of the underlying T helper cell ratio in favour of Th2, responsible for the switch in immunoglobulin isotypes. Less than 5% of the IgE in malaria represents antibodies to P. falciparum. IgE elevation is highest in patients with severe and particularly cerebral malaria and is frequently associated with an elevation of tumour necrosis factor alpha (TNF). The release of this cytokine from monocytes/macrophages may reflect crosslinking of their low affinity receptors for IgE (CD23) by IgE containing immune complexes from malarial sera. Local overproduction of TNF is considered a major pathogenic mechanism, responsible for fever and tissue lesions in severe malaria. Although TNF overproduction in malaria is generally assumed to be due to direct stimulation of effector cells by certain parasite derived toxins, the present results suggest that IgE elevation constitutes yet another mechanism contributing to the pathogenicity of P. falciparum in human malaria.