In this review I attempt to advance hypotheses that might help contribute toward understanding the molecular pathogenesis of cerebral malaria (CM) and other complications based on a now widely accepted argument that the illness and pathology occasioned by Plasmodiumfalciparum infection might not necessarily be due to the direct effects of the parasite’s ‘toxins’ and/or exoantigens or even its sequestration and consequent attendant effects in vital organs but rather to the parasite’s mediated production of microbicidal molecules by the host. Tumor necrosis factor (TNF)-α is implicated in the pathogenesis of complicated malaria. There is a positive correlation between high levels of TNF-α and severity of malaria. The role of nitric oxide in the pathophysiology of complicated malaria is not clearly understood. Mononuclear phagocytes by virtue of their capacity to secrete toxic intermediates like reactive oxygen intermediates can inhibit the growth of both murine and human plasmodia. The role of interleukin-10 (IL-10) in malaria is also not well characterized to date. IL-10 is a powerful immunosuppressor factor. It acts as a natural dampener of immunoproliferative and inflammatory responses. Although transforming growth factor-β has a crucial role in inflammation and repair, its role in complicated malaria is not too clearly understood. Furthermore, the anatomical source of these microbicidal molecules is not precisely known. The role of immune complexes (IC) in the pathophysiology of complicated malaria has hitherto not been tested. I argue here that IC play a critical role in influencing the outcome of malarial disease; IC-mediated stimulation of leukocytes to produce high levels of both TNF-α and NO and the fact that leukocytes are probably the principal anatomical source of these microbicidal and other pro-inflammatory mediators in complicated malaria provide a much more plausible explanation for the pathogenesis of CM and other complications. I also review the arguments that help contribute to rationalize hypoglycemia and hyperlactatemia in malarial disease and to some extent severe anemia. I am therefore tempted to conclude that CM and other complications are probably immune-mediated diseases or, at least, they present an inflammatory pathogenesis.

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