Distinct patterns of cytokine regulation in discrete clinical forms of Plasmodium falciparum malaria

The pathogenesis of two of the most severe complications of Plasmodium falc iparum malaria, cerebral malaria (CM) and severe malarial anaemia (SA) both appear to involve dysregulation of the immune system. We have measured pla sma levels of TNF and its two receptors in Ghanaian children with strictly defined cerebral malaria (CM), severe malarial anaemia (SA), or uncomplicat ed malaria (UM) in two independent studies in an area of seasonal, hyperend emic transmission of P. falciparum. Levels of TNF, soluble TNF receptor 1 ( sTNF-R1) and 2 (sTNF-R2) were found to be significantly higher in CM than i n the other clinical categories of P. falciparum malaria patients. Levels o f both receptors depended on clinical category, whereas only sTNF-R1 levels were significantly dependent on parasitemia, Detailed analysis of the inte rrelationship between these variables resolved this pattern further, and id entified marked differences between the patient categories. While levels of TNF, sTNF-R1 and sTNF-R2 correlated with parasitemia in UM, this was not t he case in CM and SA, Rather, there was a tendency towards high levels of T NF and its receptors in CM and low levels in SA without significant correla tion to parasitemia in either category. This, and the fact that malaria-ind uced increases in plasma levels of IL-10 are much lower in SA compared to C M, suggest that distinct forms of dysregulation of the immune response to i nfection contribute to the pathogenesis of CM and SA.