The host inflammatory response may be involved in the pathogenesis of severe malaria. High plasma levels of pro-inflammatory cytokines, notably tumour necrosis factor (TNP), are found in African children with cerebral malaria. Experimental evidence also implicates TNF in the pathogenic process of severe malarial anaemia. We have examined the association of polymorphisms in the TNF gene promoter region with severe malaria in a large case-control study of Gambian children. Cerebral malaria, but

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... t severe malarial anaemia, was found to be associated with the TNF-308 A promoter allele (TNF2). Homozygotes for this allele had a relative risk of 7 for death or severe neurological sequelae due to cerebral malaria and this association was independent of variation in the neighbouring HLA class I and class II alleles. In the same population severe malarial anaemia was associated with the TNF-238 A promoter allele with an odds ratio of 2.5 after stratification for HLA type. These data suggest that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection and that severe malarial anaemia and cerebral malaria are influenced by separate genetic factors situated in the neighbourhood of the TNF gene. TNF is an endogenous pyrogen and a critical mediator of malaria fever. However, high plasma levels of TNF are sometimes found in afebrile African children with Plasmodium falciparum parasitaemia. A proposed mechanism for this apparent clinical tolerance is that soluble forms of TNF receptors (sTNF-R55 and sTNF-R75), that are known to inhibit TNF bioactivity in vitro, modulate the pyrogenic effect of TNF in vivo. We have measured the plasma levels of TNF, sTNF-R55 and sTNF-R75 in relation to episodes of malaria fever detected in a cross-sectional study of rural Gambian children during the malaria transmission season. TNF levels were significantly higher in children who were both parasitaemic and febrile, compared to those who were parasitaemic but afebrile and those who had no detectable parasitaemia. In c [...]