Tumor necrosis factor ␣ (TNF␣) is a potent immunomodulator and proinf lammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. For example, plasma levels of TNF␣ are positively correlated with severity and mortality in malaria and leishmaniasis. We have previously described a polymorphism at ؊308 in the TNF␣ promoter and shown that the rare allele, TNF2, lies on the extended haplotype HLA-A1-B8-DR3-DQ2, which is associated with autoimmunity and high TNF␣ production. Homozygosity for TNF2 carries a sevenfold increased risk of death from cerebral malaria. Here we demonstrate, with reporter genes under the control of the two allelic TNF promoters, that TNF2 is a much stronger transcriptional activator than the common allele (TNF1) in a human B cell line. Footprint analysis using DNase I and B cell nuclear extract showed the generation of a hypersensitive site at ؊308 and an adjacent area of protection. There was no difference in affinity of the DNA-binding protein(s) between the two alleles. These results show that this polymorphism has direct effects on TNF␣ gene regulation and may be responsible for the association of TNF2 with high TNF␣ phenotype and more severe disease in infections such as malaria and leishmaniasis.

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