Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria.

Tumour-necrosis factor-alpha (TNF-alpha) is believed to have an important role in the pathogenesis of severe infectious disease and fatal cerebral malaria is associated with high circulating levels of this cytokine. In a large case-control study in Gambian children we find that homozygotes for the TNF2 allele, a variant of the TNF-alpha gene promoter region, have a relative risk of 7 for death or severe neurological sequelae due to cerebral malaria. Although the TNF2 allele is in linkage disequilibrium with several neighbouring HLA alleles, we show that this disease association is independent of HLA class I and class II variation. These data suggest that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection. The maintenance of the TNF2 allele at a gene frequency of 0.16 in The Gambia implies that the increased risk of cerebral malaria in homozygotes is counterbalanced by some biological advantage

Common west African HLA antigens are associated with protection from severe malaria.

A large case-control study of malaria in West African children shows that a human leucocyte class I antigen (HLA-Bw53) and an HLA class II haplotype (DRB1*1302-DQB1*0501), common in West Africans but rare in other racial groups, are independently associated with protection from severe malaria. In this population they account for as great a reduction in disease incidence as the sickle-cell haemoglobin variant. These data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens

Class I HLA-restricted cytotoxic T lymphocyte responses against malaria-elucidation on the basis of HLA peptide binding motifs

In animal models, CD8+ T cells are a critical effector mechanism in the protective immunity against malaria. Conventional approaches to the development of many vaccines, including those against malaria, have however proved inadequate. In particular, an alternative approach is needed for the development of vaccines designed to induce a cellular immune response mediated by CD8+ T cells. Advances in the field of molecular immunology during the past decade have provided an insight into the presentation of peptides by MHC class I molecules and their recognition by CD8+ T cells. These studies have provided a conceptual basis for the development of efficacious parasitic and viral vaccines. By a combination of immunochemical and cellular immunologic analyses based on specific peptide binding motifs, a subunit malaria vaccine that includes CD8+ T cell epitopes restricted by the most common class I HLA alleles, including HLA-A2, can now be constructed