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K. R. Manogue

Bio: K. R. Manogue is an academic researcher from Rockefeller University. The author has contributed to research in topics: Malaria & Plasmodium falciparum. The author has an hindex of 1, co-authored 1 publications receiving 835 citations.

Papers
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Journal ArticleDOI
TL;DR: It is concluded that increased TNF production is a normal host response to P falciparum infection, but that excessive levels of production may predispose to cerebral malaria and a fatal outcome.

861 citations


Cited by
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Journal ArticleDOI
TL;DR: It is demonstrated, 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.
Abstract: Tumor necrosis factor α (TNFα) is a potent immunomodulator and proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. For example, plasma levels of TNFα are positively correlated with severity and mortality in malaria and leishmaniasis. We have previously described a polymorphism at −308 in the TNFα 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 TNFα 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 TNFα gene regulation and may be responsible for the association of TNF2 with high TNFα phenotype and more severe disease in infections such as malaria and leishmaniasis.

2,275 citations

Journal ArticleDOI
TL;DR: The central role of TNF in inflammation has been demonstrated by the ability of agents that block the action of T NF to treat a range of inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis.
Abstract: TNF was originally described as a circulating factor that can cause necrosis of tumours, but has since been identified as a key regulator of the inflammatory response This review describes the known signalling pathways and cell biological effects of TNF, and our understanding of the role of TNF in human disease TNF interacts with two different receptors, designated TNFR1 and TNFR2, which are differentially expressed on cells and tissues and initiate both distinct and overlapping signal transduction pathways These diverse signalling cascades lead to a range of cellular responses, which include cell death, survival, differentiation, proliferation and migration Vascular endothelial cells respond to TNF by undergoing a number of pro-inflammatory changes, which increase leukocyte adhesion, transendothelial migration and vascular leak and promote thrombosis The central role of TNF in inflammation has been demonstrated by the ability of agents that block the action of TNF to treat a range of inflammatory conditions, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease and psoriasis The increased incidence of infection in patients receiving anti-TNF treatment has highlighted the physiological role of TNF in infectious diseases

1,645 citations

Journal ArticleDOI
15 Aug 1991-Nature
TL;DR: Data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.
Abstract: 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.

1,554 citations

Journal ArticleDOI
06 Oct 1994-Nature
TL;DR: 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, suggesting that regulatory polymorphisms of cytokine genes can affect the outcome of severe infection.
Abstract: 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.

1,181 citations

Journal ArticleDOI
12 Nov 1993-Science
TL;DR: The immunopathogenic mechanisms underlying human immunodeficiency virus (HIV) disease are extremely complex; the disease process is multifactorial with multiple overlapping phases as mentioned in this paper, and therapeutic strategies in HIV disease must not be unidimensional, but rather must be linked to the complex pathogenic components of the disease and must address where feasible each of the recognized pathogenic processes for the possibility of therapeutic intervention.
Abstract: The immunopathogenic mechanisms underlying human immunodeficiency virus (HIV) disease are extremely complex; the disease process is multifactorial with multiple overlapping phases. Viral burden is substantial and viral replication occurs throughout the entire course of HIV infection. Inappropriate immune activation and elevated secretion of certain cytokines compound the pathogenic process. Profound immunosuppression ultimately occurs together with a disruption of the microenvironment of the immune system, which is probably unable to regenerate spontaneously. Thus, therapeutic strategies in HIV disease must not be unidimensional, but rather must be linked to the complex pathogenic components of the disease and must address where feasible each of the recognized pathogenic processes for the possibility of therapeutic intervention.

812 citations