Engwerda, C.R., Mynott, T.L., Sawhney, S. et al. (3 more authors) (2002) Locally up-regulated lymphotoxin a, not systemic tumor necrosis factor a, is the principle mediator of murine cerebral malaria. Journal of Experimental Medicine, 195 (10). pp. 1371-1377. ISSN 0022-1007
Abstract
Cerebral malaria (CM) causes death in children and nonimmune adults. TNF-{alpha} has been thought to play a key role in the development of CM. In contrast, the role of the related cyto-kine lymphotoxin {alpha} (LT{alpha}) in CM has been overlooked. Here we show that LT{alpha}, not TNF{alpha}, is the principal mediator of murine CM. Mice deficient in TNF{alpha} (B6.TNF{alpha}-/-) were as susceptible to CM caused by Plasmodium berghei (ANKA) as C57BL/6 mice, and died 6 to 8 d after infection after developing neurological signs of CM, associated with perivascular brain hemorrhage. Significantly, the development of CM in B6.TNF{alpha}-/- mice was not associated with increased intracellular adhesion molecule (ICAM)-1 expression on cerebral vasculature and the intraluminal accumulation of complement receptor 3 (CR3)-positive leukocytes was moderate. In contrast, mice deficient in LT{alpha} (B6.LT{alpha}-/-) were completely resistant to CM and died 11 to 14 d after infection with severe anemia and hyperparasitemia. No difference in blood parasite burden was found between C57BL/6, B6.TNF{alpha}-/-, and B6.LT{alpha}-/- mice at the onset of CM symptoms in the two susceptible strains. In addition, studies in bone marrow (BM) chimeric mice showed the persistence of cerebral LT{alpha} mRNA after irradiation and engraftment of LT{alpha}-deficient BM, indicating that LT{alpha} originated from a radiation-resistant cell population.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | York RAE Import |
Date Deposited: | 22 Apr 2009 10:01 |
Last Modified: | 22 Apr 2009 10:01 |
Published Version: | http://dx.doi.org/10.1084/jem.20020128 |
Status: | Published |
Publisher: | Rockefeller University Press |
Identification Number: | 10.1084/jem.20020128 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:6662 |