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Locally up-regulated lymphotoxin a, not systemic tumor necrosis factor a, is the principle mediator of murine cerebral malaria

Engwerda, C.R., Mynott, T.L., Sawhney, S., De Souza, J.B., Bickle, Q.D. and Kaye, P.M. (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

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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.

Item Type: Article
Academic Units: The University of 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
URI: http://eprints.whiterose.ac.uk/id/eprint/6662

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