Locally Up-regulated Lymphotoxin {alpha}, Not Systemic Tumor Necrosis Factor {alpha}, Is the Principle Mediator of Murine Cerebral Malaria

doi:10.1084/jem.20020128

Published 20 May 2002. doi:10.1084/jem.20020128

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© Rockefeller University Press, 0022-1007/2002/5/1371/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 10, May 20, 2002 1371-1377

Brief Definitive Report

Locally Up-regulated Lymphotoxin ${alpha}$ , Not Systemic Tumor Necrosis Factor ${alpha}$ , Is the Principle Mediator of Murine Cerebral Malaria

Christian R. Engwerda¹, Tracey L. Mynott², Sanjeet Sawhney¹, J. Brian De Souza³, Quentin D. Bickle¹ and Paul M. Kaye¹

¹ Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom
² Centre for Molecular Microbiology and Infection, Imperial College of Science, Technology and Medicine, London SW7 2AZ, United Kingdom
³ Department of Immunology, Royal Free and University College London Medical School, Windeyer Institute of Medical Science, London W1P 6DB, United Kingdom

Address correspondence to Christian Engwerda, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel St., London WC1E 7HT, UK. Phone: 44-207-927-2424; Fax: 44-207-323-5687; E-mail: christian.engwerda{at}lshtm.ac.uk

Cerebral malaria (CM) causes death in children and nonimmuneadults. TNF- ${alpha}$ has been thought to play a key role in the developmentof 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 afterdeveloping neurological signs of CM, associated with perivascularbrain hemorrhage. Significantly, the development of CM in B6.TNF ${alpha}$ ^-/-mice was not associated with increased intracellular adhesionmolecule (ICAM)-1 expression on cerebral vasculature and theintraluminal accumulation of complement receptor 3 (CR3)-positiveleukocytes was moderate. In contrast, mice deficient in LT ${alpha}$ (B6.LT ${alpha}$ ^-/-)were completely resistant to CM and died 11 to 14 d after infectionwith severe anemia and hyperparasitemia. No difference in bloodparasite 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 showedthe persistence of cerebral LT ${alpha}$ mRNA after irradiation and engraftmentof LT ${alpha}$ -deficient BM, indicating that LT ${alpha}$ originated from a radiation-resistantcell population.

Key Words: parasitic disease • protozoan infection • Plasmodium berghei • immunopathology • infection

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