%0 Journal Article
%T Both Functional LT¦Â Receptor and TNF Receptor 2 Are Required for the Development of Experimental Cerebral Malaria
%A Dieudonn¨¦e Togbe
%A Paulo Loureiro de Sousa
%A Mathilde Fauconnier
%A Victorine Boissay
%A Lizette Fick
%A Stefanie Scheu
%A Klaus Pfeffer
%A Robert Menard
%A Georges E. Grau
%A Bich-Thuy Doan
%A Jean Claude Beloeil
%A Laurent Renia
%A Anna M. Hansen
%A Helen J. Ball
%A Nicholas H. Hunt
%A Bernhard Ryffel
%A Valerie F. J. Quesniaux
%J PLOS ONE
%D 2008
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0002608
%X Background TNF-related lymphotoxin ¦Á (LT¦Á) is essential for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The pathway involved has been attributed to TNFR2. Here we show a second arm of LT¦Á-signaling essential for ECM development through LT¦Â-R, receptor of LT¦Á1¦Â2 heterotrimer. Methodology/Principal Findings LT¦ÂR deficient mice did not develop the neurological signs seen in PbA induced ECM but died at three weeks with high parasitaemia and severe anemia like LT¦Á¦Â deficient mice. Resistance of LT¦Á¦Â or LT¦ÂR deficient mice correlated with unaltered cerebral microcirculation and absence of ischemia, as documented by magnetic resonance imaging and angiography, associated with lack of microvascular obstruction, while wild-type mice developed distinct microvascular pathology. Recruitment and activation of perforin+ CD8+ T cells, and their ICAM-1 expression were clearly attenuated in the brain of resistant mice. An essential contribution of LIGHT, another LT¦ÂR ligand, could be excluded, as LIGHT deficient mice rapidly succumbed to ECM. Conclusions/Significance LT¦ÂR expressed on radioresistant resident stromal, probably endothelial cells, rather than hematopoietic cells, are essential for the development of ECM, as assessed by hematopoietic reconstitution experiment. Therefore, the data suggest that both functional LT¦ÂR and TNFR2 signaling are required and non-redundant for the development of microvascular pathology resulting in fatal ECM.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0002608