title: Both functional LTbeta receptor and TNF receptor 2 are required for the development of experimental cerebral malaria.
abstract: BACKGROUND
  TNF-related lymphotoxin alpha (LTalpha) 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 LTalpha-signaling essential for ECM development through LTbeta-R, receptor of LTalpha1beta2 heterotrimer.
  
  
  RESULTS
  LTbetaR 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 LTalphabeta deficient mice. Resistance of LTalphabeta or LTbetaR 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 LTbetaR ligand, could be excluded, as LIGHT deficient mice rapidly succumbed to ECM.
  
  
  CONCLUSIONS
  LTbetaR 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 LTbetaR and TNFR2 signaling are required and non-redundant for the development of microvascular pathology resulting in fatal ECM.
authors.affiliation: University of Orléans and CNRS, Molecular Immunology and Embryology UMR6218, Orleans, France.
authors.forename: Dieudonnée
authors.initials: D
authors.lastname: Togbe
authors.forename: Paulo Loureiro
authors.initials: PL
authors.lastname: de Sousa
authors.forename: Mathilde
authors.initials: M
authors.lastname: Fauconnier
authors.forename: Victorine
authors.initials: V
authors.lastname: Boissay
authors.forename: Lizette
authors.initials: L
authors.lastname: Fick
authors.forename: Stefanie
authors.initials: S
authors.lastname: Scheu
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Robert
authors.initials: R
authors.lastname: Menard
authors.forename: Georges E
authors.initials: GE
authors.lastname: Grau
authors.forename: Bich-Thuy
authors.initials: BT
authors.lastname: Doan
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Beloeil
authors.forename: Laurent
authors.initials: L
authors.lastname: Renia
authors.forename: Anna M
authors.initials: AM
authors.lastname: Hansen
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Ball
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Hunt
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Valerie F J
authors.initials: VF
authors.lastname: Quesniaux
mesh_terms: D000818:Animals; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D016779:Malaria, Cerebral / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D010962:Plasmodium berghei / Q000472:pathogenicity; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D053259:Lymphotoxin beta Receptor; D047889:Receptors, Tumor Necrosis Factor, Type II