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• W2088304428 abstract "We explored the role of CD40-CD40L (CD154) in the severe malaria elicited by Plasmodium berghei anka infection in mice. Mortality was >90% by day 8 after infection in +/+ mice, but markedly decreased in CD40−/− or in CD40L−/− mice, as well as in +/+ mice treated with anti-CD40L monoclonal antibody. Parasitemia was similar in the different conditions. Breakdown of the blood-brain barrier was evident in infected +/+, but not in CD40−/− mice. Thrombocytopenia was less severe in CD40−/− mice than in the +/+ controls. Sequestration of macrophages in brain venules and alveolar capillaries was reduced in CD40−/− or in CD40L−/− mice, whereas sequestration of parasitized red blood cells or polymorphonuclear leukocytes in alveolar capillaries was CD40-CD40L-independent. CD40 mRNA was increased in the brain and lung of infected mice whereas CD40L was increased in the lung. Tumor necrosis factor plasma levels were similarly increased in infected +/+ or CD40−/− mice. Expression of CD54 and its mRNA levels in the brain were moderately decreased in CD40-deficient mice. Thus the mortality associated with severe malaria requires CD40-CD40L interaction that contributes to the breakdown of the blood-brain barrier, macrophage sequestration, and platelet consumption. We explored the role of CD40-CD40L (CD154) in the severe malaria elicited by Plasmodium berghei anka infection in mice. Mortality was >90% by day 8 after infection in +/+ mice, but markedly decreased in CD40−/− or in CD40L−/− mice, as well as in +/+ mice treated with anti-CD40L monoclonal antibody. Parasitemia was similar in the different conditions. Breakdown of the blood-brain barrier was evident in infected +/+, but not in CD40−/− mice. Thrombocytopenia was less severe in CD40−/− mice than in the +/+ controls. Sequestration of macrophages in brain venules and alveolar capillaries was reduced in CD40−/− or in CD40L−/− mice, whereas sequestration of parasitized red blood cells or polymorphonuclear leukocytes in alveolar capillaries was CD40-CD40L-independent. CD40 mRNA was increased in the brain and lung of infected mice whereas CD40L was increased in the lung. Tumor necrosis factor plasma levels were similarly increased in infected +/+ or CD40−/− mice. Expression of CD54 and its mRNA levels in the brain were moderately decreased in CD40-deficient mice. Thus the mortality associated with severe malaria requires CD40-CD40L interaction that contributes to the breakdown of the blood-brain barrier, macrophage sequestration, and platelet consumption. Infection of mice by Plasmodium berghei anka (PbA) results, in susceptible strains, to a lethal syndrome, commonly named cerebral malaria, in which mice die 7 to 9 days after infection in a state of coma associated with neurological manifestations,1Wright DH The effect of neonatal thymectomy on the survival of golden hamsters infected with Plasmodium berghei.Br J Exp Pathol. 1968; 49: 379-384PubMed Google Scholar, 2White NJ Ho M Advances in parasitology. The Pathophysiology of Malaria. Academic Press, New York1992: 84-173Google Scholar Prominent in this syndrome are a breakdown of the blood-brain barrier, microhemorrhages, and sequestration of macrophages and platelets in the cortical venules.3Thumwood CM Hunt NH Clark IA Cowden WB Breakdown of the blood-brain barrier in murine cerebral malaria.Parasitology. 1988; 96: 579-589Crossref PubMed Scopus (125) Google Scholar, 4Clark IA Macmicking JD Gray KM Rockett KA Cowden WB Malaria mimicry with tumor necrosis factor. Contrasts between species of murine malaria and plasmodium falciparum.Am J Pathol. 1992; 140: 325-336PubMed Google Scholar, 5Senaldi G Vesin C Chang R Grau G Piguet PF An effector role of neutrophils in the pathogenesis of murine severe malaria.Infect Immun. 1994; 62: 1144-1149PubMed Google Scholar, 6Favre N Willimann K Ryffel B Weiss N Imhof BA Rudin W Lucas R Piguet PF Role of ICAM-1 in the development of murine cerebral malaria.Microbes Infect. 1999; 1: 961-968Crossref PubMed Scopus (112) Google Scholar In addition, there is a sequestration of macrophages, polymorphonuclear leukocytes (PMNs), parasitized red blood cells (pRBCs), and platelets in other organs, notably the lung.5Senaldi G Vesin C Chang R Grau G Piguet PF An effector role of neutrophils in the pathogenesis of murine severe malaria.Infect Immun. 1994; 62: 1144-1149PubMed Google Scholar, 6Favre N Willimann K Ryffel B Weiss N Imhof BA Rudin W Lucas R Piguet PF Role of ICAM-1 in the development of murine cerebral malaria.Microbes Infect. 1999; 1: 961-968Crossref PubMed Scopus (112) Google Scholar, 7Coquelin F Boulard Y Mora-Silvera E Richard F Chabaud AG Landau I Final stage maturation of the erythrocytic schizonts of rodent Plasmodium in the lungs.C R Acad Sci (III). 1999; 322: 55-62Crossref PubMed Scopus (20) Google Scholar Hence, because this syndrome is not limited to the brain, it is also referred as severe malaria (SM). Various studies using antibodies, recombinant cytokines, or knock-out mice have shown that the secretion of tumor necrosis factor (TNF) is an important effector of the mortality of SM.8Grau GE Fajardo LF Piguet PF Allet B Lambert PH Vassalli P Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria.Science. 1987; 237: 1210-1212Crossref PubMed Scopus (616) Google Scholar, 9Grau GE Heremans H Piguet PF Pointaire P Lambert PH Billiau A Vassalli P Monoclonal antibody against interferon-gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor.Proc Natl Acad Sci USA. 1989; 86: 5572-5574Crossref PubMed Scopus (283) Google Scholar, 10Rudin W Eugster HP Bordmann G Bonato J Muller M Yamage M Ryffel B Resistance to cerebral malaria in tumor necrosis factor-alpha/beta-deficient mice is associated with a reduction of intercellular adhesion molecule-1 up-regulation and T helper type 1 response.Am J Pathol. 1997; 150: 257-266PubMed Google Scholar Further studies with TNF receptor (TNFR)-deficient mice have shown that mortality is dependent on the TNFR2 and not the TNFR1,11Lucas R Juillard P Decoster E Redard M Burger D Donati Y Giroud C Monso Hinard C De Kesel T Buurman WA et al.Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria.Eur J Immunol. 1997; 27: 1719-1725Crossref PubMed Scopus (164) Google Scholar whereas the reverse is true in the majority of immunological and/or infectious diseases.12Rothe J Lesslauer W Lotscher H Lang Y Koebel P Kontgen F Althage A Zinkernagel R Steinmetz M Bluethman H Mice lacking the tumor necrosis receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes.Nature. 1993; 364: 798-802Crossref PubMed Scopus (1148) Google ScholarTNF production is induced by an immune response, elicited by the presence of the parasite in the blood.13Grau GE Piguet PF Engers HD Louis JA Vassalli P Lambert PH L3T4+ T lymphocytes play a major role in the pathogenesis of murine cerebral malaria.J Immunol. 1986; 137: 2348-2354PubMed Google Scholar Indeed, depletion of CD4 T lymphocyte prevents the acute mortality of PbA infection in mice, apparently by decreasing TNF production.1Wright DH The effect of neonatal thymectomy on the survival of golden hamsters infected with Plasmodium berghei.Br J Exp Pathol. 1968; 49: 379-384PubMed Google Scholar, 13Grau GE Piguet PF Engers HD Louis JA Vassalli P Lambert PH L3T4+ T lymphocytes play a major role in the pathogenesis of murine cerebral malaria.J Immunol. 1986; 137: 2348-2354PubMed Google Scholar TNF might be responsible for some of the manifestations of SM, such as the hypoglycemia and the sequestration of cells in the microcirculation. TNF is known to increase the expression of the adhesion molecules CD54 (ICAM-1) and CD106 (VCAM) on endothelia,14Lucas R Lou JN Juillard P Moore M Bluethmann H Grau GE Respective role of TNF receptors in the development of experimental cerebral malaria.J Neuroimmunol. 1997; 72: 143-148Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar, 15Imhof BA Dunon D Leukocyte migration and adhesion.Adv Immunol. 1995; 58: 345-416Crossref PubMed Google Scholar, 16Ma N Hunt NH Madigan MC Chan Ling T Correlation between enhanced vascular permeability, up-regulation of cellular adhesion molecules, and monocyte adhesion to the endothelium in the retina during the development of fatal murine cerebral malaria.Am J Pathol. 1996; 149: 1745-1762PubMed Google Scholar which might contribute to increasing the adhesion of leukocytes and other cells and thereby disturbing the microcirculation in the brain and other organs. This pathogenic hypothesis is supported by the increased expression of CD54 and CD106 in the brain microcirculation during SM and the delayed mortality seen in mice treated with anti-CD11a mAb (LFA-1, a β2 integrin determinant)6Favre N Willimann K Ryffel B Weiss N Imhof BA Rudin W Lucas R Piguet PF Role of ICAM-1 in the development of murine cerebral malaria.Microbes Infect. 1999; 1: 961-968Crossref PubMed Scopus (112) Google Scholar, 17Grau GE Pointaire P Piguet PF Vesin C Rosen H Stamenkovic I Takei F Vassalli P Late administration of monoclonal antibody to leukocyte function antigen 1 abrogates incipient murine cerebral malaria.Eur J Immunol. 1991; 21: 2265-2267Crossref PubMed Scopus (114) Google Scholar or in CD54-deficient mice.18Falanga PB Butcher EC Late treatment with anti-LFA-1(CD11a) antibody prevents cerebral malaria in a mouse model.Eur J Immunol. 1991; 21: 2259-2263Crossref PubMed Scopus (62) Google ScholarCD40 is a cell receptor belonging to the TNF receptor superfamily that can modulate cell proliferation, differentiation, and death.19Grell M Zimmermann G Gottfried E Chen CM Grunwald U Huang DCS Lee YHW Durkop H Engelmann H Scheurich P et al.Induction of cell death by tumor necrosis factor (TNF) receptor 2, CD40 and CD30: a role for TNF-R1 activation by endogenous membrane-anchored TNF.EMBO J. 1999; 18: 3034-3043Crossref PubMed Scopus (259) Google Scholar Studies based on mice genetically deficient in CD40 or its ligand CD40L (CD154) as well as the use of anti-CD40L mAb have demonstrated that this system plays an important role in both humoral and cell-mediated immunity.20Kawabe T Naka T Yoshida K Tanaka T Fujiwara H Suematsu S Yoshida N Kishimoto T Kikutani H The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation.Immunity. 1994; 1: 167-178Abstract Full Text PDF PubMed Scopus (972) Google Scholar, 21Grewal IS Flawell RA CD40 and CD154 in cell-mediated immunity.Ann Rev Immunol. 1998; 16: 111-135Crossref PubMed Scopus (1323) Google Scholar Presence of CD40 has been reported on B lymphocytes, platelets, mast cells, endothelial cells, and dendritic cells, whereas the source of CD40L includes T lymphocytes, macrophages, and platelets.21Grewal IS Flawell RA CD40 and CD154 in cell-mediated immunity.Ann Rev Immunol. 1998; 16: 111-135Crossref PubMed Scopus (1323) Google Scholar, 22Henn V Slupsky JR Grafe M Anagnostopoulos I Forster R Mueller-Berghaus G Kroczek R CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells.Nature. 1998; 391: 591-594Crossref PubMed Scopus (1730) Google Scholar Response to infectious agents; rejection of allograft; autoimmune diseases, such as encephalitis, arthritis, atherosclerosis and pulmonary fibrosis, are attenuated in mice with a perturbation of the CD40-CD40L signaling.21Grewal IS Flawell RA CD40 and CD154 in cell-mediated immunity.Ann Rev Immunol. 1998; 16: 111-135Crossref PubMed Scopus (1323) Google Scholar Understanding of the role of CD40-CD40L in cell-mediated immunity is presently incomplete because CD40-CD40L seems to be critical for the resistance to some intracellular parasites such as Leishmania,23Kamanaka M Yu P Yasui T Yoshida K Kawabe T Hori T Kishimoto T Kitutani H Protective role of CD40 in Leishmania major infection at two distinct phases of cell-mediated immunity.Immunity. 1996; 4: 275-281Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar but not others such as mycobacteria.24Campos-Neto A Ovendale P Bement T Koppi TA Fanslow WC Rossi MA Alderson MR CD40 ligand is not essential for the development of cell-mediated immunity and resistance to mycobacterium tuberculosis.J Immunol. 1998; 160: 2037-2041PubMed Google Scholar CD40-CD40L signaling has been reported to induce the expression of adhesion molecules CD54, CD62E, and CD106 on endothelial cells from the umbilical vein,25Yellin MJ Brett J Baum D Matsushima A Szabolcs M Stern D Chess L Functional interactions of T cells with endothelial cells: the role of CD40L-CD40-mediated signals.J Exp Med. 1995; 182: 1857-1864Crossref PubMed Scopus (240) Google Scholar that might be relevant to the pathogenesis of SM, as discussed above.In this report, we explored the role of CD40-CD40L in the course of PbA-induced SM. Mortality was completely abrogated in CD40−/−, CD40L−/−, as well as in mice treated with the anti-CD40L mAb, indicating an essential role of this system in the pathogenesis of SM.Materials and MethodsMiceCD40L−/− and CD54−/− mice,6Favre N Willimann K Ryffel B Weiss N Imhof BA Rudin W Lucas R Piguet PF Role of ICAM-1 in the development of murine cerebral malaria.Microbes Infect. 1999; 1: 961-968Crossref PubMed Scopus (112) Google Scholar isolated on the C57BL/6 background, were obtained from the Jackson Laboratory (Bar Harbor, ME). CD40−/− were obtained from R. Geha, Boston, MA.26Castigli E Alt FW Davidson L Bottaro A Mizoguchi E Bhan A Geha RS CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation.Proc Natl Acad Sci USA. 1994; 91: 12135-12139Crossref PubMed Scopus (235) Google Scholar Mice were bred in our animal facilities as well as the C57BL/6J (B6) also obtained from the Jackson Laboratory, which were used as wild-type (+/+) controls.PbA and TreatmentPbA has been passed in rodents1Wright DH The effect of neonatal thymectomy on the survival of golden hamsters infected with Plasmodium berghei.Br J Exp Pathol. 1968; 49: 379-384PubMed Google Scholar and mice were infected by an intravenous injection of 5 × 104 parasitized red blood cells (pRBCs).Anti-CD40L mAb was derived from the hybridoma MR1 of hamster origin.27Noelle RJ Roy M Shepherd DM Stamenkovic I Ledbetter JA Aruffo A A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells.Proc Natl Acad Sci USA. 1992; 89: 6550-6554Crossref PubMed Scopus (790) Google Scholar mAbs or nonimmune hamster IgG, as a control, were purified by protein A-Sepharose. Mice were injected with the anti-CD40L mAb or nonimmune hamster IgG (250 μg IgG, ip) on day 6 after infection.BloodBlood (0.015 ml) was isolated from the retro-orbital plexus of ethrane-anesthetized mice using heparinized capillaries and diluted in ethylenediaminetetraacetic acid (1% final), in accord with the Swiss national guidelines. Blood elements were counted in a cell counter (Casy 1, Schärfe system, D-72760 Reutlingen, Fluka, 9470-CH). Parasitemia was counted on blood smears stained with May-Grunwald-Giemsa.Assessment of Vascular LeakMice (three wild-type and three mutant) were injected intravenously with 0.2 ml of 1% Evans blue on day 6, shortly before death of the wild-type mice. One hour later, mice were sacrificed and the staining of brain sections was assessed as an indicator of increased capillary permeability.Light and Electron MicroscopyMice were sacrificed by an intraperitoneal injection of nembutal and the aorta was cut. Brain was isolated and immersion-fixed in formaldehyde 5% in ethanol 70%. Frontal sections were prepared for ordinary histology. Venules within the cortex were examined and the endothelial cells and macrophages were counted. Endothelial cells were counted (>50/sections) as well as the number of macrophages and the sequestration was evaluated by the macrophage/endothelial ratio. Megakaryocytopoiesis was evaluated on sections of the spleen, by counting at a magnification of 400-fold, the number of megakaryocytes/microscopic field, as described previously.28Piguet PF Vesin C Laperousaz CD Rochat A Role of plasminogen activators and of urokinase receptor (uPAR, CD87) in platelet kinetics in mice.Hematol J. 2000; 1: 199-205Crossref PubMed Scopus (9) Google ScholarTo examine the lung, the thorax was opened and the lung was fixed by intratracheal instillation of glutaraldehyde (5% in 0.1 mol/L cacodylate buffer) and processed for epon embedding. A section was taken in the left lobe across the hilus. Thin sections were prepared from two blocks/mouse taken from the parenchyma. Thin sections were examined with a Philips 400 electron microscope at 60 kV. Cells within alveolar capillaries were examined and red blood cells (RBCs), parasitized RBCs (pRBCs), platelets, and PMNs were counted. Approximately 100 RBCs were counted per each individual thin section. RBCs were used as a neutral indicator of blood stasis and sequestration was evaluated by the platelets/RBCs and PMN/RBC ratios.ImmunohistochemistryFrozen tissue sections were immunostained as described elsewhere. Briefly, 5-μm sections were incubated overnight at room temperature with rat mAbs: anti-CD54 and anti-CD106 mAbs, as described previously,6Favre N Willimann K Ryffel B Weiss N Imhof BA Rudin W Lucas R Piguet PF Role of ICAM-1 in the development of murine cerebral malaria.Microbes Infect. 1999; 1: 961-968Crossref PubMed Scopus (112) Google Scholar or anti-CD40 mAb FGK45.29Rolink A Melchers F Andersson J The Scid but not the Rag-2 gene product is required for S mu-S epsilon heavy chain class switching.Immunity. 1996; 5: 319-330Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar After washing, sections were incubated 1 hour with fluorescein isothiocyanate-labeled goat anti-rat IgG (Southern Biotechnology, Bioreba, Reinach, Switzerland).Evaluation of TNF Serum LevelTNF-α was evaluated on the citrated plasma, using the mouse enzyme-linked immunosorbent assay Dy 410 (R&D Systems, Inc, Minneapolis, MN), which detects both free and receptor-bound TNF, with a sensitivity of 12 pg/ml.Evaluation of CD40L, CD40, TNF-α, and CD54 mRNA LevelsTNF-α (TNF),30Piguet PF Collart MA Grau GE Kapanci Y Vassalli P Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis.J Exp Med. 1989; 170: 655-663Crossref PubMed Scopus (496) Google Scholar CD40L,31Mendoza RB Cantwell MJ Kipps TJ Immunostimulatory effects of a plasmid expressing CD40 ligand (CD154) on gene immunization.J Immunol. 1997; 159: 5777-5781PubMed Google Scholar CD40,32Grimaldi JC Torres R Kozak CA Chang R Clark EA Howard M Cockayne DA Genomic structure and chromosomal mapping of the murine CD40 gene.J Immunol. 1992; 149: 3921-3926PubMed Google Scholar and CD5433Horley KJ Carpeinto C Baker B Takei F Molecular cloning of murine intercellular adhesion molecule (ICAM-1).EMBO J. 1989; 8: 2889Crossref PubMed Scopus (144) Google Scholar mRNA levels were evaluated on Northern blots, using 32P-labeled dUTP riboprobes. Quantification of mRNA was performed using the Arcus II system of quantification of scanned gels (Agfa, Mortsel, Belgium) with the Image Quant Analysis (Molecular Dynamics, Sunnyvale, CA) integration. The values were normalized to the 18S RNA and the amount of mRNA was expressed in arbitrary units.34Barazzone C Horowitz S Donati Y Vesin C Rochat A Rodriguez I Piguet PF Oxygen toxicity in mouse lung: pathways to cell death.Am J Respir Cell Mol Biol. 1998; 19: 573-581Crossref PubMed Scopus (230) Google ScholarStatistical EvaluationSignificance analysis of survival curves was determined by Fisher's exact test. Groups of values were compared using Student's t-test or the nonparametric Mann and Whitney test.35Mann HB Whitney DR On a test of whether one or two random variables is stochastically larger than the other.Ann Math Statist. 1947; 18: 50-60Crossref Google ScholarResultsMorbidity and MortalityInfection with PbA results, in susceptible mice, in a lethal complication 7 to 9 days after infection.8Grau GE Fajardo LF Piguet PF Allet B Lambert PH Vassalli P Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria.Science. 1987; 237: 1210-1212Crossref PubMed Scopus (616) Google Scholar More than 90% of the infected +/+ mice were dead on day 8 after infection, while the CD40−/− (Figure 1A) or the CD40L−/− (not shown) did survive beyond day 12. A few hours before death, mice became hypothermic and comatose, and because a temperature below 33°C is invariably followed by death, this criteria was used as an end point in the majority of the experiments for ethical reasons. Thus, hypothermia was evident on days 7 to 8 after infection in infected +/+, but absent or markedly attenuated in CD40−/−, CD40L−/− mice, as well as in +/+ mice treated with anti-CD40L mAbs (Figure 1, B and C).Blood-Brain BarrierA breakdown of the blood-brain barrier, detected by a leakage of Evans blue, as well as an increase of the vascular permeability in other organs, such as the lung, are evident during PbA-induced SM.3Thumwood CM Hunt NH Clark IA Cowden WB Breakdown of the blood-brain barrier in murine cerebral malaria.Parasitology. 1988; 96: 579-589Crossref PubMed Scopus (125) Google Scholar, 6Favre N Willimann K Ryffel B Weiss N Imhof BA Rudin W Lucas R Piguet PF Role of ICAM-1 in the development of murine cerebral malaria.Microbes Infect. 1999; 1: 961-968Crossref PubMed Scopus (112) Google Scholar A marked increase of the leak was evident in infected +/+, but not in CD40−/− mice (Figure 2).Figure 2Blood-brain barrier. Noninfected +/+ and infected +/+ and CD40−/− mice were injected with Evans blue 7 days after infection. There is an increase of leak of Evans blue in the brain (top) and lung (bottom) in infected +/+, but not in infected CD40−/− mice. Infected CD40−/− are similar to a noninfected +/+ mouse.View Large Image Figure ViewerDownload Hi-res image Download (PPT)ParasitemiaParasitemia was similar in +/+, CD40−/− and CD40L−/− mice until day 8 after infection when the +/+ died (Figure 3) while in the CD40−/− and CD40L−/− mice, parasitemia kept increasing the following days. Mortality was therefore not related to difference in parasitemia.Figure 3Parasitemia in +/+, CD40−/− and CD40L−/− mice. Mean (+SD, n = 10) of the percentage of pRBCs various times after infection. Wild-type (+/+) mice were all dead by day 8 after infection.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In +/+ mice treated with anti-CD40L mAb, no significant change appeared in the percentage of parasitized red blood cells (not shown).Splenomegaly after PbA InfectionSeven days after infection, the spleen increased approximately threefold in size, and this was evident in +/+ as well as in CD40−/− mice, whereas in CD40L−/− mice, the splenomegaly was less pronounced (Figure 4). In contrast, the size of the lymph nodes did not change significantly in +/+ infected mice (not shown).Figure 4Splenomegaly after PbA infection. Weight of the spleen (mean + SD, n = 5) 7 to 8 days after infection.View Large Image Figure ViewerDownload Hi-res image Download (PPT)PlateletsSM is associated with a severe thrombocytopenia because of a reduced platelet life span.36Grau GE Piguet PF Gretener D Vesin C Lambert PH Immunopathology of thrombocytopenia in experimental malaria.Immunology. 1988; 65: 501-506PubMed Google Scholar On the 7th day after infection, +/+ mice were severely thrombocytopenic, but thrombocytopenia was attenuated significantly, but to a modest extent, in CD40−/− mice and more markedly in CD40L−/− (Figure 5A). Thrombocytopenia was also significantly attenuated in +/+ mice treated with the anti-CD40L mAb, compared to those treated with the control IgG (Figure 5B).Figure 5Platelet counts during SM. A: Platelet counts 7 days after infection. Wild-type mice (+/+) are significantly thrombocytopenic, compared to noninfected mice (n = 8, P < 0.01), whereas thrombocytopenia is significantly (P < 0.05) attenuated in infected CD40−/− and CD40L−/−, compared to +/+ mice. B: Values are the mean (+SD, n = 7) of the platelet counts 7 days after infection. Infected +/+ mice were treated on the 6th day after infection with nIgG or anti-CD40L mAb.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Cell SequestrationPbA-induced SM is associated with the sequestration of various cell types, notably in the brain and lung. In the brain, macrophage sequestration was evident in the cortical venules of infected +/+ mice and, as seen in Figure 6, this was markedly reduced in infected CD40−/− or CD40L−/− mice. In mice treated with the anti-CD40L mAb, the modification of sequestration was less conclusive. In some mice, sequestration was decreased, whereas in others, it was modified by an increase of lymphocyte sequestration together with macrophages. Sequestration of PMNs is not known to occur in the cerebral blood vessels of PbA-infected mice and was not observed in the present study (not shown). pRBCs are present in the brain microcirculation and were sometimes observed in contact with the venular endothelium by transmission electron microscopy (not shown), in accord with a recent report.37Hearn J Rayment N Landon DN Katz DR de Souza JB Immunopathology of cerebral malaria: morphological evidence of parasite sequestration in murine brain vasculature.Infect Immun. 2000; 68: 5364-5376Crossref PubMed Scopus (130) Google Scholar However, when the percentage of pRBCs in the brain venules and capillaries was evaluated by transmission electron microscopy, it was not higher than in the systemic circulation, in contrast to what was observed in alveolar capillaries (see below), therefore arguing against a selective retention of pRBCs in brain microcirculation. Microhemorrhages are common in PbA-infected CBA mice,5Senaldi G Vesin C Chang R Grau G Piguet PF An effector role of neutrophils in the pathogenesis of murine severe malaria.Infect Immun. 1994; 62: 1144-1149PubMed Google Scholar whereas in contrast, these are rare in mice of C57BL/6 background, and were therefore not evaluated in the present experiments.Figure 6Cell sequestration in brain venules. A and B: Cortical venules of infected +/+ (A) or CD40−/− (B) mice. An important sequestration of leukocytes is evident in A, but not in B (original magnification, ×400). C: Macrophages and endothelial cells in cortical venules were counted on H&E-stained sections by light microscopy. The results are expressed as the mean (+SD, n = 5) of the ratio of macrophages/endothelial cells seen in cortical venules.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In the lung, sequestration in the alveolar capillaries includes macrophages, PMNs, platelets, and pRBCs.6Favre N Willimann K Ryffel B Weiss N Imhof BA Rudin W Lucas R Piguet PF Role of ICAM-1 in the development of murine cerebral malaria.Microbes Infect. 1999; 1: 961-968Crossref PubMed Scopus (112) Google Scholar As evaluated by semiquantitative electron microscopy, sequestration of macrophages was significantly decreased in CD40−/−, whereas sequestration of PMNs, pRBCs, and platelets was similar to that seen in +/+ mice (Figure 7, A and B, and Figure 8A). Similar results were obtained in three infected CD40L−/− mice studied (not shown). Using blood smears, it has been reported that the percentage of pRBCs is higher in the lung than in the peripheral blood.7Coquelin F Boulard Y Mora-Silvera E Richard F Chabaud AG Landau I Final stage maturation of the erythrocytic schizonts of rodent Plasmodium in the lungs.C R Acad Sci (III). 1999; 322: 55-62Crossref PubMed Scopus (20) Google Scholar With the present method, we also observed a higher percentage of pRBCs in the alveolar capillaries than in the large blood vessels of the lung, indicating a selective adhesion of pRBCs in alveolar capillaries (Figure 7C and Figure 8B). This was similar in +/+ and CD40−/− infected mice (Figure 8B), as well as in CD40L−/− mice (not shown). In CD54−/−, in contrast to CD40−/−, no difference between the percentage of pRBCs in large blood vessels and alveolar capillaries was observed (Figure 8B). These observations indicate that the sequestration of pRBCs in alveolar capillaries requires CD54, but not CD40.Figure 7A and B: Alveolar capillaries from an infected +/+ (A) or CD40−/− (B) mice. An increased cellularity of the alveolar septa is evident in A but not in B, which is similar to noninfected +/+ mice (not shown). Macrophage sequestration is also evident in the venules (v) in A but not in B. C: An alveolar capillary from an infected +/+ is seen by transmission electron microscopy. A macrophage (mac), a red blood cell (rbc), and a parasitized red blood cell (prbc) in an advanced stage of maturation are seen inside the capillary. Original magnifications: ×400 (A and B), ×6500 (C).View Large Image Figure ViewerDownload Hi-res" @default.
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• W2088304428 title "Role of CD40-CD40L in Mouse Severe Malaria" @default.
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