Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the induction of T-helper cell subsets during the course of lethal or nonlethal bloodstage Plasmodium yoelii 17X infection in C57BL/6 mice, which are relatively susceptible to these intraerythrocytic parasites. C57BL/6 mice infected with the nonlethal variant (PyNL) showed a moderate level of parasitemia and resolution of primary acute infection by week 4. Mice infected with the lethal variant (PyL) developed fulminating parasitemia and ultimately died. T-helper subset function was assessed during infection by determining the kinetics of in vitro production of the Th1-derived cytokine interferon-gamma (IFN-gamma) and the Th2-derived cytokine interleukin 10 (IL-10) by means of bioassay and enzyme-linked immunosorbent assay (ELISA), respectively. Spleen cells obtained from mice infected with PyL within the 1st week of infection produced high levels of IL-10 and IFN-gamma in response to malaria antigen. IL-10 also appeared in sera from PyL-infected mice at the same time at which the in vitro IL-10 response peaked. In contrast, spleen cells from mice infected with PyNL failed to produce IL-10 during the course of infection. CD4+ T-lymphocytes from mice infected with the lethal variant were a major source of IL-10, although non T-cells were also involved in the production of IL-10 during this malaria infection. In addition, the initial burst of IL-10 in response to malaria antigens was seen concomitantly with the production of IFN-gamma within the 1st week of infection. These results indicate that both Th1 and Th2 subsets of T-helper lymphocytes are activated during infection with the lethal variant of P. yoelii and support the contention of other investigators that a strong Th2 response early in infection is associated with the lethal outcome of malaria.
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PMID:Production of interleukin 10 during malaria caused by lethal and nonlethal variants of Plasmodium yoelii yoelii. 873 75

A blood-stage malaria antigen comprising the C terminus of merozoite surface protein 1 fused to glutathione S-transferase, combined with an adjuvant formulation containing squalane, Tween 80, and pluronic L121 (AF), administered subcutaneously protected mice against death from a lethal Plasmodium yoelii infection. The protection induced by this antigen-adjuvant combination was compared with that induced by the antigen plus saponin in terms of survival from the lethal infection and clearance of parasitemia. The levels of gamma interferon and interleukin-4 in spleens were measured as indicators of Th1 and Th2 cell activation, and antibody classes and subclasses were determined by immunofluorescence. With a 10-micrograms dose of antigen and AF as adjuvant, all mice recovered, but with saponin as the adjuvant, there were only a few survivors. With 30 micrograms of antigen plus AF, the peak parasitemias were 10-fold lower than those with 10 micrograms; with saponin, survival was slightly improved. The levels of both gamma interferon and interleukin-4 rose more rapidly and to higher levels with AF as the adjuvant than with saponin, and the same was true for immunoglobulin G1 (IgG1), IgG2a, and IgG2b subclasses. Thus, in terms of both cytokine production and antibody levels, AF is a more potent adjuvant for a malaria vaccine than is saponin.
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PMID:Cytokines and antibody subclass associated with protective immunity against blood-stage malaria in mice vaccinated with the C terminus of merozoite surface protein 1 plus a novel adjuvant. 875 95

Nitric oxide (NO)-related activity has been shown to be protective against Plasmodium falciparum in vitro. It has been hypothesized, however, that excess NO production contributes to the pathogenesis of cerebral malaria. The purpose of this study was to compare markers of NO production [urinary and plasma nitrate + nitrite (NOx)], leukocyte-inducible nitric oxide synthase type 2 (NOS2), and plasma TNF-alpha and IL-10 levels with disease severity in 191 Tanzanian children with and without malaria. Urine NOx excretion and plasma NOx levels (corrected for renal impairment) were inversely related to disease severity, with levels highest in subclinical infection and lowest in fatal cerebral malaria. Results could not be explained by differences in dietary nitrate ingestion among the groups. Plasma levels of IL-10, a cytokine known to suppress NO synthesis, increased with disease severity. Leukocyte NOS2 antigen was detectable in all control children tested and in all those with subclinical infection, but was undetectable in all but one subject with cerebral malaria. This suppression of NO synthesis in cerebral malaria may contribute to pathogenesis. In contrast, high fasting NOx levels and leukocyte NOS2 in healthy controls and asymptomatic infection suggest that increased NO synthesis might protect against clinical disease. NO appears to have a protective rather than pathological role in African children with malaria.
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PMID:Nitric oxide in Tanzanian children with malaria: inverse relationship between malaria severity and nitric oxide production/nitric oxide synthase type 2 expression. 876 Aug 9

The various stages of Plasmodium falciparum (sporozoites and liver stages, asexual blood stages and gametocytes) each interact in a particular way with the human immune system. Specific immunity against the liver stages is achieved through a coordinated action of CD8 T cells and specific antibodies, the latter in collaboration with NK cells and macrophages. In this reaction, interferon-gamma plays an essential role. A non-specific "concomitant" immunity against sporozoites is based on a cytokine reaction, elicited by the blood stages. In practice, the high variability in the immunogenic structures of the sporozoite precludes completely protection against recurrent infections. The spleen macrophages have a pivotal role in the immune defense against the asexual blood stages. The elimination of merozoites and parasitized red blood cells (RBC) is facilitated by specific antibodies, produced under the control of CD4 T cells. There are, however, multiple mechanisms of immune deviation, suppression and evolutionary adaptation, which inhibit a sterilizing immunity against the blood stages. Nevertheless, symptoms may be absent in exposed adults, even when parasitemia persists. This clinical resistance, however, is relatively short-lived, once exposition is interrupted. The observation that HIV infection has no adverse effect on malaria also is a remarkable but consistent finding. All these data indicate that a strong T cell-mediated immune memory is absent in human P. falciparum infections. Cerebral malaria and some other serious complications are the consequence of insufficient elimination of parasitized erythrocytes by the spleen, presumably in combination with parasite factors (particular variant surface structures) and with human host genetics (HLA type, blood group etc.). Parasitized RBC massively stick to the endothelium of the micro-vessels and non-parasitized RBC roset around the parasitized ones. Eventually, serious problems in the micro-perfusion and in the local metabolism occur and organ failure may finally ensue. The immune reaction against the surface-antigens of the sexual stage is limited and insufficient, most probably for similar reasons as in the asexual stages. Internal structures of the gametocytes, however, are highly immunogenic, but, unfortunately. Normally cannot be reached by the immune system. Based on these fundamental data, some of the perspectives of vaccination and new therapeutic tools are critically discussed.
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PMID:[Immunology of human Plasmodium falciparum malaria]. 884 94

Most children and adults living in areas where the endemicity of Plasmodium falciparum malaria is high have significantly elevated levels of both total immunoglobulin E (IgE) and IgE antimalarial antibodies in blood. This elevation is highest in patients with cerebral malaria, suggesting a pathogenic role for this immunoglobulin isotype. In this study, we show that IgE elevation may also be seen in severe malaria without cerebral involvement and parallels an elevation of tumor necrosis factor alpha (TNF). IgE-containing serum from malaria immune donors was added to tissue culture plates coated with rabbit anti-human IgE antibodies or with P. falciparum antigen. IgE-anti-IgE complexes as well as antigen-binding IgE antibodies induced TNF release from peripheral blood mononuclear cells (PBMC). Nonmalaria control sera with no IgE elevation induced significantly less of this cytokine, and the TNF-inducing capacity of malaria sera was also strongly reduced by passing them over anti-IgE Sepharose columns. The cells giving rise to TNF were adherent PBMC. The release of this cytokine probably reflects cross-linking of their low-affinity receptors for IgE (CD23) by IgE-containing immune complexes known to give rise to monocyte activation via the NO transduction pathway. In line with this, adherent monocytic cells exposed to IgE complexes displayed increased expression of CD23. As the malaria sera contained IgG anti-IgE antibodies, such complexes probably also play a role in the induction of TNF in vivo. Overproduction of TNF is considered a major pathogenic mechanism responsible for fever and tissue lesions in P. falciparum malaria. This overproduction is generally assumed to reflect a direct stimulation of effector cells by certain parasite-derived toxins. Our results suggest that IgE elevation constitutes yet another important mechanism involved in excessive TNF induction in this disease.
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PMID:Immunoglobulin E, a pathogenic factor in Plasmodium falciparum malaria. 897

Plasmid DNA vaccines capable of preventing viral, bacterial, and parasitic infections are currently under development. Our labs have shown that a plasmid DNA vaccine encoding the circumsporozoite protein of the malaria parasite elicits protective immunity against live sporozoite challenge in adult BALB/c mice. We now find that the same DNA vaccine induces tolerance rather than immunity when administered to 2-5 d-old mice. Neonatally tolerized animals were unable to mount antibody, cytokine or cytotoxic responses when rechallenged with DNA vaccine in vitro or in vivo. Tolerance was specific for immunogenic epitopes expressed by the vaccine-encoded, endogenously produced antigen. Mice challenged with exogenous circumsporozoite protein produced antibodies against a different set of epitopes, and were not tolerized. These findings demonstrate important differences in the nature and specificity of the immune response elicited by DNA vaccines versus conventional protein immunogens.
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PMID:Induction of neonatal tolerance by plasmid DNA vaccination of mice. 898 14

Murine malarial parasites have long been characterized by their requirement for either antibody-mediated immunity (AMI) or cell-mediated immunity (CMI) for suppression of acute parasitemia, with Plasmodium yoelii reportedly requiring AMI for suppression and P. chabaudi requiring CMI. To assess this characterization in terms of the current T(H1)/T(H2)-CMI/AMI hypothesis, we infected gene-targeted "knockout" mice lacking either a type-1 cytokine (IL-2 or IFN-gamma) or a type-2 cytokine (IL-4 or IL-10) with one or the other species of Plasmodium. We observed that type-1 cytokine-deficient mice developed exacerbated malaria with either P. yoelii or P. chabaudi, compared with that seen in heterozygote controls. Moreover, type-2 cytokine knockout mice showed a similar time course of infection with either parasite compared with that seen with their controls. We conclude that the mechanism of resolution of these well characterized malarial infections cannot be linked definitely to these T(H1)- and T(H2)-associated cytokines as predicted by the T(H1)/T(H2)-CMI/AMI hypothesis.
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PMID:The time course of selected malarial infections in cytokine-deficient mice. 903 Jun 70

Culture of endothelial cells started two decades ago and is now a useful tool in understanding endothelial physiology and the study of the interaction of endothelial cells with blood cells and various mediators. In vitro proliferation can be measured by [3H]thymidine incorporation in defined conditions and gives reproducible results. Endothelial cells can be activated by several stimuli, including cytokines such as tumor necrosis factor-alpha and interleukin-1. Part of endothelial cell activation is defined by expression or overexpression of leukocyte adhesion molecules. Intracellular adhesion molecule (ICAM), E-selection and vascular adhesion molecule (VCAM) are receptor molecules for leukocyte adhesion. Leukocyte adhesion to endothelium can be measured in static but also in rheologically defined flow conditions. Normal red blood cells (RBCs) do not adhere to endothelium, while RBC from patients with sickle cell anemia, diabetes mellitus, and malaria have an increased adhesion to endothelium which is mediated by specific VCAM, receptor for advanced glycated end-products (RAGE), and ICAM, respectively. Binding of blood cells or activation by cytokine is followed by a series of reactions in endothelial cells associated with the modulation of prostacyclin, nitric oxide, tissue factor, and cytokine production. Modification of endothelial cell functions in culture is correlated to in vivo alteration of vascular wall properties, further supporting these cells in culture as a relevant experimental model.
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PMID:Endothelial cells in culture: an experimental model for the study of vascular dysfunctions. 903 9

Fatal murine cerebral malaria (FMCM) is an immunopathological process. The depletion of CD4+ T cells, or the administration of antioxidants or antibodies against certain cytokines, protect the mice against cerebral complications. We previously have shown that astrocytes, microglia, and monocytes play a role in the development of FMCM, suggesting that an active immune response occurs locally within the central nervous system. We now have investigated the functional involvement of glia and monocytes in FMCM by assessing 1) the production, 2) the temporal appearance, and 3) the cellular source of cytokine mRNA and protein in the brain. Brain sections from uninfected and FMCM mice were analyzed for the presence of cytokine mRNA and protein by in situ hybridization and immunohistochemistry. Tumor necrosis factor (TNF)-alpha mRNA and protein were associated with microglia and astrocytes, monocytes, and the cerebral vascular endothelium in FMCM mice but not uninfected animals. TNF-alpha mRNA was first detected several days before the animals showed cerebral symptoms and died. Interleukin (IL)-1 beta mRNA was found in the brains of both uninfected and FMCM mice. However, IL-1 beta protein was associated only with monocytes, the meningeal vascular endothelium, and neurons in the fronto-parietal cortex in the FMCM brains. No IL-4 or IL-6 mRNAs were detected in either group. These results provide the strongest evidence to date that cytokines, in particular TNF-alpha, produced locally in the central nervous system play a role in the pathogenesis of FMCM.
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PMID:Tumor necrosis factor-alpha expression in the brain during fatal murine cerebral malaria: evidence for production by microglia and astrocytes. 909 2

Tumor necrosis factor alpha (TNF alpha) is a potent immunomodulator and proinflammatory cytokine that has been implicated in the pathogenesis of autoimmune and infectious diseases. For example, plasma levels of TNF alpha are positively correlated with severity and mortality in malaria and leishmaniasis. We have previously described a polymorphism at -308 in the TNF alpha promoter and shown that the rare allele, TNF2, lies on the extended haplotype HLA-A1-B8-DR3-DQ2, which is associated with autoimmunity and high TNF alpha production. Homozygosity for TNF2 carries a sevenfold increased risk of death from cerebral malaria. Here we demonstrate, with reporter genes under the control of the two allelic TNF promoters, that TNF2 is a much stronger transcriptional activator than the common allele (TNF1) in a human B cell line. Footprint analysis using DNase I and B cell nuclear extract showed the generation of a hypersensitive site at -308 and an adjacent area of protection. There was no difference in affinity of the DNA-binding protein(s) between the two alleles. These results show that this polymorphism has direct effects on TNF alpha gene regulation and may be responsible for the association of TNF2 with high TNF alpha phenotype and more severe disease in infections such as malaria and leishmaniasis.
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PMID:Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. 909 69


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