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)

It was reported previously that cloned Th1 cells, but not Th2 cells, raised to malaria antigens, produce nitric oxide (NO) when activated with specific antigen or mitogen. Furthermore, NO inhibits the proliferation of, and production of interleukin-2 (IL-2) and interferon-gamma by, Th1 but not Th2 cells. By dose-response analysis, I demonstrate here that Th1 cells produce optimal levels of IL-2 and a proliferative response, and no detectable NO, when stimulated with relatively low concentrations of antigen or mitogen in vitro. As the antigen/mitogen increased, however, high levels of NO were produced, accompanied by a concomitant reduction in IL-2 secretion and T cell proliferation. At the highest concentrations of antigen/mitogen examined, addition of recombinant IL-2 reversed the NO-mediated downregulation of T cell proliferation. These results suggest that NO may serve as a self-regulatory molecule preventing the over-expansion of Th1 cells. At the other extreme, exogenous IL-2 may act to counter-regulate the suppressive effect of high concentrations of NO on Th1 cell proliferation, thereby maintaining homeostasis.
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PMID:Counter-regulation of T helper 1 cell proliferation by nitric oxide and interleukin-2. 914 87

Testosterone induces susceptibility to Plasmodium chabaudi malaria by imposing restrictions on those mechanisms which mediate resistance controlled by genes of the H-2 complex and the non-H-2 background in mice. This study investigated whether these restrictions are abolished after withdrawal of testosterone. Female mice of the inbred strain C57BL/10 were treated with 0.9 mg testosterone twice a week for 3 weeks and testosterone was then withdrawn for 12 weeks. The treatment raised plasma testosterone levels from 0.18 ng/ml to 3.79 ng/ml. After the testosterone treatment, these levels progressively dropped and reached 0.21 ng/ml by week 12 after testosterone withdrawal. Surprisingly, however, the testosterone-induced susceptibility still persisted. When mice were challenged on week 12 after testosterone withdrawal, P. chabaudi infections were still fatal in testosterone-treated mice, in contrast to self-healing infections in resistant, i.e. untreated, control mice. In addition, testosterone caused a persistent decrease in the levels of total IgG antibodies, especially IgG1 and IgG2b isotypes. In contrast, testosterone-induced changes in spleen cells, such as the reduction in number by 50%, the relative increase in CD8+ cells and the decrease in Ig+ cells, as well as the acquisition of the susceptible phenotype, were completely reversed on week 10 after testosterone withdrawal at the latest. Testosterone did not affect the production of the TH1-signalling cytokine interferon-gamma and the TH2-signalling cytokines interleukin (IL)-4 and IL-10 in response to P. chabaudi malaria. Together, our data indicated that the gene-controlled host resistance to P. chabaudi malaria is subject to superior hormonal imprinting: when once induced by testosterone, mechanisms which suppress resistance thus causing susceptibility persist independently of testosterone.
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PMID:Testosterone-induced susceptibility to Plasmodium chabaudi malaria: persistence after withdrawal of testosterone. 916 17

Tumor necrosis factor (TNF) has been implicated in the pathogenesis of experimental cerebral malaria (CM), but the respective role of its two types of receptors has not been established. A significant increase in the expression of TNF-receptor 2 (TNFR2, p75), but not of TNFR1 (p55), was found on brain microvessels at the time of CM in susceptible animals. Moreover, mice genetically deficient for TNFR2 (Tnfr2null) were significantly protected from experimental CM, in contrast to TNFR1-deficient (Tnfr1null) mice, which were as susceptible as wild-type mice. To identify the factors involved in the protection from CM conferred by the lack of TNFR2, we assessed in both knockout and control mice the serum concentrations of mediators that are critical for the development of CM, as well as the up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the brain microvessels. No significant difference in serum levels of TNF and interferon-gamma was found between infected wild-type and Tnfr1null or Tnfr2null mice. Interestingly, the pronounced ICAM-1 up-regulation and leukocyte sequestration, typically occurring in brain microvessels of CM-susceptible animals, was detected in infected control and Tnfr1null mice-both of which developed CM-whereas no such ICAM-1 up-regulation or leukocyte sequestration was observed in Tnfr2null mice, which were protected from CM. Making use of microvascular endothelium cells (MVEC) isolated from wild-type, Tnfr1null or Tnfr2null mice, we show that soluble TNF requires the presence of both TNF receptors, whereas membrane-bound TNF only needs TNFR2 for TNF-mediated ICAM-1 up-regulation in brain MVEC. Thus, only in MVEC lacking TNFR2, neither membrane-bound nor soluble TNF cause the up-regulation of ICAM-1 in vitro. In conclusion, these results indicate that the interaction between membrane TNF and TNFR2 is crucial in the development of this neurological syndrome.
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PMID:Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria. 924 83

Interferon-gamma receptor (IFN-gamma R) deficient mice parasitized with blood-stage Plasmodium chabaudi chabaudi were used to assess the anti-malarial activity of interferon-gamma (IFN-gamma). There was no significant difference in the parasitaemia between the two types of mice during the first peak of parasitaemia. However, IFN-gamma R deficient mice displayed an increased leucocytosis and a high mortality rate, whereas all of the wild type mice survived. IFN-gamma R deficient mice, unlike wild type mice, developed a pronounced second parasitaemia peak, 9 to 11 days after the first one, with a parasitaemia of up to 65% associated with mortality. Furthermore, increased serum levels of nitric oxide (NO) were only found in wild type mice at the peak of parasitaemia, whereas it remained at background levels in IFN-gamma R deficient mice. Parasite-specific antibody production was not significantly different in IFN-gamma R deficient mice, as compared to wild type mice. In addition, both wild type and IFN-gamma R deficient mice were equally protected upon reinfection. These results indicate a delayed development of protective immunity and imply a crucial function for the IFN-gamma R in the control of blood stage malaria during the initial three weeks of infection.
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PMID:The course of Plasmodium chabaudi chabaudi infections in interferon-gamma receptor deficient mice. 929 96

Vgamma9Vdelta2-encoded T cell receptors (TCR) expressed by most human peripheral blood gammadelta T cells mediate the recognition of nonpeptidic phosphoantigens from various pathogens without any known requirement for HLA molecules. Functionally mature Vgamma9Vdelta2 T cells display a potent natural killer (NK)-like cytotoxic activity, share with NK cells the expression of inhibitory receptors for HLA class I molecules, and release a plethora of cytokines, most notably interferon-gamma and tumor necrosis factor alpha. Hence, through local activation, the early recruitment and stimulation of Vgamma9Vdelta2 T cells may promote efficient anti-infectious immunity. However, a chronic overactivation of this T cell subset may result in immunopathology. The meeting held in St. Vincent, Val d'Aosta, Italy (symposium on gammadelta T cells in natural immunity to infections: a rationale for vaccine development organized by the World Foundation for AIDS Research and Prevention, the UNESCO, and the Italian National Research Council, December 2-4, 1996) focused on the importance of gammadelta T cell activation and anergy for the pathogenesis of tuberculosis, malaria, and HIV infections.
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PMID:Gammadelta T cell activation or anergy during infections: the role of nonpeptidic TCR ligands and HLA class I molecules. 930 66

While the C-terminal repeat region of Pf155/RESA, a Plasmodium falciparum vaccine candidate has been extensively studied for B- and T-cell reactivities, little is so far known about the non-repeat region in this respect. The present study aimed at investigating the non-repeat sequence 171-227 of Pf155/RESA for T- and B-cell epitopes. Eight overlapping peptides were synthesised and assayed for their ability to stimulate peripheral blood mononuclear cells obtained from P. falciparum-immune donors to proliferate and to induce secretion of interferon-gamma (IFN-gamma) and/or interleukin 4 (IL-4) using the ELISPOT assay. The plasmas of the corresponding donors were tested for antibody reactivity with the same peptides in ELISA. The individual cellular responses to the different peptides varied and in general they were not correlated, emphasising the importance of including several parameters for T-cell activation. The most frequent T-cell responses (proliferation, IFN-gamma and/or IL-4) were seen with two partially overlapping peptides corresponding to the sequences 171-185 and 181-195 that induced responses in 71 and 62% of the donors, respectively. Although, the frequency of responders was high, the magnitude of the responses was generally low. Two overlapping peptides corresponding to the sequence 186-206 bound antibodies from a large number of plasma samples. IL-4 producing cells were frequently found in donors whose sera contained antibodies to the corresponding peptide. However, there was no absolute correlation and many donors having anti-peptide antibodies could also be induced to produce IFN-gamma. In conclusion, the non-repeat region of Pf155/RESA contains several epitopes inducing functionally distinct T-cell responses. The sequence 171-206 was found to contain both B- and T-cell epitopes recognised by almost all individuals naturally primed to malaria. Thus, this sequence should be a useful tool in future immuno-epidemiological studies and/or for inclusion into a subunit vaccine against the asexual blood stages of the P. falciparum parasite.
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PMID:T- and B-cell responses of malaria immune individuals to synthetic peptides corresponding to non-repeat sequences in the N-terminal region of the Plasmodium falciparum antigen Pf155/RESA. 935 1

Tumor necrosis factor-alpha (TNF) is known to be an important mediator in the pathogenesis of several inflammatory diseases. Vascular endothelial cells represent a major target of TNF effects. Platelet sequestration has been found in brain microvessels during experimental cerebral malaria and lung in experimental pulmonary fibrosis, implying that it may participate in TNF-dependent microvascular pathology. In this study, we investigated the mechanisms of platelet-endothelial interaction, using co-cultures between platelets and TNF-activated mouse brain microvascular endothelial cells (MVECs). Adhesion and fusion of platelets to MVECs was evidenced by electron microscopy, dye transfer, and flow cytometry. It was induced by TNF and interferon-gamma and depended on LFA-1 expressed on the platelet surface and ICAM-1 expressed on MVECs. The adhesion and fusion also led to the transfer of platelet markers on the MVEC surface, rendering these more adherent for leukocytes, and to an enhanced MVEC sensitivity to TNF-induced injury. These results suggest that platelets can participate in TNF-induced microvascular pathology.
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PMID:Platelets play an important role in TNF-induced microvascular endothelial cell pathology. 935 66

This review is aimed at emphasizing the need for basic neuroscience research on two tropical diseases, malaria and sleeping sickness (African trypanosomiasis), that still represent major health problems and in which severe involvement of the nervous system is frequently the direct cause of death. The life cycles of the two parasites, the protozoan Plasmodium and Trypanosoma brucei, which are the causative agents of malaria and sleeping sickness, respectively, are briefly reviewed. The historical contribution to the pathogenesis and therapy of malaria by a renowned pioneer in neuroscience, Camillo Golgi, is pointed out. The different strategies for survival in the host by the intracellular Plasmodium and the extracellular African trypanosomes are summarized; such strategies include sites favorable for hiding or replication of the parasites in the host, antigenic variation, and interactions with the cytokine network of the host. In particular, tumor necrosis factor-alpha and interferon-gamma may play a role in these infections. The parasites may paradoxically interact with cytokines to their benefit. However, cytokine receptors are expressed on neuronal subsets sensitive to cytokine action, and stimulation of these subsets may cause neuronal dysfunctions during the infections. Finally, the clinical symptoms of cerebral malaria and African trypanosomiasis and research aiming at deciphering their pathogenetic mechanisms that could affect the nervous system at a molecular level are described. The need for neuroscientists in this endeavor is emphasized.
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PMID:Neurobiology of cerebral malaria and African sleeping sickness. 936 1

The physiopathology of experimental cerebral malaria (CM), an acute neurological complication of Plasmodium berghei ANKA (PbA) infection, involves interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), two cytokines that are known to modulate major histocompatibility complex (MHC) molecule expression. The aim of this study was to evaluate whether the genetic susceptibility to CM is related to the constitutive or IFN-gamma-induced expression of MHC molecules on brain microvessels. To this end, brain microvascular endothelial cells (B-MVEC) were isolated from CM-susceptible (CM-S, CBA/J) and resistant (CM-R, BALB/c) mice. By flow cytometry, we found that less than 5% of CM-S B-MVEC constitutively expressed MHC class I molecules, in contrast to up to 90% of CM-R B-MVEC. Upon stimulation with IFN-gamma, the percentage of positive cells for MHC class I molecules in CM-S B-MVEC became comparable to CM-R B-MVEC, but a higher fluorescence intensity existed on CM-S B-MVEC compared with CM-R B-MVEC. MHC class II molecules were not constitutively expressed on B-MVEC from either strain. IFN-gamma-induced expression of MHC class II (I-A, I-E) molecules was significantly higher in CM-S than CM-R B-MVEC both in percentage of positive cells and fluorescence intensity. These data demonstrate that absent or low MHC class I and higher inducibility of MHC class II expression on B-MVEC are associated with the genetic susceptibility to CM.
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PMID:Expression of major histocompatibility complex antigens on mouse brain microvascular endothelial cells in relation to susceptibility to cerebral malaria. 937 Sep 24

In this study, we examined the effects of interleukin-10 (IL-10) on the outcome of experimental cerebral malaria (CM), a lethal neurological syndrome that occurs in susceptible strains of mice after infection with Plasmodium berghei ANKA (PbA). Constitutive IL-10 mRNA levels were significantly higher in the spleen and brain of resistant animals. In vivo neutralization of endogenous IL-10 in CM-resistant mice induced the neurological syndrome in 35.7% of these mice, as opposed to 7.7% in controls. IL-10 inhibited PbA antigen-specific interferon-gamma (IFN-gamma) production in vitro but not tumour necrosis factor (TNF) serum levels in vivo. Susceptible mice, on the other hand, were significantly protected against CM when injected with recombinant IL-10. Overall, our findings suggest that IL-10 plays a protective role against experimental cerebral malaria.
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PMID:Interleukin-10 modulates susceptibility in experimental cerebral malaria. 937 91


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