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)

Pregnant women, especially primigravidas, are highly susceptible to malaria infection, resulting in maternal anemia and low birth weight infants. Because circulating parasitemia is rare in the newborn, the cause of poor fetal outcomes has been unclear. We measured cytokine concentrations in placentas collected from women delivering in urban hospitals in malaria-holoendemic or nonendemic areas of Kenya. Normal placentas displayed a bias toward type 2 cytokines; type 1 cytokines IFN-gamma and IL-2 were absent in placentas not exposed to malaria but present in a large proportion of placentas from a holoendemic area. TNF-alpha and TGF-beta concentrations were significantly higher, and IL-10 concentrations significantly lower, in placentas from the holoendemic area. Among primigravidas, placental TNF-alpha concentrations were significantly higher in the presence of severe maternal anemia, and both IFN-gamma and TNF-alpha were significantly elevated when a low birth weight, rather than normal weight, infant was delivered. We conclude that maternal malaria decreases IL-10 concentrations and elicits IFN-gamma, IL-2, and TNF-alpha in the placenta, shifting the balance toward type 1 cytokines. This is the first demonstration that these placental cytokine changes are associated with poor pregnancy outcomes in humans.
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PMID:Malaria elicits type 1 cytokines in the human placenta: IFN-gamma and TNF-alpha associated with pregnancy outcomes. 949 98

We examined the circulating levels of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 alpha, IL-6, granulocyte macrophage-colony stimulating factor (GM-CSF), and the anti-inflammatory cytokine IL-10, and their expression in kidneys acutely infected with murine malaria parasite P. berghei ANKA in C57BL/6J mice. Groups of six mice sacrificed on days 5, 10, 15, and 20, and normal controls were used for cytokine analysis. High concentrations of TNF-alpha and IL-10 were detected in plasma as shown by ELISA, and elevated levels of mRNA specific for TNF-alpha and IL-10 in infected kidneys were demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Kidney sections stained with antibodies against TNF-alpha, IL-1 alpha, IL-6, GM-CSF and IL-10 for immunohistochemistry showed markedly enhanced staining for TNF-alpha, and progressively increased staining for IL-1 alpha and IL-6 both in the tubules and the walls of arteries during the course of infection. The endothelia of blood vessels and inflammatory cells located around small arteries showed positive staining for GM-CSF from day 10 onwards. Unlike the staining for proinflammatory cytokines, the anti-inflammatory cytokine IL-10 showed strongly positive staining in normal tubules and walls of arteries, especially in the brush border of proximal tubules, but the staining intensity decreased dramatically after day 15 post-infection. A strongly positive correlation was found between the antibody staining for TNF-alpha/IL-1 alpha in tubules, and the severity of proteinuria. In contrast, there was an inverse correlation between the staining for IL-10 with TNF-alpha/IL-1 alpha, and the degree of proteinuria. Plenty of pigmented macrophages showed positive staining both for proinflammatory and anti-inflammatory cytokines in the tubulointerstitium. Our findings imply that the up-regulation of proinflammatory cytokines and the dysregulation of anti-inflammatory cytokines are involved in the pathogenesis of tubulointerstitial nephritis associated with malaria.
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PMID:Dysregulation of cytokine expression in tubulointerstitial nephritis associated with murine malaria. 955 90

We studied whether the infection with a blood-stage murine malaria lethal Plasmodium berghei NK65 induces IL-12 production, and if so, how the IL-12 production is involved in the protection or pathogenesis. The infection of C57BL/6 mice enhanced mRNA expression of IL-12 p40 and also IFN-gamma, IL-4, and IL-10 in both spleen and liver during the early course of the infection. It also enhanced the mRNA expression of TNF-alpha, Fas ligand, and cytokine-inducible nitric oxide synthase. Increased IL-12 p40 production was also observed in the culture supernatant of spleen cells and in sera of infected mice. In addition, the infection caused massive liver injury with elevated serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and body weight loss. Treatment of these infected mice with neutralizing mAb against IL-12 prolonged the survival and diminished the liver injury with reduced elevation of serum serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase activities and decreased body weight loss. However, the anti-IL-12 treatment did not affect parasitemia, and all these mice eventually died. Similar results were obtained when infected mice were treated with neutralizing mAb against IFN-gamma. Moreover, anti-IL-12 treatment greatly reduced the secretion and mRNA expression of IFN-gamma in both spleen and liver. These results suggest that the lethal P. berghei NK65 infection induces IL-12 production and that the IL-12 is involved in the pathogenesis of liver injury via IFN-gamma production rather than the protection.
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PMID:A pathogenic role of IL-12 in blood-stage murine malaria lethal strain Plasmodium berghei NK65 infection. 960 53

Tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 are implicated in the pathogenesis of severe Plasmodium falciparum malaria. In this study, the effect of IL-10 on their production by peripheral blood mononuclear cells (PBMC) from acutely infected patients was examined. Exogenous IL-10 inhibited malarial antigen-induced cytokine production by reducing mRNA accumulation. Maximal inhibition occurred when IL-10 was added in the first 2 h of stimulation. Conversely, the addition of anti-IL-10 markedly enhanced TNF-alpha, IL-1beta, and IL-6 production. The effect was significantly greater on PBMC from patients with uncomplicated infection than PBMC from patients with severe disease. Kinetics studies showed that TNF-alpha, IL-6, and IL-1beta were produced within 2-4 h of stimulation, while IL-10 was first detectable after 8 h. These findings suggest that IL-10 counter-regulates the proinflammatory response to P. falciparum. Severe falciparum malaria may be associated with an inadequate negative feedback response by IL-10.
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PMID:Endogenous interleukin-10 modulates proinflammatory response in Plasmodium falciparum malaria. 969 35

Cytokine responses in human host-protective immunity to malaria have yet to be completely elucidated. No data appear to exist on the cytokine patterns in non-human primate models immunized with malarial antigens. Expression of mRNA transcripts of 10 cytokines, the adhesion molecule ICAM-1 and inducible nitric oxide synthase (iNOS) in peripheral-blood mononuclear cells (PBMC) from nine Aotus monkeys was analysed by reverse-transcriptase PCR. Five of the monkeys had been immunized with multiple-antigen peptides (MAP) of the Plasmodium vivax circumsporozoite protein and two with constructs of the P. falciparum merozoite surface protein-1 (MSP-1). The other two monkeys served as non-immunized controls. PBMC were cultured for 24 h after stimulation with phytohaemagglutinin mitogen, MAP and MSP-1 antigens. Elevated expression of interleukin-6 (IL-6), IL-10, IL-12, tumour necrosis factor-alpha (TNF-alpha), TNF-beta and iNOS was seen in response to the MAP. Monkeys immunized with either P. falciparum MSP r190L or synthetic 190L peptides expressed predominantly the type-1 cytokines (IL-1 beta, IL-12, interferon-gamma, TNF-alpha, TNF-beta) characteristic of splenic, cell-mediated activity with macrophage activation and nitric oxide production.
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PMID:Expression of cytokine genes in Aotus monkeys immunized with synthetic and recombinant Plasmodium vivax and P. falciparum antigens. 979 28

The balance between Th1 cytokines (tumor necrosis factor [TNF]-alpha, interferon [IFN]-gamma) and Th2 cytokines (interleukin [IL]-10, -4) may be critical in the development of severe falciparum malaria. Therefore, plasma concentrations of these cytokines were determined in children with various manifestations of malaria. Plasma levels of IFN-gamma and IL-4 were undetectable in most children. However, TNF-alpha and IL-10 were significantly elevated in children with high-density parasitemia and malaria anemia compared with children in control groups. In children with mild malaria, IL-10, but not TNF-alpha, was significantly elevated. While the highest concentrations of TNF-alpha were found in children with malaria anemia, IL-10 levels were highest in children with high-density uncomplicated malaria. The mean ratio of IL-10 to TNF-alpha was significantly higher in children with mild and high-density parasitemia (4.64, P<.005) than in children with malaria anemia (1.77). Thus, higher levels of IL-10 over TNF-alpha may prevent development of malaria anemia by controlling the excessive inflammatory activities of TNF-alpha.
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PMID:A low interleukin-10 tumor necrosis factor-alpha ratio is associated with malaria anemia in children residing in a holoendemic malaria region in western Kenya. 1051 52

Using strict inclusion criteria, we conducted a hospital-based, case-control study in which 100 Gabonese children with severe Plasmodium falciparum malaria were matched for age, gender and provenance with 100 children presenting with mild malaria. Parasite antigen-specific cellular and humoral immunological responses were measured and compared with post-treatment parasite clearance times in each group. Significantly faster parasite clearance times were associated with in vitro production of IL-10 by acute-phase peripheral blood mononuclear cells (PBMC) in response to both liver and asexual stage parasite antigens, but not with proliferative, IFN-gamma, or TNF responses to the same antigens. In addition, in those children with mild malaria, higher levels of acute-phase antibody responses to liver stage antigen-1 (LSA-1) were associated with faster parasite clearance times, and were correlated with the presence of IL-10 responses to the same antigen. No such associations were found for IL-10 or antibody responses to a range of asexual blood stage antigens. Those with severe malaria had significantly lower levels of anti-LSA-1 antibodies compared to their counterparts with mild malaria. In conclusion, the results of this study suggest that parasite antigen-specific IL-10-mediated antibody responses may play a role in the control of asexual stage parasite multiplication in P. falciparum malaria.
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PMID:Parasite antigen-specific interleukin-10 and antibody reponses predict accelerated parasite clearance in Plasmodium falciparum malaria. 988 8

In areas in which malaria is holoendemic, primigravidae and secundigravidae, compared with multigravidae, are highly susceptible to placental malaria (PM). The nature of gravidity-dependent immune protection against PM was investigated by measuring in vitro production of cytokines by placental intervillous blood mononuclear cells (IVBMC). The results demonstrated that interferon (IFN)-gamma may be a critical factor in protection against PM: production of this cytokine by PM-negative multigravid IVBMC was elevated compared with PM-negative primigravid and secundigravid and PM-positive multigravid cells. Low IFN-gamma responsiveness to malarial antigen stimulation, most evident in the latter group, was balanced by increased interleukin (IL)-4 production, suggesting that counter-regulation of these two cytokines may be a crucial determinant in susceptibility to PM. A counter-regulatory relationship between IL-10 and tumor necrosis factor-alpha was also observed in response to malarial antigen stimulation. These data suggest that elevated production of IFN-gamma, as part of a carefully regulated cytokine network, is important in the control of PM.
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PMID:Immunity to placental malaria. I. Elevated production of interferon-gamma by placental blood mononuclear cells is associated with protection in an area with high transmission of malaria. 1019 Dec 26

In this study, we describe protection of BALB/c mice by immunization with heat-killed T. gondii tachyzoites against infection with Plasmodium yoelii 17XL which causes cerebral malaria and death in mice by day 7-8 post infection. Immunization resulted significant reduction in parasitemia at the peak period of infection. Protection induced by heat-killed T. gondii was associated with marked increase in NK cell number and IFN-gamma mRNA expression early in the infection. The level of IFN-gamma or TNF-alpha was found to diminish in T. gondii-treated mice as the infection progressed to the late stage. This declined response of IFN-gamma or TNF-alpha was associated with marked increase in the expression of IL-10, a counterregulatory cytokine. Pretreatment of mice with live T. gondii induced poor level of protection as compared with that of heat-killed parasites. Mice that received P. yoelii infection alone, had an elevated IFN-gamma response in the late stage of infection. Development of cerebral malaria in untreated mice was accompanied by an augmented production of TNF-alpha and nitric oxide (NO), the proinflammatory mediators. These findings suggest that nonspecific immunization with T. gondii leads to restoration of an early IFN-gamma response in P. yoelii-infected mice and in the establishment of an immunoregulatory mechanism that effectively antagonizes the disease-promoting effects of proinflammatory cytokines in the late phase of infection.
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PMID:Immunization with heat-killed Toxoplasma gondii stimulates an early IFN-gamma response and induces protection against virulent murine malaria. 1041 9

A baculovirus recombinant antigen corresponding to the C-terminal 19 000 MW fragment of Plasmodium falciparum merozoite surface protein 1 (MSP119), has been used to prime T cells from individuals with no previous exposure to malaria, to provide help for the induction of a parasite specific antibody response in vitro. Although MSP119 alone could induce a small but detectable T-cell response, which included interleukin-4 (IL-4) secretion, this response was significantly increased by the presence of IL-2. In addition, IL-4 was shown to synergize with IL-2 for the induction of antigen-specific T-cell responses. If interferon-gamma (IFN-gamma), IL-12, or neutralizing anti-IL-4 antibody was present at the time of priming, the T-cell responses were abolished. Parasite-specific immunoglobulin G (IgG) could be detected after secondary restimulation with MSP119, IL-10 and anti-CD40 monoclonal antibody in cultures containing MSP119 primed T cells, autologous B cells, IL-2 and IL-4. No antibody was secreted in the absence of primed T cells in this B-cell culture assay. These data show that recombinant MSP119, a leading malaria vaccine candidate, can prime non-immune human lymphocytes under defined in vitro experimental conditions, which include regulatory cytokines and/or other costimulatory molecules. This is a complementary approach for exploring immunogenic mechanisms of potential vaccine candidates such as P. falciparum antigens in humans.
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PMID:Immune responses to Plasmodium falciparum-merozoite surface protein 1 (MSP1) antigen, II. Induction of parasite-specific immunoglobulin G in unsensitized human B cells after in vitro T-cell priming with MSP119. 1044 73


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