Reduced levels of transforming growth factor-β1, interleukin-12 and increased migration inhibitory factor are associated with severe malaria

Chaiyaroj, Sansanee C.; Rutta, Acleus S. M.; Muenthaisong, Kedsuda; Watkins, P; Ubol, Mathukon Na; Looareesuwan, Sornchai

doi:10.1016/j.actatropica.2003.10.010

Cited by 87 publications

(108 citation statements)

References 31 publications

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“…Evidence also suggests that both TGF-␤ and IL-10 can be produced very rapidly, from innate sources, during murine malaria infections and are required to down-regulate potentially pathogenic inflammatory responses once parasitemia is brought under control (26 -28); however, in both mice and humans, excessive concentrations of TGF-␤ and IL-10 early in infection inhibit type-1 immune responses and thus facilitate parasite growth (29,30). Conversely, in clinical human infections, failure to produce sufficient TGF-␤ or IL-10 is associated with acute (31) and severe malaria (17,32,33), and severe malarial anemia (34,35). Finally, high ratios of IFN-␥, TNF-␣, and IL-12 to TGF-␤ or IL-10 are associated with decreased risk of malaria infection but increased risk of clinical disease in those who do become infected (22).…”

Section: R Esearch On the Immunology Of Malaria Infection Has Beenmentioning

confidence: 99%

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

Walther

Woodruff

Edele

et al. 2006

The Journal of Immunology

141

118

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Taking advantage of a sporozoite challenge model established to evaluate the efficacy of new malaria vaccine candidates, we have explored the kinetics of systemic cytokine responses during the prepatent period of Plasmodium falciparum infection in 18 unvaccinated, previously malaria-naive subjects, using a highly sensitive, bead-based multiplex assay, and relate these data to peripheral parasite densities as measured by quantitative real-time PCR. These data are complemented with the analysis of cytokine production measured in vitro from whole blood or PBMC, stimulated with P. falciparum-infected RBC. We found considerable qualitative and quantitative interindividual variability in the innate responses, with subjects falling into three groups according to the strength of their inflammatory response. One group secreted moderate levels of IFN-γ and IL-10, but no detectable IL-12p70. A second group produced detectable levels of circulating IL-12p70 and developed very high levels of IFN-γ and IL-10. The third group failed to up-regulate any significant proinflammatory responses, but showed the highest levels of TGF-β. Proinflammatory responses were associated with more rapid control of parasite growth but only at the cost of developing clinical symptoms, suggesting that the initial innate response may have far-reaching consequences on disease outcome. Furthermore, the in vitro observations on cytokine kinetics presented here, suggest that intact schizont-stage infected RBC can trigger innate responses before rupture of the infected RBC.

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Section: R Esearch On the Immunology Of Malaria Infection Has Beenmentioning

confidence: 99%

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

Walther

Woodruff

Edele

et al. 2006

The Journal of Immunology

141

118

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“…Regulation of TGF-␤ production is crucial in determining the outcome of infection in mice (12); reduced levels promote inflammation and parasite clearance during early infection, whereas increased levels during the later phase of infection are associated with reduced pathology and disease control (12,13). In humans the absolute ratios of proinflammatory and antiinflammatory cytokines are important determinants of susceptibility to severe disease (14), and decreased levels of TGF-␤ are associated with severity (15).…”

Section: Tgf-␤ 1 Released From Activated Platelets Can Inducementioning

confidence: 99%

TGF-β1 Released from Activated Platelets Can Induce TNF-Stimulated Human Brain Endothelium Apoptosis: A New Mechanism for Microvascular Lesion during Cerebral Malaria

Wassmer

Souza

Frère

et al. 2006

The Journal of Immunology

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Platelets have recently been shown to accumulate in brain microvessels of patients with cerebral malaria and to modulate the binding of Plasmodium falciparum-infected red cells to human brain endothelium in vitro. In the present study we used a platelet-endothelial cell coculture model to investigate the mechanisms by which platelets modify the function of human brain microvascular endothelial cells (HBEC). Platelets were found to have a proapoptotic effect on TNF-activated HBEC, and this was contact-dependent, as inhibiting platelet binding prevented endothelial cell killing. We also showed that the supernatants of thrombin-activated platelets killed TNF-stimulated HBEC and that TGF-β1 was the main molecule involved in endothelial cell death, because its inhibition completely abrogated the activated-platelet supernatant effect. Our data illustrate another aspect of the duality of TGF-β1 in malaria and may provide new insights into the pathogenesis of cerebral malaria.

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“…However, immune-mediated pathologypredominantly observed in non-immune and semi-immune subjects -has been linked to sustained and/or excessive inflammatory responses in animal malaria models [2] and human disease [3]. Indeed, ratios of inflammatory to regulatory cytokines seem to determine the severity of disease: low levels of TGF-b [4][5][6] and IL-10 [7,8] have been associated with acute or severe malaria, and high ratios of IFN-g, TNF-a and IL-12 to TGF-b or IL-10 are associated with decreased risk of malaria infection but increased risk of clinical disease in those who do become infected [9,10]. Moreover, in vitro parasite-induced IFN-g production by PBMC is considerably lower among clinically immune individuals than among semi-immune subjects [11,12].…”

Section: Introductionmentioning

confidence: 99%

Homeostatic regulation of T effector to Treg ratios in an area of seasonal malaria transmission

et al. 2009

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An important aspect of clinical immunity to malaria is the ability to down-regulate inflammatory responses, once parasitaemia is under control, in order to avoid immunemediated pathology. The role of classical (CD4 CD127lo/À FOXP3 1 ) Treg in this process, however, remains controversial. Thus, we have characterized the frequency, phenotype and function of Treg populations, over time, in healthy individuals in The Gambia. We observed that both the percentage and the absolute number of CD4lo/À T cells were higher among individuals living in a rural village with highly seasonal malaria transmission than among individuals living in an urban area where malaria rarely occurs. These CD4 1 FOXP31 CD127 lo/À T cells exhibited an effector memory and apoptosis-prone phenotype and suppressed cytokine production in response to malaria antigen. Cells from individuals exposed to malaria expressed significantly higher levels of mRNA for forkhead box P3 and T-box 21 (T-BET) at the end of the malaria transmission season than at the end of the non-transmission season. Importantly, the ratio of T-BET to forkhead box P3 was remarkably consistent between populations and over time, indicating that in healthy individuals, a transient increase in Th1 responses during the malaria transmission season is balanced by a commensurate Treg response, ensuring that immune homeostasis is maintained.Key words: Human . Malaria . Regulation . T cells Supporting Information available online IntroductionA strong pro-inflammatory response, characterized by IFN-g and TNF-a, contributes to the initial killing and clearance of malariainfected RBC [1]. However, immune-mediated pathologypredominantly observed in non-immune and semi-immune subjects -has been linked to sustained and/or excessive inflammatory responses in animal malaria models [2] and human disease [3]. Indeed, ratios of inflammatory to regulatory cytokines seem to determine the severity of disease: low levels of and 8] have been associated with acute or severe malaria, and high ratios of IFN-g, TNF-a and IL-12 to TGF-b or IL-10 are associated with decreased risk of malaria infection but increased risk of clinical disease in those who do Ã These authors contributed equally to this work. 1288become infected [9,10]. Moreover, in vitro parasite-induced IFN-g production by PBMC is considerably lower among clinically immune individuals than among semi-immune subjects [11,12]. This has led to the hypothesis that the ability to down-regulate inflammatory responses -once parasitaemia is under control -is crucial to avoid immune-mediated pathology, and may therefore be an important feature of clinical immunity to malaria [3,13].The balance between pro-inflammatory and regulatory immune mechanisms is crucial in determining the outcome of many parasitic infections [13,14]: pro-inflammatory responses, though essential to clear infection, can also lead to severe disease and need to be very tightly regulated in order to maintain immune homeostasis.Treg, first characterised by a high level of CD25 expressi...

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Reduced levels of transforming growth factor-β1, interleukin-12 and increased migration inhibitory factor are associated with severe malaria

Cited by 87 publications

References 31 publications

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

Innate Immune Responses to Human Malaria: Heterogeneous Cytokine Responses to Blood-Stage Plasmodium falciparum Correlate with Parasitological and Clinical Outcomes

TGF-β1 Released from Activated Platelets Can Induce TNF-Stimulated Human Brain Endothelium Apoptosis: A New Mechanism for Microvascular Lesion during Cerebral Malaria

Homeostatic regulation of T effector to Treg ratios in an area of seasonal malaria transmission

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