Background: There is an increase of serum levels of IgE duringPlasmodium falciparuminfections in individuals living in endemic areas. These IgEs either protect against malaria or increase malaria pathogenesis. To get an insight into the exact role played by IgE in the outcome ofP. falciparuminfection, total IgE levels and functional anti-parasite IgE response were studied in children and adults, from two different endemic areas Gabon and India, exhibiting either uncomplicated malaria, severe non cerebral malaria or cerebral malaria, in comparison with control individuals.Methodology and results: Blood samples were collected from controls andP. falciparum-infected patients before treatment on the day of hospitalization (day 0) in India and, in addition, on days 7 and 30 after treatment in Gabon. Total IgE levels were determined by ELISA and functionalP. falciparum-specific IgE were estimated using a mast cell line RBL-2H3 transfected with a human Fcε RI α-chain that triggers degranulation upon human IgE cross-linking. Mann Whitney and Kruskall Wallis tests were used to compare groups and the Spearman test was used for correlations.Total IgE levels were confirmed to increase upon infection and differ with level of transmission and age but were not directly related to the disease phenotype. All studied groups exhibited functional parasite-specific IgEs able to induce mast cell degranulationin vitroin the presence ofP. falciparumantigens. Plasma IgE levels correlated with those of IL-10 in uncomplicated malaria patients from Gabon. In Indian patients, plasma IFN-γ , TNF and IL-10 levels were significantly correlated with IgE concentrations in all groups.Conclusion: Circulating levels of total IgE do not appear to correlate with protection or pathology, or with anti-inflammatory cytokine pattern bias during malaria. On the contrary, theP. falciparum-specific IgE response seems to contribute to the control of parasites, since functional activity was higher in asymptomatic and uncomplicated malaria patients than in severe or cerebral malaria groups.

Cerebral malaria is the most severe complication of human infection withPlasmodium falciparum. It was shown thatPlasmodium bergheiANKA-induced cerebral malaria was prevented in 100% of mice depleted of CD8⁺T cells 1 day prior to the development of neurological signs. However, the importance of parasites in the brains of these mice was never clearly investigated. Moreover, the relevance of this model to human cerebral malaria has been questioned many times, especially concerning the relative importance of leukocytes versus parasitized erythrocytes sequestered in the brain. Here, we show that mice protected from cerebral malaria by CD8⁺T-cell depletion have significantly fewer parasites in the brain. Treatment of infected mice with an antimalarial drug 15 to 20 h prior to the estimated time of death also protected mice from cerebral malaria without altering the number of CD8⁺T cells in the brain. These mice subsequently developed cerebral malaria with parasitized red blood cells in the brain. Our results clearly demonstrated that sequestration of CD8⁺T cells in the brain is not sufficient for the development of cerebral malaria in C57BL/6 mice but that the concomitant presence of parasitized red blood cells is crucial for the onset of pathology. Importantly, these results also demonstrated that the experimental cerebral malaria model shares many features with human pathology and might be a relevant model to study its pathogenesis.

We investigated the role of interferon (IFN)–γ, interleukin (IL)–1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)-α, and transforming growth factor (TGF)–β in clinically well-defined groups of Plasmodium falciparum–infected patients manifesting mild malaria (MM), severe noncerebral malaria (SM), or cerebral malaria (CM) and in control subjects from Gondia, a malaria-endemic site in India, as well as in healthy subjects from non–malaria-endemic areas. Two-way coupled cluster analysis revealed 2 clusters of cytokines relevant to clinical subgroups of disease. The first cluster was composed of IFN-γ, IL-2, IL-5, IL-6, and IL-12, the levels of which were significantly increased during infection but were predominant in patients with MM and allowed us to distinguish them from patients with SM or CM. The second cluster was composed of TGF-β, TNF-α, IL-10, and IL-1β, the levels of which were highly correlated with each other in the different clinical groups of patients and significantly increased with disease severity, particularly in CM. Discriminant analyses allowed us to propose a minimal model. Levels of cytokines such as IL-5, IL-1β, IL-10, and IL-2 increase with infection. Levels of IL-12, IL-5, and IL-6 discriminate severe forms of malaria from MM. Finally, levels of IL-1β, IL-12, and IFN-γ are relevant for the discrimination of CM from SM: high IL-1β levels are associated with CM, and high IL-12 and IFN-γ levels are associated with SM

We have studied the effect of natural and recombinant human interferons (HuIFN-alpha, -beta, and -gamma), and interleukin 1 (IL-1) on development of sporozoites of Plasmodium falciparum in cultures of functional hepatocytes. HuIFN-gamma inhibits hepatic schizogony of P. falciparum at very low concentrations (0.1 to 10 international units/ml), the target being the hepatocyte. Application after sporozoite inoculation is effective, suggesting an intracellular mechanism. There is also an 84% inhibition after application from 4 to 6 days following inoculation so that by day 6, there was a disappearance of a significant number of schizonts previously present at day 4, indicating more than a parasitostatic effect, and probably a postassembly action. HuIFN-alpha and -beta were effective, but only at 1000-fold higher concentrations than HuIFN-gamma. IL-1 (5 U/ml) also inhibited hepatic development of P. falciparum sporozoites; however, IL-1 treatment was effective only when applied before sporozoite inoculation.