An early burst of IFN-γ induced by the pre-erythrocytic stage favours Plasmodium yoelii parasitaemia in B6 mice

<p>Abstract</p> <p>Background</p> <p>In murine models of malaria, an early proinflammatory response has been associated with the resolution of blood-stage infection. To dissect the protective immune mechanims that allow the control of parasitaemia, the early immune response of C57BL/6 mice induced during a non-lethal plasmodial infection was analysed.</p> <p>Methods</p> <p>Mice were infected with <it>Plasmodium yoelii </it>265BY sporozoites, the natural invasive form of the parasite, in order to complete its full life cycle. The concentrations of three proinflammatory cytokines in the sera of mice were determined by ELISA at different time points of infection. The contribution of the liver and the spleen to this cytokinic response was evaluated and the cytokine-producing lymphocytes were identified by flow cytometry. The physiological relevance of these results was tested by monitoring parasitaemia in genetically deficient C57BL/6 mice or wild-type mice treated with anti-cytokine neutralizing antibody. Finally, the cytokinic response in sera of mice infected with parasitized-RBCs was analysed.</p> <p>Results</p> <p>The early immune response of C57BL/6 mice to sporozoite-induced malaria is characterized by a peak of IFN-γ in the serum at day 5 of infection and splenic CD4 T lymphocytes are the major producer of this cytokine at this time point. Somewhat unexpected, the parasitaemia is significantly lower in <it>P. yoelii</it>-infected mice in the absence of IFN-γ. More precisely, at early time points of infection, IFN-γ favours parasitaemia, whereas helping to clear efficiently the blood-stage parasites at later time points. Interestingly, the early IFN-γ burst is induced by the pre-erythrocytic stage.</p> <p>Conclusion</p> <p>These results challenge the current view regarding the role of IFN-γ on the control of parasite growth since they show that IFN-γ is not an essential mediator of protection in <it>P. yoelii</it>-infected C57BL/6 mice. Moreover, the mice parasitaemia is more efficiently controlled in the absence of an early IFN-γ production, suggesting that this cytokine promotes parasite's growth. Finally, this early burst of IFN-γ is induced by the pre-erythrocytic stage, showing the impact of this stage on the immune response taking place during the subsequent erythrocytic stage.</p

Constitutive Endocytosis and Degradation of the Pre-T Cell Receptor

The pre-T cell receptor (TCR) signals constitutively in the absence of putative ligands on thymic stroma and signal transduction correlates with translocation of the pre-TCR into glycolipid-enriched microdomains (rafts) in the plasma membrane. Here, we show that the pre-TCR is constitutively routed to lysosomes after reaching the cell surface. The cell-autonomous down-regulation of the pre-TCR requires activation of the src-like kinase p56lck, actin polymerization, and dynamin. Constitutive signaling and degradation represents a feature of the pre-TCR because the γδTCR expressed in the same cell line does not exhibit these features. This is also evident by the observation that the protein adaptor/ubiquitin ligase c-Cbl is phosphorylated and selectively translocated into rafts in pre-TCR– but not γδTCR-expressing cells. A role of c-Cbl–mediated ubiquitination in pre-TCR degradation is supported by the reduction of degradation through pharmacological inhibition of the proteasome and through a dominant-negative c-Cbl ubiquitin ligase as well as by increased pre-TCR surface expression on immature thymocytes in c-Cbl–deficient mice. The pre-TCR internalization contributes significantly to the low surface level of the receptor on developing T cells, and may in fact be a requirement for optimal pre-TCR function

Multifaceted Role of Heme during Severe Plasmodium falciparum Infections in India

Several immunomodulatory factors are involved in malaria pathogenesis. Among them, heme has been shown to play a role in the pathophysiology of severe malaria in rodents, but its role in human severe malaria remains unclear. Circulating levels of total heme and its main scavenger, hemopexin, along with cytokine/chemokine levels and biological parameters, including hemoglobin and creatinine levels, as well as transaminase activities, were measured in the plasma of 237 Plasmodium falciparum-infected patients living in the state of Odisha, India, where malaria is endemic. All patients were categorized into well-defined groups of mild malaria, cerebral malaria (CM), or severe noncerebral malaria, which included acute renal failure (ARF) and hepatopathy. Our results show a significant increase in total plasma heme levels with malaria severity, especially for CM and malarial ARF. Spearman rank correlation and canonical correlation analyses have shown a correlation between total heme, hemopexin, interleukin-10, tumor necrosis factor alpha, gamma interferon-induced protein 10 (IP-10), and monocyte chemotactic protein 1 (MCP-1) levels. In addition, canonical correlations revealed that heme, along with IP-10, was associated with the CM pathophysiology, whereas both IP-10 and MCP-1 together with heme discriminated ARF. Altogether, our data indicate that heme, in association with cytokines and chemokines, is involved in the pathophysiology of both CM and ARF but through different mechanisms.Indo-French Centre for the Promotion of Advanced Research, Associated International Laboratory Systems (LIA; CNRS), Immunology and Genetics of Infectious Diseases (SIGID), Department of Biotechnology from the Ministry of Science and Technology of India (DBT), Tata Institute of Fundamental Research (TIFR) (intramural funds), Université Lille (doctoral contract), IFCPAR (Raman-Charpak award), College Doctoral Lille Nord de France (AAP n10 award), Fondation des Treille, Conseil Régional du Nord-Pas de Calais

Auto-antibodies targeting brain antigens in Plasmodium falciparum infected patients as biomarkers of Cerebral Malaria

International audiencen.

Self-Reactivities to the Non-Erythroid Alpha Spectrin Correlate with Cerebral Malaria in Gabonese Children

BACKGROUND: Hypergammaglobulinemia and polyclonal B-cell activation commonly occur in Plasmodium sp. infections. Some of the antibodies produced recognize self-components and are correlated with disease severity in P. falciparum malaria. However, it is not known whether some self-reactive antibodies produced during P. falciparum infection contribute to the events leading to cerebral malaria (CM). We show here a correlation between self-antibody responses to a human brain protein and high levels of circulating TNF alpha (TNFα), with the manifestation of CM in Gabonese children. METHODOLOGY: To study the role of self-reactive antibodies associated to the development of P. falciparum cerebral malaria, we used a combination of quantitative immunoblotting and multivariate analysis to analyse correlation between the reactivity of circulating IgG with a human brain protein extract and TNFα concentrations in cohorts of uninfected controls (UI) and P. falciparum-infected Gabonese children developing uncomplicated malaria (UM), severe non-cerebral malaria (SNCM), or CM. RESULTS/CONCLUSION: The repertoire of brain antigens recognized by plasma IgGs was more diverse in infected than in UI individuals. Anti-brain reactivity was significantly higher in the CM group than in the UM and SNCM groups. IgG self-reactivity to brain antigens was also correlated with plasma IgG levels and age. We found that 90% of CM patients displayed reactivity to a high-molecular mass band containing the spectrin non-erythroid alpha chain. Reactivity with this band was correlated with high TNFα concentrations in CM patients. These results strongly suggest that an antibody response to brain antigens induced by P. falciparum infection may be associated with pathogenic mechanisms in patients developing CM

Caractérisation des populations lymphocytaires Tab lors de maladies infectieuses (mise au point de nouvelles méthodes d'analyse des répertoires immunitaires)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Etude des anticorps auto-réactifs produits au cours de l'infection par Plasmodium falciparum (implication dans la protection ou la pathogenèse du neuropaludisme)

Les études antérieures traitant du rôle des auto-anticorps dans la protection ou la pathogenèse du paludisme grave sont peu nombreuses. Notre approche consiste a analyser l auto-réactivité globale des IgG et des IgE au cours de l infection par P. falciparum, chez des patients vivant en zone d endémie palustre repartis en cinq groupes: patients non infectés par P. falciparum (NI), porteurs asymptomatiques (IA), accès palustre simple (AS), accès palustre graves sans atteinte neurologique (AG), neuropaludisme (NP). Nos résultats mettent en évidence une réponse auto-réactive des IgG associée aux concentrations plasmatiques d IL-10 chez les IA, dont les IgE reconnaissaient particulièrement les protéines 14-3-3 et -spectrine non érythrocytaire; alors que la réponse pathogène est corrélée aux taux plasmatiques du TNF chez les patients développant un NP. Chez ces derniers, l auto-réactivité particulièrement dirigée contre l -spectrine cérébrale, était également associée aux concentrations de TNF . Ces observations suggèrent que la réponse auto-immune induite au cours de l infection par P. falciparum est impliquée aussi bien dans la protection contre la maladie que dans la pathogenèse du neuropaludisme. Les IgE anti-14-3-3 pourraient jouer un rôle important dans la protection contre la maladie, et la réactivité anti- -spectrine associée aux taux de TNF pourrait être un marqueur de gravité du paludisme.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Etude des facteurs immunologiques et génétiques associés à la genèse du neuropaludisme induit par Plasmodium berghei ANKA

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Etude des réponses des lymphocytes NKT et NK à l' infection par Plasmodium yoelii 265BY chez la souris C57BI/6

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Immune networks : frequencies of antibody and idiotype producing B cell clones in various steady states

El copyright pertenece a The Rockefeller University PressThe network theory of the immune system can be reduced to the interactions between soluble and cell-bound idiotypes and combining sites, independently of the functional properties of the lymphocytes bearing those elements . After its original exposition, however, much attention has been drawn to the functionally opposing consequences of the activity mediated by distinct classes of lymphocytes. The "plusminus" general network interactions have thus been progressively substituted by "mini-networks" of suppressor and helper T cells, often disconnected from the overall regulatory influences maintaining steady states in a complete, and therefore circular, repertoire . It appeared important, therefore, to establish a primary, quantitative description of the immune elements in various steady states to provide the basis for a description of immune networks . This, on the other hand, would perhaps contribute to resolving the present problems of predicting pathways in network interactions and the consequences of specific manipulations . We have initiated these attempts by determining B cell precursor frequencies in quantitative assays , under conditions that limit only for the clonal precursor itself. This was done in a well-characterized system prototype of network regulation using monoclonal idiotypes and anti-idiotypesPeer reviewe