Dominant Role of CD80–CD86 Over CD40 and ICOSL in the Massive Polyclonal B Cell Activation Mediated by LATY136F CD4+ T Cells

Coordinated interactions between T and B cells are crucial for inducing physiological B cell responses. Mutant mice in which tyrosine 136 of linker for activation of T cell (LAT) is replaced by a phenylalanine (LatY136F) exhibit a strong CD4+ T cell proliferation in the absence of intended immunization. The resulting effector T cells produce high amounts of TH2 cytokines and are extremely efficient at inducing polyclonal B cell activation. As a consequence, these LatY136F mutant mice showed massive germinal center formations and hypergammaglobulinemia. Here, we analyzed the involvement of different costimulators and their ligands in such T–B interactions both in vitro and in vivo, using blocking antibodies, knockout mice, and adoptive transfer experiments. Surprisingly, we showed in vitro that although B cell activation required contact with T cells, CD40, and inducible T cell costimulator molecule-ligand (ICOSL) signaling were not necessary for this process. These observations were further confirmed in vivo, where none of these molecules were required for the unfolding of the LAT CD4+ T cell expansion and the subsequent polyclonal B cell activation, although, the absence of CD40 led to a reduction of the follicular B cell response. These results indicate that the crucial functions played by CD40 and ICOSL in germinal center formation and isotype switching in physiological humoral responses are partly overcome in LatY136F mice. By comparison, the absence of CD80–CD86 was found to almost completely block the in vitro B cell activation mediated by LatY136F CD4+ T cells. The role of CD80–CD86 in T–B cooperation in vivo remained elusive due to the upstream implication of these costimulatory molecules in the expansion of LatY136F CD4+ T cells. Together, our data suggest that CD80 and CD86 costimulators play a key role in the polyclonal B cell activation mediated by LatY136F CD4+ T cells even though additional costimulatory molecules or cytokines are likely to be required in this process

Short fluorodeoxyuridine exposure of different human glioblastoma lines induces high-level accumulation of S-phase cells that avidly incorporate 125I-iododeoxyuridine

Purpose: Radio-iododeoxyuridine (IdUrd) is a potential Auger radiation therapy agent incorporated into DNA during the synthesis phase. In this study we sought to optimise S-phase targeting by modulating cellular cycling and radio-IdUrd DNA incorporation using short non-toxic fluorodeoxyuridine (FdUrd) incubations. Methods: Three human glioblastoma cell lines with different p53 expression were pre-treated with various FdUrd conditions. After different intervals, 125I-IdUrd DNA incorporation was measured. Fluorescence-activated cell sorter cell cycle analysis was performed after identical intervals post FdUrd pre-treatment. Results: The highest increase in 125I-IdUrd DNA incorporation was induced by 1-h incubation with 1μM FdUrd. Increase in radio-IdUrd DNA incorporation was greatest 16-24h after FdUrd, reaching factors of ≥7.5 over baseline incorporation in the three cell lines. Furthermore, cell synchronisation in S phase was observed with a peak of ≥69.5% in the three cell lines at 16 and 24h post FdUrd, corresponding to an increase of 2.5-4.1 over baseline. Conclusion: FdUrd-induced thymidine synthesis inhibition led to S-phase accumulation that was maximal after an interval of 16-24h and time-correlated with the highest radio-IdUrd DNA incorporation. These observations might allow the rational design of an Auger radiation therapy targeting a maximal number of S-phase cells in single treatment cycle

Comparison of diagnostic methods for the detection and quantification of the four sympatric Plasmodium species in field samples from Papua New Guinea

Accurate diagnosis of Plasmodium infections is essential for malaria morbidity and mortality reduction in tropical areas. Despite great advantages of light microscopy (LM) for malaria diagnosis, its limited sensitivity is a critical shortfall for epidemiological studies. Robust molecular diagnostics tools are thus needed.; The present study describes the development of a duplex quantitative real time PCR (qPCR) assay, which specifically detects and quantifies the four human Plasmodium species. Performance of this method was compared to PCR-ligase detection reaction-fluorescent microsphere assay (PCR_LDR_FMA), nested PCR (nPCR) and LM, using field samples collected from 452 children one to five years of age from the Sepik area in Papua New Guinea. Agreement between diagnostic methods was calcualted using kappa statistics.; The agreement of qPCR with other molecular diagnostic methods was substantial for the detection of P. falciparum, but was moderate for the detection of P. vivax, P. malariae and P. ovale. P. falciparum and P. vivax prevalence by qPCR was 40.9% and 65.7% respectively. This compares to 43.8% and 73.2% by nPCR and 47.1% and 67.5% by PCR_LDR_FMA. P. malariae and P. ovale prevalence was 4.7% and 7.3% by qPCR, 3.3% and 3.8% by nPCR, and 7.7% and 4.4% by PCR_LDR_FMA. Prevalence by LM was lower for all four species, being 25.4% for P. falciparum, 54.9% for P. vivax, 2.4% for P. malariae and 0.0% for P. ovale. The quantification by qPCR closely correlated with microscopic quantification for P. falciparum and P. vivax samples (R2 = 0.825 and R2 = 0.505, respectively). The low prevalence of P. malariae and P. ovale did not permit a solid comparative analysis of quantification for these species.; The qPCR assay developed proved optimal for detection of all four Plasmodium species. Densities by LM were well reflected in quantification results by qPCR, whereby congruence was better for P. falciparum than for P. vivax. This likely is a consequence of the generally lower P. vivax densities. Easy performance of the qPCR assay, a less laborious workflow and reduced risk of contamination, together with reduced costs per sample through reduced reaction volume, opens the possibility to implement qPCR in endemic settings as a suitable diagnostic tool for large epidemiological studies

Intermittent Preventive Treatment for Malaria in Papua New Guinean Infants Exposed to Plasmodium falciparum and P. vivax: A Randomized Controlled Trial

A three-arm randomized trial conducted among infants in Papua New Guinea estimates the preventive effect against malaria episodes of intermittent preventive treatment, in an area where children are exposed to both falciparum and vivax malaria

Capacités de récupération d'une population de gorilles de plaine de l'Ouest (Gorilla gorilla gorilla) suite à un effondrement démographique engendré par une épidémie à virus Ebola

This study takes place in the context of emerging infectious diseases now recognized as a major threat to biodiversity. The impact of Ebola epidemics which induced up to 95% mortality in Western lowland gorilla populations (Gorilla gorilla gorilla) led to the classification of this taxon as "critically endangered". This study focuses on the recovery potential of gorilla populations after Ebola. On the basis of a unique set of data in preand post-epidemic periods, we evaluated the impact of the epidemic on the social structure and dynamics of a population. We then estimated its potential of recovery during the six years following the outbreak. Our results on demography and dynamics, coupled with statistical approaches and a modeling work at a demographic age and sex level, including immigration, showed 1) a deleterious impact on the breeding potential, because of the social organization of gorillas, 2) the advantages of the social flexibility and the social organization of gorillas in the recovery of the demographic structure of their population, 3) the role of immigration in the long-term recovery of population size. Our determination of the demographic features characterizing a population affected by Ebola allowed us to specify that a studied neighboring population was unaffected. These findings highlighted that Ebola impact had been heterogeneous at a regional level, which probably induced some population fragmentation. This new insight lets discuss the hypotheses on the emergence and spread of the virus and questions the impact of the fragmentation on population dynamics and recovery of affected local populations. Our results suggest a low resilience of populations of lowland gorillas against Ebola virus and the threat to population persistence. However, a better understanding of the ability of individuals to disperse at the regional level and the development of demographic models that take into account this dimension would allow to better clarify this resilience.Cette étude se place dans le contexte des maladies infectieuses émergentes maintenant reconnues comme une menace majeure de la biodiversité. Engendrant un taux de mortalité atteignant 95 %, les épidémies à virus Ebola ayant affecté les populations de gorilles de plaine de l'Ouest (Gorilla gorilla gorilla) conduisirent à la classification de ce taxon comme " En danger critique d'extinction ". Cette étude s'intéresse aux capacités de récupération de ses populations. Grâce à des données uniques d'observation en phase pré- et post-épidémique, nous avons évalué l'impact de l'épidémie sur la structure et la dynamique sociale d'une population et estimé son potentiel de récupération au cours des six ans qui ont suivi. Nos résultats de démographie et de dynamique, couplés à des approches statistique et de modélisation démographique détaillée au niveau des classes d'âge et de sexe, et intégrant l'immigration, nous ont permis de mettre en évidence 1) un impact délétère sur le potentiel reproducteur, du fait de l'organisation sociale du gorille ; 2) les atouts de la flexibilité et de l'organisation sociale dans la récupération de la structure de la population ; 3) le rôle de l'immigration pour la récupération à long-terme des effectifs. La mise en évidence de caractéristiques structurelles typiques d'une population affectée par Ebola nous a permis de montrer qu'une population voisine étudiée était indemne. Ceci met en évidence l'impact hétérogène des épidémies au niveau régional, induisant probablement un certain degré de fragmentation des populations. Ce nouvel élément permet de discuter les hypothèses d'émergence et de propagation du virus, et pose la question de l'impact de la fragmentation de la population sur sa dynamique globale et sur la récupération des populations locales affectées. Nos résultats suggèrent une faible résilience des populations de gorilles de plaine face à Ebola et la menace de ce virus pour la persistance des populations. Cependant, une meilleure connaissance du potentiel de flux d'individus au niveau régional et le développement de modèles démographiques prenant en compte cette dimension permettrait de mieux préciser cette résilience

Capacités de récupération d une population de gorilles de plaine de l Ouest (Gorilla gorilla gorilla) suite à un effondrement démographique engendré par une épidémie à virus Ebola

Engendrant un taux de mortalité atteignant 95%, les épidémies à virus Ebola ayant affecté les populations de gorilles de plaine de l Ouest conduisirent à la classification de ce taxon comme En danger critique d extinction . Cette étude s intéresse aux capacités de récupération de ses populations. Grâce à des données uniques d observation en phase pré- et post-épidémique, nous avons évalué l impact de l épidémie sur la structure et la dynamique sociale d une population et estimé son potentiel de récupération au cours des six ans qui ont suivi. Nos résultats de démographie et de dynamique, couplés à des approches statistique et de modélisation démographique détaillée au niveau des classes d âge et de sexe, et intégrant l immigration, nous ont permis montrer 1) un impact délétère sur le potentiel reproducteur; 2) les atouts de la flexibilité et de l organisation sociale dans la récupération de la structure de la population; 3) le rôle de l immigration pour la récupération à long-terme des effectifs. La mise en évidence de caractéristiques structurelles typiques d une population affectée par Ebola nous a permis de montrer qu une population voisine était indemne. Ceci montre l impact hétérogène des épidémies au niveau régional, pouvant induire une fragmentation des populations. Ce nouvel élément permet de discuter les hypothèses d émergence et de propagation du virus, et pose la question de l impact de la fragmentation de la population sur sa dynamique globale et sur la récupération des populations locales affectées. Nos résultats suggèrent une faible résilience des populations de gorilles de plaine face à Ebola et la menace de ce virus pour la persistance des populations.The impact of Ebola epidemics which induced up to 95% mortality in Western lowland gorilla populations (Gorilla gorilla gorilla) led to the classification of this taxon as "critically endangered".This study focuses on the recovery potential of gorilla populations after Ebola. On the basis of an unique set of data in pre- and post-epidemic periods, we evaluated the impact of the epidemic on the social structure and dynamics of a population. We then estimated its potential of recovery during the six years following the outbreak. Our results on demography and dynamics, coupled with statistical approaches and a modeling work at a demographic age and sex level, including immigration, showed1) a deleterious impact on the breeding potential, 2) the advantages of the social flexibility and the social organization of gorillas in the recovery of the demographic structure of their population, 3) the role of immigration in the long-term recovery of population size. Our determination of the demographic features characterizing a population affected by Ebola allowed us to specify that a studied neighboring population was unaffected. These findings highlighted that Ebola impact had been heterogeneous at a regional level, which probably induced some population fragmentation. This new insight lets discuss the hypotheses on the emergence and spread of the virus and questions the impact of the fragmentation on population dynamics and recovery of affected local populations. Our results suggest a low resilience of populations of lowland gorillas against Ebola virus and the threat to population persistence.RENNES1-BU Sciences Philo (352382102) / SudocSudocFranceF

Caractéristiques du microbiote chez le sujet âgé : Synthèse du 5e symposium « Feeding the Microbiota »

Le microbiote est le sujet de nombreuses recherches. Il est défini comme l’ensemble des microorganismes présents dans les tissus et sur les surfaces corporelles. Il est à l’interface avec de nombreux systèmes dont le système immunitaire, joue un rôle dans le métabolisme, l’immunité ou l’inflammation, et serait associé à certains mécanismes pathologiques. Sa composition et son activité métabolique sont influencées par différents facteurs comme l’âge. Cet article résume les thématiques abordées lors du 5e symposium « Feeding the Microbiota » (HUG, 6 février 2020), focalisé sur le microbiote et le vieillissement