Effet protecteur des oestrogènes sur l'encéphalomyélite auto-immune expérimentale : identification des cellules cibles à l'aide de souris invalidées pour le récepteur alpha aux oestrogènes (REalpha) de manière tissu-spécifique

La sclérose en plaques est une maladie auto-immune touchant le système nerveux central. Paradoxalement, bien qu'elle soit plus fréquente chez les femmes que chez les hommes, elle est globalement moins sévère. Par ailleurs, des phases de rémission de la maladie sont fréquemment observées chez les femmes enceintes, suggérant que les hormones sexuelles pourraient exercer un effet protecteur. Il a ainsi été clairement établi que l'administration d'E2 inhibait le développement de l'EAE. Dans ce travail, nous avons évalué le rôle des hormones ovariennes endogènes et exogènes sur la susceptibilité à l'EAE chez les souris C57BL/6 femelles, et en particulier le rôle des œstrogènes via leur récepteur nucléaire de type alpha (REalpha). Dans un premier temps, j'ai pu démontrer que l'ovariectomie accroît la susceptibilité des souris au développement de l'EAE active et passive par un mécanisme impliquant REalpha montrant que les œstrogènes endogènes, exercent un effet bénéfique sur la maladie. Cet effet protecteur des œstrogènes endogènes ne semble pas s'exercer par une action directe sur les lymphocytes T encéphalitogènes et ne nécessite pas l'expression de REalpha par les cellules hématopoïétiques. En absence d'œstrogènes endogènes, j'ai mis en évidence une augmentation du recrutement précoce des cellules inflammatoires dans le système nerveux central, suggérant qu'ils régulent la migration trans-endothéliale des lymphocytes T. Dans un second temps, j'ai confirmé le rôle crucial de REalpha dans l'effet protecteur de l'E2 in vivo. J'ai également pu montrer grâce à des souris KO conditionnelles et de greffes de moelle osseuse que le compartiment hématopoïétique représentait la cible majeure de l'E2. Ensuite, à l'aide de souris invalidées de manière sélective pour le gène de REalpha dans différentes cellules du système immunitaire, comme les cellules présentatrice d'antigène (monocytes/macrophages et cellules dendritiques) et les lymphocytes T, j'ai montré que l'activation pharmacologique de REalpha, par l'E2, dans les cellules T était requise pour observer l'effet protecteur des œstrogènes dans l'EAE. En conclusion, nos résultats établissent clairement que les œstrogènes endogènes et exogènes exercent un effet protecteur sur le développement de l'EAE par des mécanismes distincts.Multiple sclerosis (MS) is an autoimmune disease which affects the central nervous system. Although MS is more frequently observed in women, disease progression is slower in women as compared to men. Moreover, variations of disease activity during pregnancy have suggested that sex hormones could modulate the autoimmune response and inflammation. Based on these observations, the effect of estrogens administration has been evaluated in experimental autoimmune encephalomyelitis (EAE) in mice, and was shown to strongly inhibit disease development. The goal of this work was to analyze the implication of endogenous and exogenous estrogen in EAE susceptibility in females C57BL/6 mice through estrogen receptor ? signaling. In the first part of my thesis, we showed that ovariectomy increases both susceptibility and severity of mice on active as well as passive mouse induced EAE. This required a mechanism that implicated ERalpha signaling, suggesting that endogenous estrogen are important for the protective effect on EAE. The beneficial effect of endogenous estrogen doesn't seem have any action on T lymphocytes and doesn't required expression on ERalpha on hematopoietic cells. A lack of estrogen increased the early recruitment of inflammatory cells to the central nervous system, suggesting that endogenous estrogen regulates trans-endothelial migration of T lymphocytes. In the second part of my work, we confirmed the crucial role of ERalpha in the protective effect of the estrogen treatment in vivo on EAE. Using conditional ERalpha knock-out mice and bone marrow chimeras, we showed that the hematopoietic compartment is the major target of estrogens. We then used a Cre/loxP strategy to study the effect of selective deletion of ERalpha on immune cells such as monocyte/macrophages, dendritics cells or T lymphocytes on E2-mediated EAE protection. We observed that pharmacological activation of ERalpha by E2 intrinsic to T cells is crucial to mediate the anti-inflammatory effect of E2 and sustained inhibition of EAE development. In conclusion, this work provides direct genetic evidence that endogenous or exogenous estrogens protect from EAE development through distinct mechanisms that could be amenable to pharmacological manipulation to prevent central nervous system autoimmunity

The Life Cycle of Toxoplasma gondii in the Natural Environment

Chapitre 1International audienc

Mathematical modelling of Toxoplasma gondii transmission: A systematic review

Background: Toxoplasma gondii is a ubiquitous protozoan parasite that can infect virtually all warm-blooded animals. It is the causative agent of toxoplasmosis, a significant public health issue worldwide. Mathematical models are useful to study the transmission dynamics of T. gondii infection in different settings, and may be used to compare the effectiveness of prevention measures. Methods: To obtain an overview of existing mathematical models for transmission of T. gondii, a systematic review was undertaken. The review was conducted according to an a priori protocol and the results were reported according to the PRISMA guidelines. Specific search terms were developed and used in the search of three databases (Scopus, PubMed, and Embase). Results: In total, 484 unique records were retrieved from the systematic search. Among them, 15 studies that used mathematical models to study the transmission of T. gondii. These studies were categorized into four groups based on the primary aims: dynamics of transmission (n = 8), intervention (n = 5), spatial distribution (n = 1), and outbreak investigation (n = 1). Conclusions: Considering the high disease burden caused by T. gondii, the number of studies using mathematical models to understand the transmission dynamics of this parasite and to evaluate the effectiveness of intervention measures was only 15. This systematic review provides an overview of existing mathematical models and identifies the data gaps for model building. The results from this study can be helpful for further development of mathematical models and improved understanding of the transmission dynamics of T. gondii infection

Optimised protein recovery from mackerel whole fish by using sequential acid/alkaline isoelectric solubilization precipitation (ISP) extraction assisted by ultrasound

peer-reviewedThe growing fishery industry needs to find new green-processes in order to provide a solution to the huge amount of wastes and by-products that such industrial activity produces. Currently, around a 40% of the total weight of the mackerel is considered a by-product, because just the fillets are used in the food market. ISP method has been revealed as a useful tool for protein recovering, however the yield of this process is traditionally lower than enzymatic methods. In present work, the use of sequential acid/alkaline extraction and alkaline extraction assisted by ultrasound, have been implemented in order to increase the yield of the process. It has been demonstrated that (i) sequential extraction is able to recover practically 100% of total protein, and (ii) applying ultrasound to alkaline extraction is possible to recover more than 95% of total protein from mackerel by-products. Extracted proteins were characterized according to their size, and the amino acid profile of final product was determined.This project (Grant-Aid Agreement No. MFFRI/07/01) was carried out under the Sea Change Strategy with the support of the Marine Institute and the Department of Agriculture, Food and the Marine, funded under the National Development Plan 2007–2013

Meta-Profiles of Gene Expression during Aging: Limited Similarities between Mouse and Human and an Unexpectedly Decreased Inflammatory Signature

Background: Skin aging is associated with intrinsic processes that compromise the structure of the extracellular matrix while promoting loss of functional and regenerative capacity. These processes are accompanied by a large-scale shift in gene expression, but underlying mechanisms are not understood and conservation of these mechanisms between humans and mice is uncertain. Results: We used genome-wide expression profiling to investigate the aging skin transcriptome. In humans, age-related shifts in gene expression were sex-specific. In females, aging increased expression of transcripts associated with T-cells, B-cells and dendritic cells, and decreased expression of genes in regions with elevated Zeb1, AP-2 and YY1 motif density. In males, however, these effects were contrasting or absent. When age-associated gene expression patterns in human skin were compared to those in tail skin from CB6F1 mice, overall human-mouse correspondence was weak. Moreover, inflammatory gene expression patterns were not induced with aging of mouse tail skin, and well-known aging biomarkers were in fact decreased (e.g., Clec7a, Lyz1 and Lyz2). These unexpected patterns and weak human-mouse correspondence may be due to decreased abundance of antigen presenting cells in mouse tail skin with age. Conclusions: Aging is generally associated with a pro-inflammatory state, but we have identified an exception to this pattern with aging of CB6F1 mouse tail skin. Aging therefore does not uniformly heighten inflammatory status across all mouse tissues. Furthermore, we identified both intercellular and intracellular mechanisms of transcriptome aging, including those that are sex- and species-specific

Detection of Toxoplasma gondii

Detection of Toxoplasma gondii DNA in cat feces is considered indicative of the presence of T. gondii oocysts. This study aims to demonstrate that the high sensitivity of qPCR can lead to T. gondii DNA detection in cat feces in the absence of oocysts. A cat immune to toxoplasmosis was fed with a mouse experimentally infected with T. gondii. Detection of DNA of this parasite was performed by qPCR on feces passed: (i) on the day the cat ingested the infected prey; (ii) during the three previous days; and (iii) during the three following days. The kinetics of qPCR results are clearly not linked to oocyst shedding and this result demonstrates that qPCR can detect T. gondii DNA related to bradyzoites from an infected prey, in the absence of oocysts. Caution is thus recommended when interpreting T. gondii qPCR results for samples of cat feces

Aux manes de l'illustre Mirabeau liberateur de la patrie mort le deux davril 1791... : [dessin] / [P. Lélu]

Référence bibliographique : Hennin, 10928Référence bibliographique : Vidéodisque, 8234-8236Appartient à l’ensemble documentaire : Est18Rev