Défaut d’exocytose des granules lytiques : Plusieurs causes, un même effet

Une réponse immune exagérée, incontrôlée et le plus souvent fatale, connue sous le nom de syndrome hémophagocytaire (SH), est associée à un défaut de la fonction cytotoxique des lymphocytes T et natural killer (NK). Les anomalies moléculaires responsables, qui sont multiples, mettent en cause dans la plupart des cas un effecteur indispensable au fonctionnement de la machinerie lytique des lymphocytes. L’étude des lymphocytes cytotoxiques déficients en l’un ou l’autre de ces effecteurs apporte des éléments nouveaux quant à l’agencement des étapes clés de la sécrétion du contenu des granules lytiques au contact de la cellule cible. Des mécanismes moléculaires proches semblent contrôler la sécrétion vésiculaire au niveau des synapses immunologique et neurologique. D’autres effecteurs de la cytotoxicité ou du contrôle de l’homéostasie lymphocytaire à l’origine de SH doivent encore être caractérisés. Quant aux mécanismes précis de l’intervention de cette voie cytotoxique dans le maintien de l’homéostasie lymphocytaire (terminaison d’une réponse immune), ils demeurent à élucider.An in vivo disturbance of lymphocyte homeostasis occurs during the course of the hemophagocytic syndrome (HS). HS is a severe and often fatal syndrome resulting from potent and uncontrolled activation and proliferation of T-lymphocytes, mainly polyclonal CD8 lymphocytes, leading to excessive macrophage activation, high level of proinflammatory cytokine production and multiple deleterious effects. The onset of HS characterizes several inherited disorders in humans. In most of these conditions, the molecular defect impairs the granule-dependent cytotoxic activity of lymphocytes, thus highlighting the determinant role of this function in driving back the immune system to a state of equilibrium following infection. Several lines of evidence suggest that an increase in the expansion phase rather than a decrease in the contraction phase of the CD8+ T cells population characterizes the HS. Failure to kill antigen presenting cells through a transaction mechanism of cytotoxic cells should favor a sustained response, although the mechanism may be more complex than simple decrease of antigen load. Defect in the granule dependent cytotoxic function of lymphocytes result from perforin mutation in familial hemophagocytic lymphohistiocytosis type 2, from Munc13-4 (UNC13D) mutation in familial hemophagocytic lymphohistiocytosis type 3, from Rab27a mutation in Griscelli syndrome type 2, and from CHS/LYST mutation in Chediak-Higashi syndrome. The characterization of the molecular causes leading to these conditions identified Rab27a and Munc13-4 as two critical effectors of the exocytic machinery, required for the terminal transport/docking or priming of the cytotoxic granules, respectively. Different members of the Rab and Munc13 family of proteins are also used in neurotransmitter release at the neurological synapse, highlighting the similarity of the mechanisms regulating both secretory pathways. Future investigations regarding HS will continue to elucidate this exocytic pathway machinery and improve our understanding of how it finely regulates the immune response, an area that is likely to be useful for therapeutic intervention

Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming

Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-macrophage features in terms of morphology, surface markers, migratory properties and antigen presentation capacity. Microarray expression profiling indicates that UC-MSC modify the expression of metabolic-related genes and induce a M2-macrophage expression signature. Importantly, monocyte-derived DC obtained in presence of UC-MSC, polarize naïve allogeneic CD4+ T-cells into Th2 cells. Treatment of UC-MSC with an inhibitor of lactate dehydrogenase strongly decreases lactate concentration in culture supernatant and abrogates the effect on monocyte-to- DC differentiation. Metabolic analysis further revealed that UC-MSC decrease oxidative phosphorylation in differentiating monocytes while strongly increasing the spare respiratory capacity proportional to the amount of secreted lactate. Because both MSC and monocytes are recruited in vivo at the site of tissue damage and inflammation, we propose the local increase of lactate concentration induced by UC-MSC and the consequent enrichment in M2-macrophage generation as a mechanism to achieve immunomodulation

Low Penetrance, Broad Resistance, and Favorable Outcome of Interleukin 12 Receptor β1 Deficiency: Medical and Immunological Implications

The clinical phenotype of interleukin 12 receptor β1 chain (IL-12Rβ1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rβ1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rβ1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most

Mise au point d'un test de réparation des cassures double-brin de l'ADN, application au déficit immunitaire T(-) B(-) caractérisé par un défaut de recombinaison V(D)J avec radiosensibilité accrue

PARIS-BIUP (751062107) / SudocSudocFranceF

Fas ligand dans le syndrôme lymphoprolifératif avec auto-immunité (ALPS) chez l'homme

CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Phytothérapie et sphère urinaire (conseil à l'officine)

Les problèmes urinaires se manifestent de manière différente suivant les âges: énurésie chez l'enfant, cystite chez la femme, trouble de la prostate chez l'homme. Il existe plusieurs possibilités de prise en charge de ces pathologies. La phytothérapie peut être une alternative et d'ailleurs elle connaît un regain d'intérêt auprès de la population. Un recours aux nombreuses plantes diurétiques disponibles et possible pour soulager et /ou prévenir les infections du tractus urinaire ainsi que les lithiases urinaires. La nature regorge de ces plantes, d'où la difficulté de toutes les normes. Parmi les neuf plantes diurétiques abordées, on retrouve les queues de cerise, l'orthosiphon et le pissenlit réputés dans ce domaine. Les plantes immunostimulantes telles que les échinaccés et les plantes à propriété antiseptique dont la canneberge et la busserole sont généralement proposées pour prévenir les cystites récidivantes, le ginkgo dans l'incontinence urinaire et l'association éleuthérocoque et escholtzia dans l'énurésie constituent aussi d'autres remèdes naturels. Quatre plantes les plus populaires (le palmier de Floride, le prunier d'Afrique, les racines d'ortie et les graines de courge), utilisées pour soulager les symptômes de l'hypertrophie bénigne de la prostate sont également développées au cours de ce travail. Cette thèse communique les informations pour nous aider à mieux profiter des bienfaits des plantes médicinales à travers une revue critique de la littérature scientifique. Ainsi, elle permet au pharmacien de faire sa propre opinion sur les plantes ou remède les plus adaptés afin de répondre à leurs attentes.RENNES1-BU Santé (352382103) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Immunodéficiences et pathologies associées aux mutations dans STIM/ORAI

Sous l’effet de divers stimulus, l’efflux du calcium (Ca2+) stocké dans le réticulum endoplasmique induit l’ouverture de canaux calciques spécifiques à la surface membranaire cellulaire selon un processus appelé entrée capacitative du Ca2+. Le Ca2+ extracellulaire entre alors massivement dans la cellule, participe à la signalisation et remplit à nouveau les stocks. Il y a cinq ans, la découverte des protéines STIM1 et ORAI1 a permis de révéler qu’elles forment la base moléculaire des canaux calciques impliqués dans l’entrée capacitative du Ca2+. La découverte de mutations dans ORAI1 ou dans STIM1 chez des patients présentant un déficit immunitaire associé à des manifestations extra-hématopoïétiques (myopathie) a contribué à la mise en évidence de ce couple. Depuis lors, la liste sans cesse croissante de protéines partenaires de STIM1 et ORAI1 et des nouvelles pathologies associées à leurs mutations leur confère un rôle central dans le contrôle de l’homéostasie calcique cellulaire

Limits to mobility : competence and qualifications in Europe

Purpose – This paper aims to explore structural and systemic influences in the development of competence models and qualifications systems at sectoral and national levels across Europe, considering the influences of different socio-economic models of skill formation on the processes of design and provision of qualifications. Design/methodology/approach – The paper is based on a meta analysis of three European projects that used literature review, documentary analysis and interviews with practitioners and policy makers. Findings – The main methodological and practical challenges posed by varieties of competence and qualifications to inter-country comparability of qualifications are shown to be related to different socio-economic models of skill formation. Research limitations/implications – The research is limited to 13 countries and four sectors but these were carefully selected to maximise coverage of European diversity with respect to competence models, training regimes and approaches to qualifications. There is clearly a need for further research involving more countries and sectors. Practical implications – The paper offers recommendations for improving the potential of the European Qualifications Framework to promote comparability of qualifications and hence mobility of labour. These recommendations will be of interest to policy makers and practitioners involved in using the EQF and similar instruments. Originality/value – This is the first systematic attempt to explore the methodological and practical difficulties of establishing comparability between qualificationsSocialinių mokslų fakultetasVytauto Didžiojo universiteta