Reduced monocyte and macrophage TNFSF15/TL1A expression is associated with susceptibility to inflammatory bowel disease.

Chronic inflammation in inflammatory bowel disease (IBD) results from a breakdown of intestinal immune homeostasis and compromise of the intestinal barrier. Genome-wide association studies have identified over 200 genetic loci associated with risk for IBD, but the functional mechanisms of most of these genetic variants remain unknown. Polymorphisms at the TNFSF15 locus, which encodes the TNF superfamily cytokine commonly known as TL1A, are associated with susceptibility to IBD in multiple ethnic groups. In a wide variety of murine models of inflammation including models of IBD, TNFSF15 promotes immunopathology by signaling through its receptor DR3. Such evidence has led to the hypothesis that expression of this lymphocyte costimulatory cytokine increases risk for IBD. In contrast, here we show that the IBD-risk haplotype at TNFSF15 is associated with decreased expression of the gene by peripheral blood monocytes in both healthy volunteers and IBD patients. This association persists under various stimulation conditions at both the RNA and protein levels and is maintained after macrophage differentiation. Utilizing a "recall-by-genotype" bioresource for allele-specific expression measurements in a functional fine-mapping assay, we localize the polymorphism controlling TNFSF15 expression to the regulatory region upstream of the gene. Through a T cell costimulation assay, we demonstrate that genetically regulated TNFSF15 has functional relevance. These findings indicate that genetically enhanced expression of TNFSF15 in specific cell types may confer protection against the development of IBD

The TNF-Family Receptor DR3 is Essential for Diverse T Cell-Mediated Inflammatory Diseases

SummaryDR3 (TRAMP, LARD, WSL-1, TNFRSF25) is a death-domain-containing tumor necrosis factor (TNF)-family receptor primarily expressed on T cells. TL1A, the TNF-family ligand for DR3, can costimulate T cells, but the physiological function of TL1A-DR3 interactions in immune responses is not known. Using DR3-deficient mice, we identified DR3 as the receptor responsible for TL1A-induced T cell costimulation and dendritic cells as the likely source for TL1A during T cell activation. Despite its role in costimulation, DR3 was not required for in vivo T cell priming, for polarization into T helper 1 (Th1), Th2, or Th17 effector cell subtypes, or for effective control of infection with Toxoplasma gondii. Instead, DR3 expression was required on T cells for immunopathology, local T cell accumulation, and cytokine production in Experimental Autoimmune Encephalomyelitis (EAE) and allergic lung inflammation, disease models that depend on distinct effector T cell subsets. DR3 could be an attractive therapeutic target for T cell-mediated autoimmune and allergic diseases

Toll-Like Receptor 3 (TLR3) Plays a Major Role in the Formation of Rabies Virus Negri Bodies

Human neurons express the innate immune response receptor, Toll-like receptor 3 (TLR3). TLR3 levels are increased in pathological conditions such as brain virus infection. Here, we further investigated the production, cellular localisation, and function of neuronal TLR3 during neuronotropic rabies virus (RABV) infection in human neuronal cells. Following RABV infection, TLR3 is not only present in endosomes, as observed in the absence of infection, but also in detergent-resistant perinuclear inclusion bodies. As well as TLR3, these inclusion bodies contain the viral genome and viral proteins (N and P, but not G). The size and composition of inclusion bodies and the absence of a surrounding membrane, as shown by electron microscopy, suggest they correspond to the previously described Negri Bodies (NBs). NBs are not formed in the absence of TLR3, and TLR3−/− mice—in which brain tissue was less severely infected—had a better survival rate than WT mice. These observations demonstrate that TLR3 is a major molecule involved in the spatial arrangement of RABV–induced NBs and viral replication. This study shows how viruses can exploit cellular proteins and compartmentalisation for their own benefit

Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF

Abstract Background The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear. Methods We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA. Results Soluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions. Conclusions TL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA

De l'école nationale professionnelle au baccalauréat de technicien ou l'évolution d'une filière de l'enseignement technique

Françoise Meylan, Von der staatlichen Berufschule bis zum Fachabitur, oder die Entwicklung einer technischen Fachrichtung. Am Ende des XIXten Jahrhunderts gegründet, stellten sich die staatlichen Berufsschulen als eine der neuartigsten Schöpfungen der französichen technischen Ausbildung dar. Sie genossen sehr grosses Ansehen unter Wirtschaftskreisen, die heute noch mit Nostalgie davon sprechen. Der Auftrag dieser staatlichen Schulen bestand darin, Praktiker für die verschiedenen Wirtschaftszweige insbesondere den Maschinenbau aus zubilden, die imstande sein sollen, Werkmeister, Vorarbeiter, Konstruktionstechniker und Kontrolltechniker zu werden ; das heisst technische Angestellte, die sich zwischen den leitenden Angestellten und den Arbeitern befinden. Eine Einstellung durch eine Zugangsprüfung, die eine strenge Auswahl der Schüler sicherte, sowie eine Bildung zugleich theoretischer und praktischer Art, die eine Allgemeinbildung und wissenschaftliche Kenntnisse mit beruflichem Unterricht und Werkstattarbeit verbinden, trugen zu ihrem Erfolg bei. Kurz nach dem Zweiten Weltkrieg und im Zusammenhang mit der massiven Industrialisierung unseres Landes, nahmen sich die Reformer der technischen Sekundarausbildung diese Schulen zum Vorbild. Sie galten so als Prototyp der heutigen beruflichen Ausbildungen, die zum Technikerdiplom und zum Fachabitur führen. Interessiert man sich für die nationalen Berufsschulen und für ihre Enstehung, dann interessiert man sich auch für die Entwicklung der gesamten technischen Ausbildung. Deshalb gibt dieser Artikel einen kurzen historischen Uberblick der Grundlagen dieser im XIXten Jahrhundert entstandenen Ausbildung, der es nach vielen wechselvollen Erlebnissen und Kontroversen nach einigen Jahrzehnten gelungen ist, sich zu entwickeln und allgemein bekannt zu werden. Obwohl heute in dem allgemeinen Bildungssystem integriert, innerhalb dessen sie eine Option bildet, bleibt die berufliche technische Ausbildung immer noch Gegenstand von intensiven, teilweise polemischen Diskussionen und wie könnte es auch anders sein bei dem sich beschleunigenden technologischen Wandel ?Françoise Meylan, From the National Professional School to the technical high-school diploma : Development of one branch of technical education. The National Professional Schools (ENP), which were founded at the end of the 19th century, were among the most original creations of the French technical education system. They acquired a very good reputation in professional circles, where they are now talked about with nostalgia. The mission of these State schools was to « train for various industries, especially mechanical construction industries, experts capable of becoming foremen, workshop managers, controllers or overseers, i.e., technicians at an intermediate level between the management and the factory floor ». Recruitment by competitive examination, ensuring a rigorous selection of pupils, theoritical and practical training combining general instruction and scientific knowledge with professional instruction and workshop techniques, were all features contributing to the success of these schools. Immediately after the Second World War, in the context of the large-scale industrialization of France, these schools served as a model for the reformers of secondary education, and were the prototype for the present forms of training leading to technical school diplomas. If we are interested in the National Professional Schools and their origin, we are also interested in the development of tech nical education as a whole, so the article gives a brief historical description of the foundations of this type of education, which started in the 19th century, and, after many ups and downs and controversies, succeeded after a few decades in developing and achieving its freedom. It is now integrated into the general educational system, and represents one of its options, but technical education is still the subject of controversial and impassioned discussions and how could it be otherwise, in view of the acceleration of technological change ?Nées à la fin du XIXe siècle, les Écoles nationales professionnelles (ENP) apparaissent comme l'une des créations les plus originales de l'enseignement technique français. Elles acquirent une très grande renommée auprès des milieux professionnels qui en parlent aujourd'hui avec nostalgie. Ces écoles d'État avaient reçu mission : « de former pour les diverses industries et plus spécialement les industries de la construction mécanique des praticiens aptes à devenir contremaîtres, chefs d'atelier, agents d'études et de contrôle, c'est-à- dire des techniciens constituant le cadre intermédiaire entre le personnel dirigeant et le personnel ouvrier ». Un recrutement par concours assurant une sélection sévère des élèves ; une formation à la fois théorique et pratique alliant enseignement général et connaissances scientifiques à l'enseignement professionnel et aux travaux d'ateliers contribuèrent à leur succès. Au lendemain de la Seconde Guerre mondiale et dans le contexte d'industrialisation massive de notre pays, elles servirent de modèle aux réformateurs des enseignements secondaires techniques et constituèrent ainsi le prototype des formations actuelles conduisant aux brevets et baccalauréats de techniciens. Mais s'intéresser aux écoles nationales professionnelles et à leur origine, c'est autant s'intéresser à l'évolution de l'enseignement technique dans son ensemble, aussi l'article donne-t-il un bref aperçu historique des fondements de cet enseignement apparu au XIXe siècle qui, au travers de bien des vicissitudes et des controverses réussit en quelques décennies à se développer et à conquérir droit de cité. Intégré aujourd'hui dans le système éducatif général dont il constitue l'une des options, l'enseignement technique fait toujours l'objet de discussions tout aussi polémiques que passionnées et comment pourrait-il en être autrement face à l'accélération des mutations technologiques.Meylan Françoise. De l'école nationale professionnelle au baccalauréat de technicien ou l'évolution d'une filière de l'enseignement technique. In: Formation Emploi. N.4, 1983. pp. 29-46

Patients ayant vécu un accident handicapant: quel rôle infirmier ? : travail de Bachelor

Même si la problématique des accidents entraînant un handicap n’est pas nouvelle en soi, avec les progrès de la médecine de plus en plus de personnes sont sauvées de la mort mais souffrent de séquelles graves et de handicaps qui nécessitent une prise en soin spécifique. Par conséquent, des centres spécialisés ont vu le jour pour répondre à ce besoin. Ce processus s’appelle la réadaptation et l’infirmier en tant que soignant peut être amené à travailler dans ce type de structure. Afin de mieux comprendre quel est le rôle infirmier dans ce domaine, nous avons rencontré des infirmiers expérimentés dans ces prises en soin ainsi que des patients en plus de nos recherches théoriques. Dans ce travail, nous avons cherché à mettre en évidence les éléments essentiels pour que le processus de réadaptation soit optimal en confrontant la théorie avec nos entretiens