A role for CD47 in the development of experimental colitis mediated by SIRPα+CD103− dendritic cells

Mesenteric lymph node (mLN) CD103 (αE integrin)+ dendritic cells (DCs) induce regulatory T cells and gut tolerance. However, the function of intestinal CD103− DCs remains to be clarified. CD47 is the ligand of signal regulatory protein α (SIRPα) and promotes SIRPα+ myeloid cell migration. We first show that mucosal CD103− DCs selectively express SIRPα and that their frequency was augmented in the lamina propria and mLNs of mice that developed Th17-biased colitis in response to trinitrobenzene sulfonic acid. In contrast, the percentage of SIRPα+CD103− DCs and Th17 responses were decreased in CD47-deficient (CD47 knockout [KO]) mice, which remained protected from colitis. We next demonstrate that transferring wild-type (WT), but not CD47 KO, SIRPα+CD103− DCs in CD47 KO mice elicited severe Th17-associated wasting disease. CD47 expression was required on the SIRPα+CD103− DCs for efficient trafficking to mLNs in vivo, whereas it was dispensable on both DCs and T cells for Th17 polarization in vitro. Finally, administration of a CD47-Fc molecule resulted in reduced SIRPα+CD103− DC–mediated Th17 responses and the protection of WT mice from colitis. We thus propose SIRPα+CD103− DCs as a pathogenic DC subset that drives Th17-biased responses and colitis, and the CD47–SIRPα axis as a potential therapeutic target for inflammatory bowel disease

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Territoires locaux, milieux et développement en Grande Kabylie

La Grande Kabylie est généralement considérée comme une région pauvre tirant l’essentiel de sa subsistance de l’émigration et des transferts du Centre. Des ressources – naturelles, économiques, financières, humaines -, existent pourtant et auraient pu générer des dynamiques de développement, comme c’est le cas de nombreuses régions du monde où des richesses et des emplois notables sont créés à partir des potentialités locales.Pourquoi les territoires locaux de Grande Kabylie ne produisent – ils donc pas de développement, en dépit de la présence d’avantages concurrentiels notables ? Les analyses strictement économiques n’apportent pas de réponse satisfaisante à cette question qui concerne, bien entendu, l’ensemble des régions du pays, qui vivent la même situation. Les recherches actuelles privilégient des approches plus globales, comme, par exemple, les travaux du GREMI (Groupe de Recherches Européen sur les Milieux Innovateurs) qui, à la suite de P. Aydalot, ont montré tout le poids du milieu en matière de développement local. La composante territoriale et les formes de gouvernance, l’organisation et les logiques d’interaction, les dynamiques d’apprentissage expliqueraient, notamment, l’inaptitude du milieu à produire du développement en Grande Kabylie. L’enjeu de telles approches détermine, au delà de leur aspect théorique, une refonte des pratiques de l’Etat en matière de développement local.Greater Kabylie is generally considered as a poor region getting most of its livelihood from emigration and transfers from Algiers. However natural , economic, financial and human resources exist and could have generated dynamics for development, as is the case in numerous world regions where wealth and remarkable employment were created from local potentiality.Why has the local area of Greater Kabylie not produced such a development, in spite of the presence of noteworthy competitive advantages ? Strictly economic analyses don’t bring a satisfactory answer to this question, which concerns, of course the ensemble of regions in countries, which experience the same situation. Current research privileges a more global approach, as, for example, the GREMI work ( European Group Research on Innovating Milieu ), which, after P. Aydalot, has shown the importance of milieu in matter of local development. Territorial constituent and governmental forms, organization and interaction logics, apprenticeship dynamics would explain, more particularly the inaptitude of milieu to produce development in Greater Kabylie. The stake of such approaches determines, beyond their theoretical aspect, a reorganization of State practice in local development.Kabilia Grande es generalmente considerada como una región pobre sacando lo esencial de su subsistencia de la emigración y de las transferencias del Centro. Sin embargo, existen recursos - naturales, económicos, financieros, humanos -, y hubieron podido generar dinámicas de desarrollo, como es el caso de numerosas regiones del mundo en donde riquezas y notables empleos fueron creados a partir de potencialidades locales. ¿ Por qué territorios locales en Kabilia Grande no producen pues desarrollo, a pesar de la presencia de ventajas competitivas notables ? Los análisis estrictamente económicos no aportan respuesta satisfactoria a esta cuestión que atañe, evidentemente, el conjunto de las regiones del país, que viven la misma situación.Las investigaciones actuales privilegian aproximaciones más globales, como, por ejemplo, los trabajos de GREMI (Grupo de Investigación Europeo sobre los Medios Innovadores) que, a continuación de P. Aydalot, han mostrado todo el peso del medio en materia de desarrollo local. La componente territorial y las formas de gobernación , la organización y las lógicas de interacción, las dinámicas de aprendizaje explicarían, en particular, la incapacidad del medio en producir desarrollo en Kabilia Grande. El desafío de dichas aproximaciones, determina, más allá de su aspecto teórico, una refundición de las prácticas del Estado en materia de desarrollo local.تعتبر منطقة القبائل الكبرى جهة فقيرة عموما، تستمد أهم وسائل تموينها من أموال الهجرة و الأموال المحولة من المركز. هذا على الرغم من وجود موارد – طبيعية وإقتصادية و مالية و بشرية – التي بإمكانها إنتاج دنياميكيات تنموية، مثلما يحدث في العديد من المناطق بمختلف أقطار العالم، حيث أُنشئت ثروات و مناصب عمل هامة إنطلاقا من الإمكانيات المحلية. لماذا لا تنتج الأقاليم المحلية بمنطقة القبائل الكبرى تنمية، بالرغم من وجود ميزات تنافسية هامة؟ و في هذا الصدد لا تقدم التحاليل الإقتصادية المحضة أجوبة كافية لهذا السؤال الذي يهم، بطبيعة الحال، مجموع جهات الوطن التي تعيش الوضعية ذاتها. إذ تعطي الابحاث الحالية الأسبقية للمقاربات الأكثر شمولية و مثال ذلك أبحاث القريمي GREMI(مجموعة الأبحاث الأوروبية في الأوساط المبتكرة)، التي كشفت عن أهمية البيئة في مجال التنمية المحلية (ت. م) على غرار أبحات ب. أيدالو (P. Aydalot). و تفسر بصفة خاصة عجز هذه البيئة في إنتاج التنمية بمنطقة القبائل الكبرى، عدة عوامل، نذكر منها : التركيبة الإجتماعية الإقليمية و أشكال تدبير الحكم و التنظيم، وكذا طرق التفاعل و دنياميكيات التعلم. و يحدد رهان تلك المقاربات المعنية بإعادة صياغة ممارسات الدولة فيما يتعلق بالتنمية المحلية (ت. م)، بغض النظر عن طابعها النظري

Rôle de la molécule CD47 sur le lymphocyte T dans la régulation de la réponse immunitaire

L’importance respective des lymphocytes T régulateurs naturels générés dans le thymus ou induits en périphérie dans la régulation immunitaire et la résolution de l’inflammation est désormais bien établie. Nous avons contribué à mettre en évidence une nouvelle voie d’induction de lymphocytes T régulateurs périphériques à partir de cellules T humaines CD4+CD25- naïves et mémoires. Nous avons montré que l’engagement de la molécule ubiquitaire transmembranaire CD47 sur la cellule T par un anticorps monoclonal ou par le peptide 4N1K (peptide dérivé du domaine carboxy-terminal de la thrombospondine-1 et spécifique du site de liaison à CD47) induisait des lymphocytes T CD4+ régulateurs exerçant une fonction suppressive sur les lymphocytes T effecteurs. Les propriétés suppressives induites par la thrombospondine-1 confortent les fonctions anti-inflammatoires de cette protéine de la matrice extracellulaire. L’inhibition exercée par les lymphocytes T régulateurs induits dépend du contact intercellulaire entre les cellules T régulatrices et leurs cibles, et est indépendante du TGF-. Nos résultats démontrent également le rôle de CD47 sur le lymphocyte T CD4+ dans la réponse immunitaire spécifique de l’antigène in vivo. En effet, les souris BALB/c déficientes pour CD47 présentent un biais de la sécrétion d’anticorps et de cytokines de type Th1, alors que les souris BALB/c sont décrites comme exprimant un profil de production de cytokines de type Th2. Nos travaux mettent en évidence le rôle de CD47 dans l’inhibition du développement d’une réponse cellulaire et humorale de type Th1 in vivo, confirmant de précédentes études in vitro réalisées avec des cellules T CD4+ humaines. Nous présentons également le rôle inhibiteur de l’engagement de CD28 in vitro sur la différenciation en cellules Th17 des lymphocytes T CD4+ naïfs isolés de souris BALB/c. Le mécanisme proposé est dépendant de la production de l’IL-2 et de l’IFN- et indépendant de la présence de lymphocytes T régulateurs. Notre étude du rôle de deux molécules transmembranaires CD47 et CD28 exprimées sur la cellule T CD4+, contribue à une meilleure connaissance des mécanismes impliqués dans la tolérance immunologique, la résolution de l’inflammation et la différenciation des cellules T "helper" CD4+.Nowadays, the importance of natural regulatory T cells and adaptive regulatory T lymphocytes in immune regulation and resolution of inflammation are well established. We report a previously unknown pathway to generate adaptive regulatory T cells in the periphery from naive and memory human CD4+CD25- T cells. We show that the stimulation of the broadly expressed transmembrane proteins CD47 on T cells by a monoclonal antibody or by the 4NK1 peptide (carboxy-terminal peptide of thrombospondin-1 (TSP) specific of the binding site of CD47) induced regulatory T cells that exerted an inhibitory function on effector T cells. Our study on the suppressive proprieties of the TSP corroborates with reported anti-inflammatory activities of this extracellular matrix protein. The suppressive function of TSP induced regulatory T cells was contact-dependent and TGF--independent. Our data further demonstrate the role of CD47 expression on T cells in the antigenic-specific immune response in vivo. We report that the CD47-deficient BALB/c mice displayed a Th1-biased antibody and cytokine responses, instead of the Th2 cytokine profile observed in unmanipulated BALB/c mice. Our study outlines the role of CD47 as a self-control mechanism to negatively regulate type 1 cellular and humoral immune responses and most importantly confirm in vivo previous in vitro studies with human CD4+ T cells. We also report that soluble anti-CD28 monoclonal antibody suppressed in vitro differentiation of naïve CD4+ T cells isolated from BALB/c mice into IL-17-producing cells by mechanism that are IL-2 and IFN-γ-dependent but independent of the presence of regulatory T cells. Our studies highlight the suppressive function of two transmembrane molecules CD47 and CD28 expressed by CD4+ T cells in vitro and in vivo in human and mice. They thus may contribute to a better understanding of the mechanisms involved in the induction of immune tolerance, the resolution of inflammation and the differentiation of the T helper cells

Territoires locaux, milieux et développement en Grande Kabylie

La Grande Kabylie est généralement considérée comme une région pauvre tirant l’essentiel de sa subsistance de l’émigration et des transferts du Centre. Des ressources – naturelles, économiques, financières, humaines -, existent pourtant et auraient pu générer des dynamiques de développement, comme c’est le cas de nombreuses régions du monde où des richesses et des emplois notables sont créés à partir des potentialités locales.Pourquoi les territoires locaux de Grande Kabylie ne produisent – ils donc pas de développement, en dépit de la présence d’avantages concurrentiels notables ? Les analyses strictement économiques n’apportent pas de réponse satisfaisante à cette question qui concerne, bien entendu, l’ensemble des régions du pays, qui vivent la même situation. Les recherches actuelles privilégient des approches plus globales, comme, par exemple, les travaux du GREMI (Groupe de Recherches Européen sur les Milieux Innovateurs) qui, à la suite de P. Aydalot, ont montré tout le poids du milieu en matière de développement local. La composante territoriale et les formes de gouvernance, l’organisation et les logiques d’interaction, les dynamiques d’apprentissage expliqueraient, notamment, l’inaptitude du milieu à produire du développement en Grande Kabylie. L’enjeu de telles approches détermine, au delà de leur aspect théorique, une refonte des pratiques de l’Etat en matière de développement local.Greater Kabylie is generally considered as a poor region getting most of its livelihood from emigration and transfers from Algiers. However natural , economic, financial and human resources exist and could have generated dynamics for development, as is the case in numerous world regions where wealth and remarkable employment were created from local potentiality.Why has the local area of Greater Kabylie not produced such a development, in spite of the presence of noteworthy competitive advantages ? Strictly economic analyses don’t bring a satisfactory answer to this question, which concerns, of course the ensemble of regions in countries, which experience the same situation. Current research privileges a more global approach, as, for example, the GREMI work ( European Group Research on Innovating Milieu ), which, after P. Aydalot, has shown the importance of milieu in matter of local development. Territorial constituent and governmental forms, organization and interaction logics, apprenticeship dynamics would explain, more particularly the inaptitude of milieu to produce development in Greater Kabylie. The stake of such approaches determines, beyond their theoretical aspect, a reorganization of State practice in local development.Kabilia Grande es generalmente considerada como una región pobre sacando lo esencial de su subsistencia de la emigración y de las transferencias del Centro. Sin embargo, existen recursos - naturales, económicos, financieros, humanos -, y hubieron podido generar dinámicas de desarrollo, como es el caso de numerosas regiones del mundo en donde riquezas y notables empleos fueron creados a partir de potencialidades locales. ¿ Por qué territorios locales en Kabilia Grande no producen pues desarrollo, a pesar de la presencia de ventajas competitivas notables ? Los análisis estrictamente económicos no aportan respuesta satisfactoria a esta cuestión que atañe, evidentemente, el conjunto de las regiones del país, que viven la misma situación.Las investigaciones actuales privilegian aproximaciones más globales, como, por ejemplo, los trabajos de GREMI (Grupo de Investigación Europeo sobre los Medios Innovadores) que, a continuación de P. Aydalot, han mostrado todo el peso del medio en materia de desarrollo local. La componente territorial y las formas de gobernación , la organización y las lógicas de interacción, las dinámicas de aprendizaje explicarían, en particular, la incapacidad del medio en producir desarrollo en Kabilia Grande. El desafío de dichas aproximaciones, determina, más allá de su aspecto teórico, una refundición de las prácticas del Estado en materia de desarrollo local.تعتبر منطقة القبائل الكبرى جهة فقيرة عموما، تستمد أهم وسائل تموينها من أموال الهجرة و الأموال المحولة من المركز. هذا على الرغم من وجود موارد – طبيعية وإقتصادية و مالية و بشرية – التي بإمكانها إنتاج دنياميكيات تنموية، مثلما يحدث في العديد من المناطق بمختلف أقطار العالم، حيث أُنشئت ثروات و مناصب عمل هامة إنطلاقا من الإمكانيات المحلية. لماذا لا تنتج الأقاليم المحلية بمنطقة القبائل الكبرى تنمية، بالرغم من وجود ميزات تنافسية هامة؟ و في هذا الصدد لا تقدم التحاليل الإقتصادية المحضة أجوبة كافية لهذا السؤال الذي يهم، بطبيعة الحال، مجموع جهات الوطن التي تعيش الوضعية ذاتها. إذ تعطي الابحاث الحالية الأسبقية للمقاربات الأكثر شمولية و مثال ذلك أبحاث القريمي GREMI(مجموعة الأبحاث الأوروبية في الأوساط المبتكرة)، التي كشفت عن أهمية البيئة في مجال التنمية المحلية (ت. م) على غرار أبحات ب. أيدالو P. Aydalot) ). و تفسر بصفة خاصة عجز هذه البيئة في إنتاج التنمية بمنطقة القبائل الكبرى، عدة عوامل، نذكر منها : التركيبة الإجتماعية الإقليمية و أشكال تدبير الحكم و التنظيم، وكذا طرق التفاعل و دنياميكيات التعلم. و يحدد رهان تلك المقاربات المعنية بإعادة صياغة ممارسات الدولة فيما يتعلق بالتنمية المحلية (ت. م)، بغض النظر عن طابعها النظري

Synthesis, spectroscopic and mechanical properties of K and (K, Na)- geopolymers based on Algerian clays

International audienc

CD28 co-stimulation down regulates Th17 development.

Th17 cells are implicated in host defence and autoimmune diseases. CD28/B7 co-stimulation is involved in the induction and progression of autoimmune diseases, but its role in controlling murine Th17 cell fate remains to be clarified. We here report that soluble anti-CD28 mAb suppressed the differentiation of anti-CD3-stimulated naïve CD4(+) T cells into IL-17-producing cells. CD28 co-stimulation reduced the frequency of proliferating cells that produce IL-17. We provide evidence for an IL-2 and IFN-gamma-dependent mechanism of CD28-mediated IL-17 suppression. CD28 blockade of Th17 development was correlated with a decrease rather than an increase in the percentage of Foxp3(+) T cells. In APC/T cell co-cultures, mature dendritic cells (DC) were less efficient than immature DC in their ability to support Th17 cell differentiation, while CTLA4-Ig, an agent blocking CD28/B7 and CTLA4/B7 interactions, facilitated both murine and human Th17 differentiation. This study identifies the importance of B7 co-stimulatory molecules in the negative regulation of Th17 development. These unexpected results caution targeting the CD28/B7 pathways in the treatment of human autoimmune diseases

Different distribution of H1-H2 Epstein-Barr virus variant in oropharyngeal virus and in biopsies of Hodgkin's disease and in nasopharyngeal carcinoma from Algeria.

In a previous study of Epstein-Barr virus (EBV) strains in North African nasopharyngeal carcinoma (N PC) biopsies, we have found that the viral strain present was of A/F/W'-I'/Xhol kept/H1-H2 type, while the strain associated with Chinese NPC was the A/"f"/W'I'/Xhol lost/H type. Using the restriction fragment length polymorphism (RFLP) and PCR-RFLP methods, the present study analyzed the H1-H2 variant in different clinical samples from Algeria, including the saliva of healthy EBV-positive individuals and patients with NPC or Hodgkin's disease (HD), as well as HD biopsies and lymphoblastoid cell lines (LCLs) established from the oropharyngeal virus-infected cells. Our results demonstrate that, in contrast to the H1-H2 variant found in NPC biopsies, the H genotype was dominant in HD biopsies. Moreover, H genotype was also dominant in the oropharynx of healthy EBV-positive individuals, of patients with NPC and with HD. Our results clearly indicate that in North Africa the EBV strain present of NPC biopsies is different from that shed in the oropharynx. This may suggest a specific distribution of the H1-H2 variant in the NPC epithelial tumor, whereas the H genotype is dominant in HD biopsies and in the oropharynx. The specific association of both viral strains with these 2 distinct diseases in North Africa may reflect a difference in tumorigenicity