Les sélectines inhibent la fonction des lymphocytes T régulateurs et contribuent à la pathogénie du lupus érythémateux systémique

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, an interferon signature, and a defect in the T regulatory cells (Tregs) compartment. In this work, we identified that platelets from active SLE patients preferentially interacted with Tregs via the P-selectin/PSGL-1 axis. Selectin interaction with PSGL-1 blocked the regulatory/suppressive properties of Tregs and follicular Tregs by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on Tregs induced a downregulation of the TGF-beta axis, altering Tregs phenotype and limiting their immunosuppressive response. In patients, we found a significant upregulation of P- and E-selectin levels both expressed by microparticles and in their soluble forms that correlated with SLE disease activity. Finally, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease. Overall, our results identify a selectin-dependent pathway active in SLE patients and validate it as a potential therapeutic avenue.Le lupus érythémateux systémique (LES) est une maladie auto-immune systémique caractérisée par une perte de tolérance vis-à-vis des autoantigènes nucléaires, une production d’auto-anticorps, une signature interféron et une dysfonction du compartiment des lymphocytes T régulateur (Tregs). Dans ce travail, nous avons identifié que les plaquettes des patients LES actifs interagissaient de manière préférentielle avec les Tregs via l’axe P-sélectine/PSGL-1. L’interaction de la P-sélectine plaquettaire avec son ligand le PSGL-1 abolissait les fonction immunosuppressives des Tregs et des Tregs folliculaires par le biais d’une phosphorylation de Syk et d’un signal calcique intracellulaire. D’un point de vue mécanistique, l’interaction P-sélectine/PSGL-1 induisait une sous-expression de la voie TGF-béta, altérant le phénotype et les fonctions suppressives des Tregs. Chez les patients, nous avons montré une majoration significative des taux des P- et E-sélectine circulantes, sous forme soluble et microparticulaire, et ce de manière corrélé à l’activité du LES. Enfin, le blocage de la P-selectine dans un modèle murin de LES améliorait des symptômes cardinaux de la pathologies (atteinte rénale notamment). Au total, nos résultats identifient une nouvelle voie physiopathologique impliquant la P-sélectine dans le LES, et ouvre la voie pour des essais thérapeutique visant à bloquer la P-sélectine dans le LES

Selectins impair regulatory T cell function and contribute to systemic lupus erythematosus pathogenesis

Le lupus érythémateux systémique (LES) est une maladie auto-immune systémique caractérisée par une perte de tolérance vis-à-vis des autoantigènes nucléaires, une production d’auto-anticorps, une signature interféron et une dysfonction du compartiment des lymphocytes T régulateur (Tregs). Dans ce travail, nous avons identifié que les plaquettes des patients LES actifs interagissaient de manière préférentielle avec les Tregs via l’axe P-sélectine/PSGL-1. L’interaction de la P-sélectine plaquettaire avec son ligand le PSGL-1 abolissait les fonction immunosuppressives des Tregs et des Tregs folliculaires par le biais d’une phosphorylation de Syk et d’un signal calcique intracellulaire. D’un point de vue mécanistique, l’interaction P-sélectine/PSGL-1 induisait une sous-expression de la voie TGF-béta, altérant le phénotype et les fonctions suppressives des Tregs. Chez les patients, nous avons montré une majoration significative des taux des P- et E-sélectine circulantes, sous forme soluble et microparticulaire, et ce de manière corrélé à l’activité du LES. Enfin, le blocage de la P-selectine dans un modèle murin de LES améliorait des symptômes cardinaux de la pathologies (atteinte rénale notamment). Au total, nos résultats identifient une nouvelle voie physiopathologique impliquant la P-sélectine dans le LES, et ouvre la voie pour des essais thérapeutique visant à bloquer la P-sélectine dans le LES.Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance toward self-nucleic acids, autoantibody production, an interferon signature, and a defect in the T regulatory cells (Tregs) compartment. In this work, we identified that platelets from active SLE patients preferentially interacted with Tregs via the P-selectin/PSGL-1 axis. Selectin interaction with PSGL-1 blocked the regulatory/suppressive properties of Tregs and follicular Tregs by triggering Syk phosphorylation and an increase in intracytosolic calcium. Mechanistically, P-selectin engagement on Tregs induced a downregulation of the TGF-beta axis, altering Tregs phenotype and limiting their immunosuppressive response. In patients, we found a significant upregulation of P- and E-selectin levels both expressed by microparticles and in their soluble forms that correlated with SLE disease activity. Finally, blocking P-selectin in a mouse model of SLE improved cardinal features of the disease. Overall, our results identify a selectin-dependent pathway active in SLE patients and validate it as a potential therapeutic avenue

Monitoring of Epstein–Barr virus (EBV)/cytomegalovirus (CMV)/varicella-zoster virus (VZV) load in patients receiving tocilizumab for rheumatoid arthritis

International audienc

Acceptance rate and sociological factors involved in the switch from originator to biosimilar etanercept (SB4)

Objective : To study acceptance rate and factors influencing acceptance of the switch from originator etanercept (Enbrel©) to biosimilar etanercept (SB4, Bénépali©) in patients with rheumatic disease.Methods : Patients with a well-controlled rheumatic disease consulting in our rheumatology department were offered the switch for SB4. After oral and written information concerning biosimilar, free choice to accept the switch was left to the patients. The main outcome was primary switch acceptance rate defined by switch acceptance during the initial consult. Real switch adherence, socio-cultural factors and beliefs influencing switch acceptance rate were retrieved during a telephonic interview at distance from the consultation.Results : Fifty-two patients were eligible for the switch: 32 (62%) with spondyloarthritis and 20 (38%) with rheumatoid arthritis. The primary acceptance rate was 92% (48/52). Patients refusing the switch were more likely to report a bad opinion on generic drugs (100% vs 11%, p < 0.001). Other patient characteristics were roughly identical except for a statistical trend in the refusal group toward older age (61.4 vs 50.7 years, p = 0.08) and longer disease duration (26 vs 12.1 years, p = 0.05). Despite initial acceptance, two patients did not begin SB4 after receiving negative information by their regular pharmacist. Real SB4 switch rate was 85% (44/52) and 86% (38/44) of patients reported a good experience of the switch.Conclusions : Acceptance rate of the switch from originator to biosimilar etanercept is high. Patient information, physician and pharmacist knowledge on biosimilars should be taken into account in order to improve their diffusion

WB-TFh paper.tiff

Figure 2C original western blots used for Bcl6 expression comparison between Camk4-sufficient & Camk4-deficient in vitro differentiation mouse Tfh cells.Manuscript Title: CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responsesJournal: Nature Communications </p

Acceptance rate and sociological factors involved in the switch from originator to biosimilar etanercept (SB4)

Objective : To study acceptance rate and factors influencing acceptance of the switch from originator etanercept (Enbrel©) to biosimilar etanercept (SB4, Bénépali©) in patients with rheumatic disease.Methods : Patients with a well-controlled rheumatic disease consulting in our rheumatology department were offered the switch for SB4. After oral and written information concerning biosimilar, free choice to accept the switch was left to the patients. The main outcome was primary switch acceptance rate defined by switch acceptance during the initial consult. Real switch adherence, socio-cultural factors and beliefs influencing switch acceptance rate were retrieved during a telephonic interview at distance from the consultation.Results : Fifty-two patients were eligible for the switch: 32 (62%) with spondyloarthritis and 20 (38%) with rheumatoid arthritis. The primary acceptance rate was 92% (48/52). Patients refusing the switch were more likely to report a bad opinion on generic drugs (100% vs 11%, p < 0.001). Other patient characteristics were roughly identical except for a statistical trend in the refusal group toward older age (61.4 vs 50.7 years, p = 0.08) and longer disease duration (26 vs 12.1 years, p = 0.05). Despite initial acceptance, two patients did not begin SB4 after receiving negative information by their regular pharmacist. Real SB4 switch rate was 85% (44/52) and 86% (38/44) of patients reported a good experience of the switch.Conclusions : Acceptance rate of the switch from originator to biosimilar etanercept is high. Patient information, physician and pharmacist knowledge on biosimilars should be taken into account in order to improve their diffusion

Les doubles cursus médecine-sciences en France

Les doubles cursus médecine-sciences (DC/MS) permettent l’acquisition d’une formation à la recherche et d’un doctorat de sciences au cours des études médicales. En France, avant les années 2000, la formation à la recherche était réalisée durant, voire après, le troisième cycle des études médicales (internat). Des DC/MS intégrés, dits « précoces », ont été développés depuis 2003 à l’initiative du cursus national de l’École de l’Inserm Liliane Bettencourt, suivie par la création de DC/MS par diverses universités. Quel que soit le mode de réalisation du double cursus, les étudiants engagés dans ces voies d’excellence se heurtent à des difficultés qui résultent essentiellement du manque d’articulation entre les formations médicale et scientifique. Les objectifs de ce texte sont de présenter les filières DC/MS de France, de recenser les principales difficultés rencontrées par les étudiants, ainsi que de formaliser un ensemble de propositions d’aménagements pour faciliter et consolider la formation des médecins/chercheurs

L’actualité scientifique de ce début 2018 vue par les étudiants de l’AMPS

Les Brèves de ce numéro sont publiées dans le cadre d’un partenariat entre l’Association Médecine/Pharmacie/ Sciences (AMPS) et médecine/sciences. « l’AMPS rassemble les étudiants des double cursus médecine-sciences en France, et encourage les interactions Partenariat médecine/sciences - Association Médecine/ Pharmacie/Sciences (AMPS) © CIML/Inserm/CNRS/Lelouard, Hugues/Fallet, Mathieu/Mailfert, Sébastien entre la médecine et les sciences fondamentales. Son objectif est de regrouper les expertises scientifiques et cliniques de personnes mues par la même vision de la recherche scientifique et médicale française et de permettre à ses membres de bénéficier d’un échange rapide d’informations concernant les formations, les universités, les laboratoires et les avancées dans différentes disciplines. » Si vous souhaitez participer : contact AMPS : [email protected] contact m/s : [email protected] site AMPS : www.amps-asso.f

Ascorbate maintains a low plasma oxygen level

International audienceIn human blood, oxygen is mainly transported by red blood cells. Accordingly, the dissolved oxygen level in plasma is expected to be limited, although it has not been quantified yet. Here, by developing dedicated methods and tools, we determined that human plasma pO2 = 8.4 mmHg (1.1% O2). Oxygen solubility in plasma was believed to be similar to water. Here we reveal that plasma has an additional ascorbate-dependent oxygen-reduction activity. Plasma experimental oxygenation oxidizes ascorbate (49.5 μM in fresh plasma vs  15 μM). Plasma low oxygen level preserves the integrity of oxidation-sensitive components such as ubiquinol. Circulating leucocytes are well adapted to these conditions, since the abundance of their mitochondrial network is limited. These results shed a new light on the importance of oxygen exposure on leucocyte biological study, in regards with the reducing conditions they encounter in vivo; but also, on the manipulation of blood products to improve their integrity and potentially improve transfusions' efficacy

Effect of SARS-CoV-2 Vaccination on Symptoms from Post-Acute Sequelae of COVID-19: Results from the Nationwide VAXILONG Study

Introduction: Few data are available concerning the effect of SARS-CoV-2 vaccination on the persistent symptoms associated with COVID-19, also called long-COVID or post-acute sequelae of COVID-19 (PASC). Patients and methods: We conducted a nationwide online study among adult patients with PASC as defined by symptoms persisting over 4 weeks following a confirmed or probable COVID-19, without any identified alternative diagnosis. Information concerning PASC symptoms, vaccine type and scheme and its effect on PASC symptoms were studied. Results: 620 questionnaires were completed and 567 satisfied the inclusion criteria and were analyzed. The respondents’ median age was 44 (IQR 25–75: 37–50) and 83.4% were women. The initial infection was proven in 365 patients (64%) and 5.1% had been hospitalized to receive oxygen. A total of 396 patients had received at least one injection of SARS-CoV-2 vaccine at the time of the survey, after a median of 357 (198–431) days following the initially-reported SARS-CoV-2 infection. Among the 380 patients who reported persistent symptoms at the time of SARS-CoV-2 vaccination, 201 (52.8%) reported a global effect on symptoms following the injection, corresponding to an improvement in 21.8% and a worsening in 31%. There were no differences based on the type of vaccine used. After a complete vaccination scheme, 93.3% (28/30) of initially seronegative patients reported a positive anti-SARS-CoV-2 IgG. A total of 170 PASC patients had not been vaccinated. The most common reasons for postponing the SARS-CoV-2 vaccine were fear of worsening PASC symptoms (55.9%) and the belief that vaccination was contraindicated because of PASC (15.6%). Conclusion: Our study suggests that SARS-CoV-2 vaccination is well tolerated in the majority of PASC patients and has good immunogenicity. Disseminating these reassuring data might prove crucial to increasing vaccine coverage in patients with PASC