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1. Cyclophosphamide added to glucocorticoids in acute exacerbation of idiopathic pulmonary fibrosis (EXAFIP): a randomised, double-blind, placebo-controlled, phase 3 trial

Author: Abdellatif Tazi, Aurélie Le Borgne-Krams, Marine Cachanado, Tabassome Simon, Sylvain Marchand-Adam, Morgane Didier, Lidwine Wemeau-Stervinou, Sandrine Hirschi, Frédéric Rivière, Arnaud Bourdin, François Lebargy, Stéphane Dominique, Aude Gibelin, Alexandre Chabrol, Tristan Dégot, Jacques Cadranel, Martine Reynaud-Gaubert, Marie-Pierre Debray, Sylvie Leroy, Frédéric Gagnadoux, Emmanuel Bergot, François-Xavier Blanc, Alexandra Rousseau, Raphael Borie, Pierre Yves Brillet, Guillaume Beltramo, Mallorie Kerjouan, Hilario Nunes, Olivia Freynet, Julie Traclet, Bruno Crestani, Anne-Sophie Gamez, Grégoire Prévot, Jean Pastré, Dominique Israel-Biet, Marie-Christine Dombret, Laurent Plantier, Cécile Chenivesse, Laurence Berard, Ana Nieves, Emmanuel Gomez, Dominique Valeyre, Stéphane Jouneau, Anne Gondouin, Elodie Blanchard, C. Launois, Nathalie Bautin, Jean-Marc Naccache, Vincent Cottin, Antoine Parrot, Philippe Bonniaud, Centre de référence maladies rares des maladies pulmonaires rares de l’adulte (CHU Dijon) (CRMR des maladies pulmonaires rares de l’adulte), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Sorbonne Université (SU), Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Foch [Suresnes], CHU Pontchaillou [Rennes], École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Avicenne [AP-HP], Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], CHU Saint-Antoine [AP-HP], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre régional de pharmacovigilance de Marseille Provence Corse [CHU de Marseille] (CRPV-Marseille), Assistance Publique - Hôpitaux de Marseille (APHM)-CHU Marseille, CHU Dijon, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Les Hôpitaux Universitaires de Strasbourg (HUS), Nouvel Hôpital Civil de Strasbourg, Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Lille, Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Référence des Maladies Pulmonaires Rares [Hôpital Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL), Université de Lyon, CIC CHU Lyon (inserm), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital JeanMinjoz, CHU Bordeaux [Bordeaux], Hôpital Haut-Lévêque [CHU Bordeaux], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Rouen, Normandie Université (NU), CHU Tenon [AP-HP], Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), CHU Montpellier, Université de Lille, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Roche, Ministere de la Sante et des Solidarites, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Marseille-Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, education.field_of_study, Exacerbation, Cyclophosphamide, business.industry, [SDV]Life Sciences [q-bio], Population, medicine.disease, Placebo, 3. Good health, 03 medical and health sciences, Idiopathic pulmonary fibrosis, 0302 clinical medicine, 030228 respiratory system, Methylprednisolone, Internal medicine, Clinical endpoint, Medicine, 030212 general & internal medicine, business, education, Adverse effect, ComputingMilieux_MISCELLANEOUS, medicine.drug
Abstract: Summary Background The use of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is unknown. Our study was designed to evaluate the efficacy and safety of four cyclophosphamide pulses in addition to high-dose methylprednisolone in this population. Methods In this double-blind, placebo-controlled trial done in 35 departments across 31 hospitals in France, adult patients (≥18 years) with acute exacerbation of IPF and those with suspected acute exacerbation of IPF were randomly assigned in a 1:1 ratio using a web-based system to receive either intravenous pulses of cyclophosphamide (600 mg/m2) plus uromitexan as haemorrhagic cystitis prophylaxis (200 mg/m2) at the time of cyclophosphamide administration and then again, 4 h later, or placebo at days 0, 15, 30, and 60. Random assignment was stratified according to the severity of IPF and was block-balanced with variable block sizes of four or six patients. Patients receiving mechanical ventilation, with active infection, with active cancer, or who were registered on the lung transplant waiting list were excluded. All patients received standardised high-dose glucocorticoids. The investigators, patients, and the sponsor were masked to the treatment assignments. The primary endpoint was 3-month all-cause mortality, analysed by a χ2 test adhering to an intention-to-treat principle. The trial is now complete and registered with ClinicalTrials.gov , NCT02460588 . Findings Between Jan 22, 2016, and July 19, 2018, 183 patients were assessed for eligibility, of whom 120 patients were randomly assigned and 119 patients (62 [52%] with severe IPF) received at least one dose of cyclophosphamide (n=60) or placebo (n=59), all of whom were included in the intention-to-treat analysis. The 3-month all-cause mortality was 45% (27/60) in patients given cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14·5% [95% CI −3·1 to 31·6]; p=0·10). Similar results were found after adjustment by IPF severity (odds ratio [OR] 1·89 [95% CI 0·89–4·04]). The risk of death at 3 months, independent of the treatment received, was higher with severe than non-severe IPF (OR 2·62 [1·12–6·12]) and was lower with the use of antifibrotic therapy (OR 0·33 [0·13–0·82]). Adverse events were similar between groups by 6 months (25 [42%] in the cyclophosphamide group vs 30 [51%] in the placebo group) and their proportion, including infections, did not differ. Overall infection was the main adverse event and occurred in 20 (33%) of 60 patients in the cyclophosphamide group versus 21 (36%) of 59 patients in the placebo group. Interpretation In patients with acute exacerbation of IPF, adding intravenous cyclophosphamide pulses to glucocorticoids increased 3-month mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients. Funding Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC 2014–502), Roche Pharmaceuticals.
Published: 2022

2. Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial

Author: Julie Mankikian, Agnès Caille, Martine Reynaud-Gaubert, Marie-Sara Agier, Julien Bermudez, Philippe Bonniaud, Raphael Borie, Pierre-Yves Brillet, Jacques Cadranel, Isabelle Court-Fortune, Bruno Crestani, Marie-Pierre Debray, Emmanuel Gomez, Anne Gondouin, Sandrine Hirschi-Santelmo, Dominique Israel-Biet, Stéphane Jouneau, Karine Juvin, Julie Leger, Mallorie Kerjouan, Charles-Hugo Marquette, Jean-Marc Naccache, Hilario Nunes, Laurent Plantier, Grégoire Prevot, Sébastien Quetant, Julie Traclet, Victor Valentin, Yurdagul Uzunhan, Lidwine Wémeau-Stervinou, Theodora Bejan-Angoulvant, Vincent Cottin, Sylvain Marchand-Adam, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), MethodS in Patients-centered outcomes and HEalth ResEarch (SPHERE), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Nantes Université - UFR des Sciences Pharmaceutiques et Biologiques (Nantes Univ - UFR Pharmacie), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre d’Investigation Clinique [Tours] CIC 1415 (CIC ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Nord [CHU - APHM], Aix Marseille Université (AMU), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris 13 (UP13), Hôpital Avicenne [AP-HP], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Biologie Intégrative du Tissu Osseux (LBTO), Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Nouvel Hôpital Civil de Strasbourg, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Hôpital Pontchaillou, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre hospitalier Saint-Joseph [Paris], Service de pneumologie [Rennes] = Pneumology [Rennes], CHU Pontchaillou [Rennes], Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Grenoble, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, CHU Lille, EA4245 - Transplantation, Immunologie, Inflammation [Tours] (T2i), Université de Tours (UT), PHRC national, and This study was supported by a grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique) 2015
Subjects: Pulmonary and Respiratory Medicine, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract
Abstract: BackgroundStandard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first step therapies while rituximab is used as rescue therapy.MethodsIn a randomised, double blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune feature) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinico-biological data and a NSIP-like HRCT pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for six months. The primary endpoint was the change in percent of predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary endpoints included progression-free survival (PFS) up to 6 months and safety.FindingsBetween January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se1.13) in the rituximab+MMF group and −2.01 (se1.17) in the placebo+MMF group (between-group difference, 3.60 [95% CI 0.41 to 6.80]; p=0.0273). PFS was better in the rituximab+MMF group (crude HR 0.47 [95%CI 0.23 to 0.96]; p=0.03). Serious adverse events occurred in 26 patients of the rituximab+MMF group (41%) and in 23 of the placebo+MMF group (39%). Nine infections were reported in the rituximab+MMF group (five bacterial infections, 3 viral infections, 1 other) and four bacterial infections in the placebo+MMF group.InterpretationCombination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must consider the risk of viral infection.
Published: 2023

3. Clinical phenotype and cytokine profile of adult IgA vasculitis with joint involvement

Author: Delapierre, Alice, Terrier, Benjamin, Pillebout, Evangéline, Baudart, Pauline, Jourde-Chiche, Noémie, Lioger, Bertrand, Martis, Nihal, Moulis, Guillaume, Rivière, Etienne, Le Gouellec, Noémie, Raffray, Loïc, Urbanski, Geoffrey, Sanges, Sébastien, Maurier, Francois, Deroux, Alban, Mekinian, Arsène, Monteiro, Renato, Marcelli, Christian, Guillevin, Loïc, Maillot, Francois, Lucas, Bruno, Aouba, Achille, Audemard-Verger, Alexandra, Université de Caen Normandie - UFR Santé (UNICAEN Santé), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Plateforme Cytométrie et Immunobiologie [Institut Cochin] (CYBIO), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Rhumatologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Centre hospitalier [Valenciennes, Nord], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital-Clinique Claude-Bernard [Metz], Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), Biotechnologie des tissus conjonctifs et cutanés / Biology of Connective and Cutaneous Tissues (BioConnecT), Hôpital Cochin [AP-HP], CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), EA4245 - Transplantation, Immunologie, Inflammation [Tours] (T2i), Université de Tours (UT), Laboratoire d'Immunologie [CHU Caen], Immunologie parasitaire (TOURS UMR IMMUNOLOGIE PARASIT), and Faculte des Sciences Pharmaceutiques-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Henoch Schonlein purpura, Phenotype, IgA Vasculitis, Rheumatology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Cytokines, Humans, IgA vasculitisIL-1 beta, Prospective Studies, General Medicine, Gastrointestinal tract involvement, Joint involvement, Immunoglobulin A
Abstract: Joint involvement can be observed during the course of adult IgA vasculitis (IgAV). However, clinical picture, prognosis, or pathophysiological data associated with this condition have been overlooked. We aimed to describe the clinical characteristics and outcome of IgAV patients with joint involvement and look to a specific cytokine profile.We analyzed clinical and biological data from a nationwide study that included adult IgAV patients. Presentation and outcomes of patients with or without joint involvement were compared at baseline and during follow-up. Plasma cytokine measurements of IgAV patients included in a prospective study were also analyzed using multiplex assays.Among 260 patients, 62% had joint involvement. Among them, rheumatological manifestations included arthralgia (100%) or arthritis (16%), mostly involving the knees and ankles. In multivariate analysis, patients with joint involvement, compared to those without, were younger (p = 0.002; OR 0.87; 95% CI 0.80-0.95) and showed more frequent gastrointestinal tract involvement (p = 0.012; OR = 2.08; 95% CI 1.18-3.67). However, no difference in terms of clinical response, relapse, end-stage renal disease, or death was observed between groups. Among 13 cytokines measured, plasma interleukin (IL)-1β level was higher in patients with joint involvement compared to those without (mean ± SEM IL-1β, 3.5 ± 1.2 vs. 0.47 ± 0.1 pg/ml; p = 0.024) or healthy controls (vs. 1.2 ± 0.5 pg/ml; p = 0.076).Joint involvement is frequent in adult IgAV and is associated with more frequent gastrointestinal involvement. Increased plasma IL-1β levels raise the question of targeting this cytokine in patients with chronic and/or refractory joint involvement. Key Points • Joint involvement in adult IgAV is a frequent manifestation. • Joint involvement is associated with more frequent gastrointestinal manifestations. • Interleukin-1β (IL-1β) might orchestrate joint inflammation in adult IgAV. • IL-1β might be a therapeutic target in patients with chronic and/or refractory joint involvement.
Published: 2022

4. Impaired p47phox phosphorylation in neutrophils from p67phox-deficient chronic granulomatous disease patients Short title: p67phox regulates p47phox phosphorylation

Author: Belambri, Sahra Amel, Marzaioli, Viviana, Hurtado-Nedelec, Margarita, Pintard, Coralie, Liang, Shiyu, Liu, Yezhou, Boussetta, Tarek, Gougerot-Pocidalo, Marie-Anne, Ye, Richard, Dang, Pham My-Chan, El-Benna, Jamel, DANG, Pham My-Chan, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), AP-HP - Hôpital Bichat - Claude Bernard [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity
Abstract: International audience; Abstract Superoxide production by the phagocyte reduced NAD phosphate (NADPH) oxidase is essential for innate immunity as shown in chronic granulomatous disease (CGD), an immunodeficiency disease resulting from mutations in 1 of its genes. The NADPH oxidase is composed of 2 membrane proteins (gp91phox/NOX2 and p22phox) and 4 cytosolic proteins (p47phox, p67phox, p40phox, and Rac1/2). The phosphorylation of p47phox is required for NADPH oxidase activation in cells. As p47phox and p67phox can form a tight complex in cells, we hypothesized that p67phox could regulate p47phox phosphorylation. To investigate this hypothesis, we used phospho-specific antibodies against 5 major p47phox-phosphorylated sites (Ser304, Ser315, Ser320, Ser328, and Ser345) and neutrophils from healthy donors and from p67phox−/− CGD patients. Results showed that formyl-methionyl-leucyl-phenylalanine and phorbol myristate acetate induced a time- and a concentration-dependent phosphorylation of p47phox on Ser304, Ser315, Ser320, and Ser328 in healthy human neutrophils. Interestingly, in neutrophils and Epstein-Barr virus-transformed B lymphocytes from p67phox−/− CGD patients, phosphorylation of p47phox on serine residues was dramatically reduced. In COSphox cells, the presence of p67phox led to increased phosphorylation of p47phox. In vitro studies showed that recombinant p47phox was phosphorylated on Ser304, Ser315, Ser320, and Ser328 by different PKC isoforms and the addition of recombinant p67phox alone or in combination with p40phox potentiated this process. Thus, p67phox and p40phox are required for optimal p47phox phosphorylation on Ser304, Ser315, Ser320, and Ser328 in intact cells. Therefore, p67phox and p40phox are novel regulators of p47phox-phosphorylation.
Published: 2022

5. Impact of synovial biopsy procedures and disease-specific aspects on synovial tissue outcome: a systematic literature review informing the EULAR points to consider for the minimal reporting requirements in synovial tissue research in rheumatology

Author: Aurélie Najm, Félicie Costantino, Catherine Weill, Andrew Filer, Maria Antonieta D'Agostino, University of Glasgow, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), Hôpital Ambroise Paré [AP-HP], Université Paris Cité (UPCité), University of Birmingham [Birmingham], Fondazione Policlinico Universitario Agostino Gemelli IRCCS, and HAL UVSQ, Équipe
Subjects: Inflammation, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Synovitis, Settore MED/16 - REUMATOLOGIA, Biopsy, Arthritis, Synovial Membrane, Immunology, Arthritis, Rheumatoid, Cross-Sectional Studies, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Rheumatology, Rheumatoid, Humans, Immunology and Allergy
Abstract: BackgroundThe aim of this work was to summarise the literature evaluating the impact of biopsy procedures, tissue handling, tissue quality and disease-specific aspects including joint biopsied and disease stage, on synovial tissue outcome.MethodsTwo reviewers independently identified eligible studies according to the Patients, Intervention, Comparator and Outcome framework obtained for five research questions formulated during the first EULAR task force meeting to produce points to consider (PtC) for minimal reporting requirements in synovial tissue studies. The databases explored were Medline, Embase, CENTRAL and Cinhal. The risk of bias of each study was evaluated using an adapted version of the Joanna Briggs Institute checklist for analytical cross-sectional studies.ResultsOf the 7654 records yielded, 75 full texts were assessed, leading to the inclusion of 26 manuscripts in the systematic literature review (SLR). Two papers assessed the impact of biopsy procedures on the quality and quantity of tissue retrieved alongside patient tolerability; six papers focused on synovial tissue variability. Four papers studied the impact of sample handling or randomisation and 14 assessed the impact of disease stage and state, namely early or established active rheumatoid arthritis and remission on histopathological and transcriptomic results.ConclusionsThis SLR informs the EULAR PtC for minimal reporting requirements in synovial tissue research in rheumatology. Characteristics related to the study design, population, sample handling, randomisation and analysis can affect the final synovial tissue outcome in the studies reviewed. Thus, accurate reporting of these factors is required in order to ensure the scientific validity of manuscripts describing synovial tissue outcomes.
Published: 2022

6. Nurselike cells sequester B cells in disorganized lymph nodes in chronic lymphocytic leukemia via alternative production of CCL21

Author: Rim Zaaboub, Lene Vimeux, Vincent Contremoulins, Florence Cymbalista, Vincent Lévy, Emmanuel Donnadieu, Nadine Varin-Blank, Antoine Martin, Elisabetta Dondi, donnadieu, emmanuel, Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Hopital Saint-Louis [AP-HP] (AP-HP)
Subjects: [SDV] Life Sciences [q-bio], Receptors, CCR7, Chemokine CCL21, [SDV]Life Sciences [q-bio], Leukocytes, Mononuclear, Tumor Microenvironment, Humans, Hematology, Lymph Nodes, Chemokines, Leukemia, Lymphocytic, Chronic, B-Cell
Abstract: Tumor microenvironment exerts a critical role in sustaining homing, retention, and survival of chronic lymphocytic leukemia (CLL) cells in secondary lymphoid organs. Such conditions foster immune surveillance escape and resistance to therapies. The physiological microenvironment is rendered tumor permissive by an interplay of chemokines, chemokine receptors, and adhesion molecules as well as by direct interactions between malignant lymphocytes and stromal cells, T cells, and specialized macrophages referred to as nurselike cells (NLCs). To characterize this complex interplay, we investigated the altered architecture on CLL lymph nodes biopsies and observed a dramatic loss of tissue subcompartments and stromal cell networks as compared with nonmalignant lymph nodes. A supplemental high density of CD68+ cells expressing the homeostatic chemokine CCL21 was randomly distributed. Using an imaging flow cytometry approach, CCL21 mRNA and the corresponding protein were observed in single CD68+ NLCs differentiated in vitro from CLL peripheral blood mononuclear cells. The chemokine was sequestered at the NLC membrane, helping capture of CCR7-high-expressing CLL B cells. Inhibiting the CCL21/CCR7 interaction by blocking antibodies or using therapeutic ibrutinib altered the adhesion of leukemic cells. Our results indicate NLCs as providers of an alternative source of CCL21, taking over the physiological task of follicular reticular cells, whose network is deeply altered in CLL lymph nodes. By retaining malignant B cells, CCL21 provides a protective environment for their niching and survival, thus allowing tumor evasion and resistance to treatment. These findings argue for a specific targeting or reeducation of NLCs as a new immunotherapy strategy for this disease.
Published: 2021

7. The high affinity IgE receptor: a signaling update

Author: Ulrich Blank, Toshiaki Kawakami, Hua Huang, Université de Paris, Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Faculté de Médecine site Bichat, Paris, France, Université de Paris, Laboratoire d'Excellence Inflamex, Paris, France., and Chang'an University
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Immunology, Immunoglobulin E, Cell Degranulation, Exocytosis, Immunomodulation, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, Immunology and Allergy, Antigens, Enhancer, Receptor, Transcription factor, biology, Receptors, IgE, Chemistry, GATA2, Immunity, Degranulation, Mast cell, Cell biology, 030104 developmental biology, medicine.anatomical_structure, Gene Expression Regulation, biology.protein, Cytokines, Phosphorylation, Protein Binding, Signal Transduction, 030215 immunology
Abstract: International audience; Here we update receptor proximal and distant signaling events of the mast cell high affinity IgE receptor (FcεRI) launching immediate type I hypersensitivity and an inflammatory cytokine-chemokine cascade. Different physiologic antigen concentrations, their affinity, and valency for the IgE ligand produce distinct intracellular signaling events with different outcomes. Investigating mast cell degranulation has revealed a complex molecular machinery that relays proximal signaling to cytoskeletal reorganization, granule transport and membrane fusion. Several new phosphorylation- and calcium-responsive effectors have been described. FcεRI signaling also promotes de novo gene transcription. Recent progress has identified enhancers at genes that are upregulated in mast cells after stimulation through FcεRI using next generation sequencing methods. Enhancers at genes that respond to antigenic stimulation in human mast cells revealed Ca2+-dependency. Stimulation-responsive super enhancers in mouse mast cells have also been identified. Mast cell lineage-determining transcription factor GATA2 primes these enhancers to respond to antigenic stimulation.
Published: 2021

8. Otological Manifestations in Adults with Primary Ciliary Dyskinesia: A Controlled Radio-Clinical Study

Author: Mihaela Alexandru, Paul de Boissieu, Farida Benoudiba, Malik Moustarhfir, Sookyung Kim, Émilie Bequignon, Isabelle Honoré, Gilles Garcia, Rana Mitri-Frangieh, Marie Legendre, Bruno Crestani, Camille Taillé, Estelle Escudier, Bernard Maitre, Jean-François Papon, Jérôme Nevoux, Service d’ORL et de chirurgie cervico-faciale [CHU Le Kremlin-Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris-Saclay, Public Health and Epidemiology Department [Le Kremlin-Bicêtre], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Service de Neuroradiologie [CHU de Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Molecular virology and immunology – Physiopathology and therapeutic of chronic viral hepatitis (Team 18) (Inserm U955), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris-Est (UPE), Biomécanique & Appareil Respiratoire (BAR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHI Créteil, Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Service de pneumologie [CHU Bicêtre], Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), Plateforme F-CRIN, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie [CHI Créteil], Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Neurophysiologie de la Synapse Auditive, Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU de Bordeaux Pellegrin [Bordeaux]-Neuroscience Institute, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Couvet, Sandrine
Subjects: [SDV] Life Sciences [q-bio], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, chronic otitis media, [SDV]Life Sciences [q-bio], otitis media with effusion, primary ciliary dyskinesia, General Medicine, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, temporal bone CT scan, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, hearing loss
Abstract: International audience; Primary ciliary dyskinesia (PCD) is a rare genetical disease characterized by an abnormal structure or function of the cilia, causing sinusitis, otitis, and bronchiectasis. Hearing loss affects 60% of PCD patients, but data are lacking concerning hearing and temporal bone imaging in adults. Our aim was to describe clinical and radiological ear disease in adults with genetically confirmed PCD. Data were recorded from January 2018 to December 2019. PCD patients were compared with controls with bronchiectasis without PCD. Clinical examination included otomicroscopy and auditory tests. A temporal bone CT scan (TBCT) was systematically performed. Seventeen patients (34 ears) were included in each group. The eardrums were abnormal in 25 (74%) PCD ears versus 8 (24%) ears in the controls (p < 0.05). Conductive hearing loss was more frequent in the PCD group (24% vs. 12% in controls). TBCT were abnormal in 94% PCD patients vs. 32% in the controls (p < 0.05). The Main CT-scan images in PCD were middle ear inflammation (65%), mastoid condensation (62%), or ossicular anomalies (35%). With its excellent sensitivity, TBCT gives typical arguments for PCD diagnosis, adding otological signs to the usual sinus CT signs (hypoplasia, aplasia). Systematic TBCT could be useful in the initial evaluation of patients with suspicion of PCD.
Published: 2022

9. Evaluation of Pulp Repair after BiodentineTM Full Pulpotomy in a Rat Molar Model of Pulpitis

Author: Minic, Sandra, Florimond, Marion, Sadoine, Jérémy, Valot-Salengro, Anne, Chaussain, Catherine, Renard, Emmanuelle, Boukpessi, Tchilalo, Jehan, Frederic, Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Septodont, Regenerative Medicine and Skeleton (RMeS), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), Université de Paris (UP), Regenerative Medicine and Skeleton research lab (RMeS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: reparativedentin, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], animal mode, [SDV.MHEP.GEG] Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, QH301-705.5, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, dentin-pulp complex regeneration, animal model, Article, reparative dentin, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, stomatognathic system, pulpal inflammation, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Biology (General), vital pulp therapy, calcium silicate-based cement
Abstract: International audience; Dental pulp is a dynamic tissue able to heal after injury under moderate inflammatory conditions. Our study aimed to evaluate pulp repair under inflammatory conditions in rats. For this purpose, we developed a rat model of controlled pulpitis followed by pulpotomy with a tricalcium silicate-based cement. Fifty-four cavities were prepared on the occlusal face of the maxillary upper first molar of 27 eight-week-old male rats. E. coli lipopolysaccharides at 10 mg/mL or phosphate-buffered saline PBS was injected after pulp injury. Non-inflamed molars were used as controls. Levels of inflammation-related molecules were measured 6 and 24 h after induction by enzyme-linked immunosorbent assay of coronal pulp samples. Pulp capping and coronal obturation after pulpotomy were performed with tricalcium silicate-based cement. Four and fifteen days after pulpotomy, histological and immunohistochemical analysis was performed to assess pulp inflammation and repair processes. Our results showed significantly higher levels of innate inflammatory proteins (IL-1β, IL-6, TNF-α and CXCL-1) compared with those in controls. Moderate residual inflammation near the capping material was demonstrated by histology and immunohistochemistry, with the presence of few CD68-positive cells. We showed that, in this model of controlled pulpitis, pulpotomy with BiodentineTM allowed the synthesis at the injury site of a mineralized bridge formed from mineralized tissue secreted by cells displaying odontoblastic characteristics. Analysis of these data suggests overall that, with the limitations inherent to findings in animal models, pulpotomy with a silicate-based cement is a good treatment for controlling inflammation and enhancing repair in cases of controlled pulpitis.
Published: 2021

10. Effects of venoms on neutrophil respiratory burst: a major inflammatory function

Author: Pham My-Chan Dang, Margarita Hurtado-Nedelec, Jamel El-Benna, Marie-Anne Gougerot-Pocidalo, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), DANG, Pham My-Chan, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Neutrophils, Disintegrins, RC955-962, Inflammation, Review, Toxicology, Mastoporan, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 03 medical and health sciences, chemistry.chemical_compound, Phospholipase A2, Arctic medicine. Tropical medicine, RA1190-1270, medicine, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Phagosome, chemistry.chemical_classification, 0303 health sciences, Reactive oxygen species, PLA2, NADPH oxidase, Innate immune system, biology, Parabutoporin, Chemistry, Superoxide, 030302 biochemistry & molecular biology, ROS, Venom, 3. Good health, Cell biology, Respiratory burst, Infectious Diseases, QL1-991, L-amino acid oxidase, Toxicology. Poisons, biology.protein, Animal Science and Zoology, Parasitology, medicine.symptom, Zoology
Abstract: Neutrophils play a pivotal role in innate immunity and in the inflammatory response. Neutrophils are very motile cells that are rapidly recruited to the inflammatory site as the body first line of defense. Their bactericidal activity is due to the release into the phagocytic vacuole, called phagosome, of several toxic molecules directed against microbes. Neutrophil stimulation induces release of this arsenal into the phagosome and induces the assembly at the membrane of subunits of the NAPDH oxidase, the enzyme responsible for the production of superoxide anion that gives rise to other reactive oxygen species (ROS), a process called respiratory burst. Altogether, they are responsible for the bactericidal activity of the neutrophils. Excessive activation of neutrophils can lead to extensive release of these toxic agents, inducing tissue injury and the inflammatory reaction. Envenomation, caused by different animal species (bees, wasps, scorpions, snakes etc.), is well known to induce a local and acute inflammatory reaction, characterized by recruitment and activation of leukocytes and the release of several inflammatory mediators, including prostaglandins and cytokines. Venoms contain several molecules such as enzymes (phospholipase A2, L-amino acid oxidase and proteases, among others) and peptides (disintegrins, mastoporan, parabutoporin etc.). These molecules are able to stimulate or inhibit ROS production by neutrophils. The present review article gives a general overview of the main neutrophil functions focusing on ROS production and summarizes how venoms and venom molecules can affect this function.
Published: 2021

11. Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis

Author: Matthew A. Brown, Laura Diekman, Maxime Breban, Nicholas G. Martin, Yuqin Wang, Erika De Guzman, Paul Leo, Zhixiu Li, Gary J. Macfarlane, Lisa Anderson, Simon Stebbings, Margaret J. Wright, Michael M. Ward, Gareth T. Jones, Mahdi Mahmoudi, Mohammad H. Rahbar, Zi-Bing Jin, Jing Song, Huji Xu, MinJae Lee, Mengmeng Li, Xiaobing Wang, Michael H. Weisman, Andrew A. Harrison, Nurullah Akkoc, Jian Zhan, B P Wordsworth, Lianne S. Gensler, So Young Bang, Li Lin, Xin Wu, Elham Farhadi, James Cheng-Chung Wei, John D. Reveille, Helena Marzo-Ortega, Lawrie Wheeler, Chung Tei Chou, Geng Wang, Jin San Zhang, Tae-Hwan Kim, Ahmadreza Jamshidi, Queensland University of Technology [Brisbane] (QUT), Manisa Celal Bayar University, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Rhumatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), University of Aberdeen, Tehran University of Medical Sciences (TUMS), University of Leeds, National Yang Ming University (NYMU), University of Otago [Dunedin, Nouvelle-Zélande], Hanyang University, University of Queensland [Brisbane], QIMR Berghofer Medical Research Institute, Queensland Brain Institute, University of Texas Southwestern Medical Center [Dallas], Griffith University [Brisbane], Beijing Tongren Hospital, University of California [San Francisco] (UCSF), University of California, National Institutes of Health [Bethesda] (NIH), The University of Texas Health Science Center at Houston (UTHealth), University of Oxford [Oxford], ANR-10-MIDI-0002,GEMISA,GEnétique, Microbiote, Inflammation, et Spondylarthrite Ankylosante(2010), Second Military Medical University [Shanghai], Hôpital Ambroise Paré [AP-HP], Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), Leeds Teaching Hospitals NHS Trust, Taipei Veterans General Hospital [Taiwan], Chung Shan Medical University, China Medical University, Wenzhou Medical University [Wenzhou, China] (WMU), The First Affiliated Hospital of Wenzhou Medical University [Wenzhou, China], Wenzhou University [Wenzhou, China], Cedars-Sinai Medical Center, Tsinghua University [Beijing] (THU), King‘s College London, and TCRI AS Group: Jian Yin, Lei Jiang, Lin Zhou, Ting Li, Qingwen Wang, Tianwang Li, Guanmin Gao, Shengqian Xu, Weiguo Xiao, Hui Shen, Jingguo Zhou, Yuquan You, Dongbao Zhao, Qing Cai, Shengming Dai, Lan He, Ping Zhu, Zhenyu Jiang, Jian Xu, Huaxiang Wu, Lie Dai, Yang Li, Feng Ding, Xiaochun Zhu, Chongyang Liu, Dongyi He, Liyun Zhang, Zhijun Li, Futao Zhao, Hanshi Xu, Niansong Wang, Youlian Wang, Lindi Jiang, Yu Zhang, Jinwei Chen, Fang Cheng, Zhiyi Zhang, Yifang Mei, Liangjing Lv, Lingli Dong, Jing Yang, Yinong Li, Xiaodong Wang, Xiaofeng Li, Hongsheng Sun, Xianming Long, Xiao Zhang, Qinghong Yu, Xiaodan Kong, Yi Zheng, Miaojia Zhang, Yi Tao, Yisha Li, Xinwang Duan, Qianghua Wei, Xiaofei Wang, Jie Han, Rong Mu, Yiping Lin, Jian Zhu, Xiaoyuan Chen
Subjects: 0301 basic medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Immunology, General Biochemistry, Genetics and Molecular Biology, polymorphism, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Back pain, magnetic resonance imaging, Immunology and Allergy, Spondylitis, low back pain, 030203 arthritis & rheumatology, HLA-B27, Ankylosing spondylitis, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Receiver operating characteristic, business.industry, Area under the curve, spondylitis, medicine.disease, Low back pain, ankylosing, 030104 developmental biology, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, genetic, medicine.symptom, business
Abstract: ObjectiveWe sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain.MethodsPRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), HLA-B27 and sacroiliac MRI.ResultsIn people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for HLA-B27 testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with HLA-B27 testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for HLA-B27, these values were 51.9% and 97.9%, respectively.ConclusionsPRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or HLA-B27 status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.
Published: 2021

12. Live or die: PD-L1 delays neutrophil apoptosis

Author: Jamel El-Benna, Pham My-Chan Dang, Université de Paris, Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Faculté de Médecine site Bichat, Paris, France, Université de Paris, Laboratoire d'Excellence Inflamex, Paris, France., Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and DANG, Pham My-Chan
Subjects: Neutrophils, Necroptosis, Immunology, Apoptosis, Biochemistry, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, B7-H1 Antigen, 03 medical and health sciences, 0302 clinical medicine, Medicine, Efferocytosis, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, 030304 developmental biology, Phagosome, 0303 health sciences, Innate immune system, biology, business.industry, Pyroptosis, Cell Biology, Hematology, Neutrophil extracellular traps, 3. Good health, Cell biology, 030220 oncology & carcinogenesis, Myeloperoxidase, biology.protein, business
Abstract: International audience; In this issue of Blood, Wang et al. uncover a key role for programmed death ligand 1 (PD-L1), which delays neutrophil apoptosis at the inflammatory site through activation of the PI3K-AKT survival pathway 1. Polymorphonuclear neutrophils (PMN) are the most abundant circulating leukocytes, constituting 60 to 70% of circulating white blood cells. PMN are terminally differentiated and have a short life span, but are essential for innate immunity and host defense against microbes 2. They are the first cells to migrate out of the circulation and to be massively recruited at the infection site where they recognize microbes via different receptors expressed at their cell surface, inducing engulfment of the microbe into a phagosome 3,4. Killing of microbes by PMN occurs through the release into the phagosome of highly toxic agents such as reactive oxygen species (ROS) and granule contents including myeloperoxidase, glucosidases, proteases and anti-bacterial peptides. Microbes can also be trapped and killed by neutrophil extracellular traps (NETs) 5. Many processes such as apoptosis, NETosis, autophagy, pyroptosis, necroptosis and necrosis can induce the death of neutrophils 5 , upon which they are phagocytized and eliminated by local macrophages through a process called efferocytosis, resulting in the cleaning up of the infection site. Thus, PMN are critical anti-inflammatory components of the innate immune system as their physiological role is
Published: 2021

13. Basophils and IgE contribute to mixed connective tissue disease development

Author: Lamri, Yasmine, Vibhushan, Shamila, Pacreau, Emeline, Boedec, Erwan, Saidoune, Fanny, Mailleux, Arnaud, Crestani, Bruno, Blank, Ulrich, Benhamou, Marc, Papo, Thomas, Daugas, Eric, Sacré, Karim, Charles, Nicolas, Université de Paris, Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Faculté de Médecine site Bichat, Paris, France, and Université de Paris, Laboratoire d'Excellence Inflamex, Paris, France.
Subjects: [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2021

14. MAIT cells, guardians of skin and mucosa?

Author: Amine Toubal, Isabelle Nel, Agnès Lehuen, Léo Bertrand, Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR 8104, Université de Paris, Paris, France, Laboratoire d’Excellence Inflamex, Paris, France, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and ROULAND, Matthieu
Subjects: 0301 basic medicine, Vitamin b, [SDV]Life Sciences [q-bio], Immunology, Gene Expression, Review Article, Biology, Mucosal-Associated Invariant T Cells, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunology and Allergy, Animals, Homeostasis, Humans, Respiratory system, ComputingMilieux_MISCELLANEOUS, Skin, Mucous Membrane, Host Microbial Interactions, MAIT Cells, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Phenotype, Organ Specificity, Cytokines, Disease Susceptibility, Biomarkers, 030215 immunology
Abstract: Mucosal Associated Invariant T (MAIT) cells are evolutionary conserved innate-like T cells able to recognize bacterial and fungal ligands derived from vitamin B biosynthesis. These cells are particularly present in liver and blood but also populate mucosal sites including skin, oral, intestinal, respiratory, and urogenital tracts that are in contact with the environment and microbiota of their host. Growing evidence suggests important involvement of MAIT cells in safeguarding the mucosa against external microbial threats. Simultaneously, mucosal MAIT cells have been implicated in immune and inflammatory pathologies affecting these organs. Here, we review the specificities of mucosal MAIT cells, their functions in the protection and maintenance of mucosal barriers, and their interactions with other mucosal cells.
Published: 2021

15. Outcome of SARS-CoV-2 infection is linked to MAIT cell activation and cytotoxicity

Author: Léo Bertrand, Antoine C. Monteiro, Jade Ghosn, Christian Boitard, Héloïse Flament, Yazdan Yazdanpanah, Agnès Lehuen, Muriel Andrieu, Karine Bailly, Xavier Lescure, Frédéric Pène, Jean-François Gautier, Diane Descamps, Benjamin Terrier, Benjamin Saintpierre, Sandrine Luce, Christophe Paget, Youenn Jouan, Camille Rousseau, Margarita Hurtado-Nedelec, Renato C. Monteiro, Mustapha Si-Tahar, Matthieu Rouland, Benoit Visseaux, Samuel Lebourgeois, Lucie Cagninacci, Lucie Beaudoin, Nadine Ajzenberg, Anaïs Vallet-Pichard, Amine Toubal, Zouriatou Gouda, Jean-François Timsit, Thomas Baranek, Pauline Soulard, Franck Letourneur, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Cochin [AP-HP], Hôpital Lariboisière-Fernand-Widal [APHP], Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Gonzalez, Loïc, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), LabEx Inflamex, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Interleukin-1beta, Bronchoalveolar Lavage, Severity of Illness Index, Monocytes, Cohort Studies, 0302 clinical medicine, Chlorocebus aethiops, Macrophage, Cytotoxic T cell, Immunology and Allergy, RNA-Seq, Aged, 80 and over, Interleukin-15, Interleukin-18, Middle Aged, Interleukin-10, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cytokine, Female, France, Single-Cell Analysis, medicine.symptom, Cell activation, Adult, Immunology, Inflammation, Mucosal-Associated Invariant T Cells, Immunophenotyping, Proinflammatory cytokine, Young Adult, 03 medical and health sciences, Immune system, medicine, Animals, Humans, Vero Cells, Aged, Interleukin-6, SARS-CoV-2, business.industry, Macrophages, Monocyte, Interleukin-8, COVID-19, Interferon-alpha, 030104 developmental biology, Case-Control Studies, business, 030215 immunology
Abstract: International audience; Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.
Published: 2021
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16. Mast cell activation syndrome : is anaphylaxis part of the phenotype? A systematic review

Author: Moïse Michel, Vito Sabato, Joana Vitte, Ulrich Blank, Didier G. Ebo, University of Antwerp (UA), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Assistance Publique - Hôpitaux de Marseille (APHM), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Paris, Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Faculté de Médecine site Bichat, Paris, France, and Université de Paris, Laboratoire d'Excellence Inflamex, Paris, France.
Subjects: Mast cell activation syndrome, [SDV]Life Sciences [q-bio], Immunology, Tryptase, Context (language use), Disease, Immunoglobulin E, MESH: Phenotype, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Immunology and Allergy, Mast Cells, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Pathological, Anaphylaxis, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, MESH: Humans, biology, business.industry, MESH: Immunoglobulin E, Degranulation, MESH: Mast Cells, MESH: Mast Cell Activation Syndrome, medicine.disease, Phenotype, 3. Good health, MRPGRX2, MESH: Anaphylaxis, 030228 respiratory system, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Hereditary alpha-tryptasemia, Human medicine, medicine.symptom, business, Mastocytosis
Abstract: International audience; Purpose of review: Mast cell activation syndrome (MCAS) and anaphylaxis are the result of a spontaneous or triggered pathological degranulation of mast cells (MCs) and might have as substrate normal or pathological MCs (increased burden, aberrant MCs or both).Recent findings: This review summarizes the most recent evidence on immunoglobulin E (IgE)-mediated and non IgE-mediated mechanisms underlying MC activation and degranulation and highlights the importance of standardized diagnostic criteria for MCAS. Application of these criteria implies that in most cases the clinical presentation of MCAS meets the diagnostic criteria for anaphylaxis.Summary: Integrating clinical parameters and diagnostic test recognition and underlying clonal MC disease are of utmost importance for a patient-tailored approach. Hereditary alpha-tryptasemia can be encountered in context of anaphylaxis, MCAS and primary MC disorders.
Published: 2021

17. Rodent Models of Spondyloarthritis Have Decreased White and Bone Marrow Adipose Tissue Depots

Author: Furesi, Giulia, Fert, Ingrid, Beaufrère, Marie, Araujo, Luiza M.M., Glatigny, Simon, Baschant, Ulrike, von Bonin, Malte, Hofbauer, Lorenz Christian, Horwood, Nicole J., Breban, Maxime, Rauner, M., HAL UVSQ, Équipe, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), Hôpital Ambroise Paré [AP-HP], University of East Anglia [Norwich] (UEA), 860898 Horizon 2020 Framework Programme, H2020 Deutsche Forschungsgemeinschaft, DFG Versus Arthritis: 20372, This work was supported by grants from the Deutsche Forschungsgemeinschaft and the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860898 to MR and LH, as well as NH, supported by Versus Arthritis Grant No. 20372., and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
Subjects: CD4-Positive T-Lymphocytes, Mice, Inbred BALB C, HLA-B27 transgenic rat, [SDV]Life Sciences [q-bio], Immunology, Interleukin-17, Mice, Transgenic, spondyloarthritis, Rats, Inbred F344, SKG mouse, Rats, [SDV] Life Sciences [q-bio], Disease Models, Animal, Mice, bone marrow fat, IL-17, Adipose Tissue, Bone Marrow, Spondylarthritis, Animals, Female, Rats, Transgenic, HLA-B27 Antigen, Original Research
Abstract: International audience; Bone marrow adipose tissue (BMAT) has recently been recognized as a distinct fat depot with endocrine functions. However, if and how it is regulated by chronic inflammation remains unknown. Here, we investigate the amount of white fat and BMAT in HLA-B27 transgenic rats and curdlan-challenged SKG mice, two well-established models of chronic inflammatory spondyloarthritis (SpA). Subcutaneous and gonadal white adipose tissue and BMAT was reduced by 65-70% and by up to 90% in both experimental models. Consistently, B27 rats had a 2-3-fold decrease in the serum concentrations of the adipocyte-derived cytokines adiponectin and leptin as well as a 2-fold lower concentration of triglycerides. The bone marrow of B27 rats was further characterized by higher numbers of neutrophils, lower numbers of erythroblast precursors, and higher numbers of IL-17 producing CD4+ T cells. IL-17 concentration was also increased in the serum of B27 rats. Using a cell culture model, we show that high levels of IL-17 in the serum of B27 rats negatively impacted adipogenesis (-76%), an effect that was reversed in the presence of neutralizing anti-IL-17 antibody. In summary, these findings show BMAT is severely reduced in two experimental models of chronic inflammatory SpA and suggest that IL-17 is involved in this process.
Published: 2021

18. Mast cells drive pathologic vascular lesions in Takayasu arteritis

Author: Jean-Marie Launay, David Klatzmann, Aurélie S. Leroyer, D. Saadoun, Ulrich Blank, Paul Régnier, Alexandre Le Joncour, Gilles Kaplanski, Michelle Rosenzwajg, Anna Maciejewski-Duval, Anne-Claire Desbois, Patrice Cacoub, Fabien Koskas, Edwige Tellier, Michel Arock, Patrick Bruneval, Laurent Chiche, Mohamed Jarraya, Stéphane Barete, Cloé Comarmond, Pierre Fouret, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Imagerie médicale et quantitative, and Center of Research on Inflammation, INSERM UMR S1149 and Centre National de la Recherche Scientifique Experimental Research Laboratory 8252, Universite de Paris, Sorbonne Paris Cite, Laboratoire d'Excellence INFLAMEX, Paris, France
Subjects: 0301 basic medicine, Male, Pathology, Platelet-derived growth factor, Angiogenesis, [SDV]Life Sciences [q-bio], Vascular permeability, chemistry.chemical_compound, 0302 clinical medicine, Fibrosis, Immunology and Allergy, Mast Cells, ComputingMilieux_MISCELLANEOUS, Aorta, Cells, Cultured, Large vessel vasculitis, Middle Aged, Mast cell, Endothelial stem cell, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adult, medicine.medical_specialty, vascular remodeling, Immunology, Neovascularization, Physiologic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Collagen Type I, Capillary Permeability, 03 medical and health sciences, medicine.artery, medicine, Human Umbilical Vein Endothelial Cells, Animals, Humans, Takayasu, business.industry, Fibroblasts, medicine.disease, Interleukin-33, Takayasu Arteritis, Actins, Mice, Mutant Strains, Fibronectins, Mice, Inbred C57BL, 030104 developmental biology, chemistry, business, mast cell, 030215 immunology
Abstract: International audience; Background: Takayasu arteritis (TAK) is a large vessel vasculitis resulting in artery wall remodeling with segmental stenosis and/or aneurysm formation. Mast cells (MCs) are instrumental in bridging cell injury and inflammatory response.Objectives: This study sought to investigate the contribution of MCs on vessel permeability, angiogenesis, and fibrosis in patients with TAK. Methods: MC activation and their tissue expression were assessed in sera and in aorta from patients with TAK and from healthy donors (HDs). In vivo permeability was assessed using a modified Miles assay. Subconfluent cultured human umbilic vein endothelial cells and fibroblasts were used in vitro to investigate the effects of MC mediators on angiogenesis and fibrogenesis.Results: This study found increased levels of MC activation markers (histamine and indoleamine 2,3-dioxygenase) in sera of patients with TAK compared with in sera of HDs. Marked expression of MCs was shown in aortic lesions of patients with TAK compared with in those of noninflammatory aorta controls. Using Miles assay, this study showed that sera of patients with TAK significantly increased vascular permeability in vivo as compared with that of HDs. Vessel permeability was abrogated in MC-deficient mice. MCs stimulated by sera of patients with TAK supported neoangiogenesis (increased human umbilic vein endothelial cell proliferation and branches) and fibrosis by inducing increased production of fibronectin, type 1 collagen, and a-smooth muscle actin by fibroblasts as compared to MCs stimulated by sera of HD.Conclusions: MCs are a key regulator of vascular lesions in patients with TAK and may represent a new therapeutic target in large vessel vasculitis.
Published: 2020

19. Mast cells crosstalk with B cells in the gut and sustain IgA response in the inflamed intestine

Author: Ulrich Blank, Gunilla B. Karlsson Hedestam, Gregory Gautier, Shamila Vibhushan, Francesca Mion, Claudio Tripodo, Beatrice Belmonte, Carlo Pucillo, Viviana Valeri, Monika Adori, Silvia Tonon, Alessandro Gulino, Université de Paris, Centre de Recherche sur l'Inflammation, INSERM UMR1149, CNRS ERL8252, Faculté de Médecine site Bichat, Paris, France, Université de Paris, Laboratoire d'Excellence Inflamex, Paris, France., Valeri V., Tonon S., Vibhushan S., Gulino A., Belmonte B., Adori M., Karlsson Hedestam G.B., Gautier G., Tripodo C., Blank U., Mion F., and Pucillo C.E.M.
Subjects: 0301 basic medicine, Cell type, Colon, [SDV]Life Sciences [q-bio], Immunology, Population, Inflammation, Basophil, Biology, Settore MED/08 - Anatomia Patologica, behavioral disciplines and activities, Inflammatory bowel disease, cell-to-cell interplay, colitis, IgA,innate-like B cells, mast cells, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Immunology and Allergy, Animals, Mast Cells, Colitis, Intestinal Mucosa, education, B cell, ComputingMilieux_MISCELLANEOUS, education.field_of_study, B-Lymphocytes, Tumor Necrosis Factor-alpha, Dextran Sulfate, medicine.disease, Inflammatory Bowel Diseases, humanities, Innate-like B cells, Gastrointestinal Microbiome, Immunoglobulin A, Mice, Inbred C57BL, Crosstalk (biology), 030104 developmental biology, medicine.anatomical_structure, Cell-to-cell interplay, IgA, Mast cells, medicine.symptom, 030215 immunology
Abstract: B lymphocytes are among the cell types whose effector functions are modulated by mast cells (MCs). The B/MC crosstalk emerged in several pathological settings, notably the colon of inflammatory bowel disease (IBD) patients is a privileged site in which MCs and IgA+ cells physically interact. Herein, by inducing conditional depletion of MCs in red MC and basophil (RMB) mice, we show that MCs control B cell distribution in the gut and IgA serum levels. Moreover, in dextran sulfate sodium (DSS)-treated RMB mice, the presence of MCs is fundamental for the enlargement of the IgA+ population in the bowel and the increase of systemic IgA production. Since both conventional B-2 and peritoneal-derived B cells populate the intestine and communicate with MCs in physiological conditions and during inflammation, we further explored this interplay through the use of co-cultures. We show that MCs finely regulate different aspects of splenic B cell biology while peritoneal B cells are unresponsive to the supporting effects provided by MCs. Interestingly, peritoneal B cells induce a pro-inflammatory skewing in MCs, characterized by increased ST2 and TNF-α expression. Altogether, this study uncovers the versatility of the B/MC liaison and highlights key aspects for the resolution of intestinal inflammation.
Published: 2020

20. HLA–B27 Subtypes Predisposing to Ankylosing Spondylitis Accumulate in an Endoplasmic Reticulum–Derived Compartment Apart From the Peptide-Loading Complex

Author: Claudine André, Gilles Chiocchia, Aurélie Noteuil, Aude Jobart-Malfait, Maxime Breban, Ketia Ermoza, Nadège Jah, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), Hôpital Ambroise Paré [AP-HP], ING20130526783/Fondation pour la Recherche Médicale (FRM), Institut National de la Recherche Agronomique, INRA, Société Française de Rhumatologie, We thank personnel of the Flow Cytometry and Cellular Imaging Facility, UVSQ, UFR Sant?-Simone Veil (Montigny-le-Bretonneux, France) for technical assistance. We are also grateful to Dr. Simon Powis, School of Medicine, University of St Andrews (St Andrews, UK) for providing us with rabbit anti-tapasin antibody. This work benefited from the facilities and expertise at Microscopie et Imagerie des Micro-organismes Animaux Aliments?Microscope Electronique ? Transmission, Animal Genetics and Integrative Biology, National Institute for Agricultural Research, AgroParisTech (Jouy-en-Josas, France). We also thank personnel of the Biological Resources Center of Cochin Hospital (Paris, France) for the production of the human lymphoblastoid B cell lines., and HAL UVSQ, Équipe
Subjects: Protein Folding, Intravital Microscopy, Calnexin, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 0302 clinical medicine, Immunology and Allergy, chaperone, HLA-B27 Antigen, β2-microglobulin, 0303 health sciences, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Microscopy, Confocal, biology, Chemistry, Vesicle, intracellular vesicles, Transfection, spondyloarthritis, endoplasmic reticulum, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Rats, Transgenic, musculoskeletal diseases, Immunology, Blotting, Western, Protein Disulfide-Isomerases, Major histocompatibility complex, 03 medical and health sciences, Rheumatology, ankylosing spondylitis, Animals, Humans, Genetic Predisposition to Disease, HSP70 Heat-Shock Proteins, Spondylitis, Ankylosing, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, 030304 developmental biology, HLA-B27, Endoplasmic reticulum, Cytoplasmic Vesicles, Colocalization, Membrane Proteins, Dendritic Cells, Molecular biology, Rats, Microscopy, Electron, Microscopy, Fluorescence, Chaperone (protein), biology.protein, MHC, Calreticulin, beta 2-Microglobulin, 030215 immunology, HeLa Cells, Molecular Chaperones
Abstract: International audience; Objective: It was previously shown that HLA–B27 subtypes predisposing to spondyloarthritis (SpA), i.e., B*27:02, B*27:05, and B*27:07, displayed an increased propensity to form intracellular oligomers and to accumulate at a high density in cytoplasmic vesicles, as compared to the non–SpA-associated HLA–B*07:02 and HLA–B*27:06. This study was undertaken to characterize the nature and content of HLA–B–containing vesicles and to further examine their relevance to SpA predisposition. Methods: Vesicles containing HLA–B proteins were detected in transfected HeLa cells and in cells from SpA patients or HLA–B27/human β2-microglobulin (hβ2m)–transgenic rats, by microscopy. The nature and content of HLA–B–containing vesicles were characterized in colocalization experiments with appropriate markers. Results: The SpA-associated HLA–B*27:04 subtype accumulated at higher levels (P < 10−5) in cytoplasmic vesicles compared to HLA–B*27:06, from which it differs only by 2 substitutions, reinforcing the correlation between vesicle formation and SpA predisposition. Colocalization studies showed that those vesicles contained misfolded HLA–B heavy chain along with β2m and endoplasmic reticulum (ER) chaperones (calnexin, calreticulin, BiP, glucose-regulated protein 94-kd) and belonged to the ER but were distinct from the peptide-loading complex (PLC). Similar vesicles were observed in immune cells from HLA–B27+ SpA patients, in greater abundance than in healthy controls (P < 0.01), and in dendritic cells from HLA–B27/hβ2m transgenic rats, correlating with SpA susceptibility. Conclusion: Accumulation of misfolded HLA–B heavy chain along with β2m and ER chaperones into ER-derived vesicles distinct from the PLC is a characteristic feature of HLA–B27 subtypes predisposing to SpA. This phenomenon could contribute to HLA–B27 pathogenicity, via a noncanonical mechanism.
Published: 2020

21. Mucosal-associated invariant T cells promote inflammation and intestinal dysbiosis leading to metabolic dysfunction during obesity

Author: Toubal, Amine, Kiaf, Badr, Beaudoin, Lucie, Cagninacci, Lucie, Rhimi, Moez, Fruchet, Blandine, da Silva, Jennifer, Corbett, Alexandra J., Simoni, Yannick, Lantz, Olivier, Rossjohn, Jamie, McCluskey, James, Lesnik, Philippe, Maguin, Emmanuelle, Lehuen, Agnès, Bodescot, Myriam, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Appel à projets générique - Rôle des cellules T invariantes associées aux muqueuses (MAIT) dans l'obésité chez l'homme et dans les modèles murins - - OBEMAIT2014 - ANR-14-CE12-0018 - Appel à projets générique - VALID, Compréhension des mécanismes inflammatoires protecteurs dans le diabète - - PROVIDE2015 - ANR-15-CE14-0029 - AAPG2015 - VALID, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Melbourne, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Monash University [Clayton], Cardiff University, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratory of Excellence INFLAMEX RHU QUID-NASH Fondation pour la Recherche Médicale EQU201903007779project CMCU-PHC Utique 14G0816Campus France 30666QMSociété Francophone de Diabétologie Fondation Francophone pour la Recherche sur le Diabète European Science Foundation (ESF), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), ANR-14-CE12-0018,OBEMAIT,Rôle des cellules T invariantes associées aux muqueuses (MAIT) dans l'obésité chez l'homme et dans les modèles murins(2014), ANR-15-CE14-0029,PROVIDE,Compréhension des mécanismes inflammatoires protecteurs dans le diabète(2015), Microbiota Interaction with Human and Animal (MIHA), Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: EXPRESSION, HIGH-FAT DIET, Science, [SDV]Life Sciences [q-bio], Receptors, Antigen, T-Cell, Diet, High-Fat, Ligands, Article, Mucosal-Associated Invariant T Cells, Mice, Ileum, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, Lymphocyte Count, Intestinal Mucosa, MACROPHAGES, lcsh:Science, Monocytes and macrophages, Inflammation, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, INSULIN-RESISTANCE, [SDV.BA]Life Sciences [q-bio]/Animal biology, GUT MICROBIOTA, MR1, Type 2 diabetes, Chronic inflammation, Glucose Tolerance Test, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Magnetic Resonance Imaging, Gastrointestinal Microbiome, Pterins, Intestines, Mice, Inbred C57BL, RECEPTOR HETEROGENEITY, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Phenotype, ADIPOSE-TISSUE, Adipose Tissue, IMMUNE CELLS, Mucosal immunology, Cytokines, Dysbiosis, lcsh:Q, PPAR-GAMMA
Abstract: Obesity is associated with low-grade chronic inflammation promoting insulin-resistance and diabetes. Gut microbiota dysbiosis is a consequence as well as a driver of obesity and diabetes. Mucosal-associated invariant T cells (MAIT) are innate-like T cells expressing a semi-invariant T cell receptor restricted to the non-classical MHC class I molecule MR1 presenting bacterial ligands. Here we show that during obesity MAIT cells promote inflammation in both adipose tissue and ileum, leading to insulin resistance and impaired glucose and lipid metabolism. MAIT cells act in adipose tissue by inducing M1 macrophage polarization in an MR1-dependent manner and in the gut by inducing microbiota dysbiosis and loss of gut integrity. Both MAIT cell-induced tissue alterations contribute to metabolic dysfunction. Treatment with MAIT cell inhibitory ligand demonstrates its potential as a strategy against inflammation, dysbiosis and metabolic disorders., Inflammation, immune cells and the host microbiota are intimately linked in the pathophysiology of obesity and diabetes. Here the authors show mucosal-associated invariant T cells fuel inflammation in the tissues and serve a function in promoting metabolic breakdown, polarising macrophage populations and inducing dysbiosis of the intestinal microbiota.
Published: 2020

22. The Modulation of NADPH Oxidase Activity in Human Neutrophils by Moroccan Strains of Leishmania major and Leishmania tropica Is Not Associated with p47phox Phosphorylation

Author: Myriam Riyad, Dounia Darif, Christophe Desterke, Jérôme Estaquier, Hasnaa Maksouri, Khadija Akarid, Meryem Lemrani, Pham My-Chan Dang, University Hassan II [Casablanca], Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Laval [Québec] (ULaval), Université Paris-Saclay, Institut Pasteur du Maroc, Réseau International des Instituts Pasteur (RIIP), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), DANG, Pham My-Chan, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: 0301 basic medicine, Microbiology (medical), Leishmania tropica, Phagocyte, QH301-705.5, 030231 tropical medicine, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Microbiology, Leishmania, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, neutrophils, NADPH oxidase complex, Virology, parasitic diseases, medicine, Leishmania major, Biology (General), [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, NADPH oxidase, biology, Superoxide, ROS, biology.organism_classification, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, chemistry, biology.protein, Phosphorylation, p47phox, p47 phox
Abstract: Polymorphonuclear neutrophils (PMNs) are the first phagocyte recruited and infected by Leishmania. They synthetize superoxide anions (O2−) under the control of the NADPH oxidase complex. In Morocco, Leishmania major and L. tropica are the main species responsible for cutaneous leishmaniasis (CL). The impact of these parasites on human PMN functions is still unclear. We evaluated the in vitro capacity of primary Moroccan strains of L. major and L. tropica to modulate PMN O2− production and p47phox phosphorylation status of the NADPH oxidase complex. PMNs were isolated from healthy blood donors, and their infection rate was measured by microscopy. O2− production was measured by superoxide dismutase–inhibitable reduction of cytochrome C. P47phox phosphorylation was analyzed by Western blot using specific antibodies against Ser328 and Ser345 sites. Whereas we did not observe any difference in PMN infectivity rate, our results indicated that only L. tropica promastigotes inhibited both fMLF- and PMA-mediated O2− production independently of p47phox phosphorylation. Leishmania soluble antigens (SLAs) from both species significantly inhibited O2− induced by fMLF or PMA. However, they only decreased PMA-induced p47phox phosphorylation. L. major and L. tropica modulated differently O2− production by human PMNs independently of p47phox phosphorylation. The inhibition of ROS production by L. tropica could be a mechanism of its survival within PMNs that might explain the reported chronic pathogenicity of L. tropica CL.
Published: 2021

23. Le fardeau des spondyloarthrites graves en France : évaluation de la prévalence, des comorbidités et des coûts à l’échelle nationale

Author: Julie Gourmelen, Pascal Claudepierre, Thibault de Chalus, Maxime Breban, Francis Fagnani, G. Cukierman, Caroline Laurendeau, Jean-Michel Joubert, Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Cemka-eval [Bourg La Reine], UCB Pharma, Colombes, Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Ambroise Paré [AP-HP], Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP)
Subjects: 030203 arthritis & rheumatology, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, [SDV]Life Sciences [q-bio], Spondylarthrite ankylosante, Échantillon généraliste des bénéficiaires, Coûts directs, 030212 general & internal medicine, Poids de la maladie, Spondyloarthrite
Abstract: Resume Objectifs Estimer le nombre de patients presentant une spondyolarthrite (SpA) grave en France, decrire leurs comorbidites et consigner et valoriser leur consommation de soins. Methodes Les donnees ont ete extraites de l’Echantillon generaliste des beneficiaires qui couvre 1/97e des personnes couvertes par l’assurance maladie en France. Tous les patients beneficiant d’une prise en charge a 100 % (ALD, affection de longue duree) au titre d’une SpA grave en 2012 (y compris ceux presentant des dommages structuraux et/ou des poussees frequentes) ont ete identifies et un groupe temoin apparie par frequence selon l’âge et le sexe a ete selectionne. Les comorbidites severes ont ete documentees selon les categories de l’ALD. La consommation de soins a ete consignee et valorisee du point de vue de l’organisme payeur. Les taux de comorbidites et les couts ont ete compares entre les patients atteints de SpA et les temoins par une methode de test non parametrique. Resultats Au total, 827 patients admis en ALD au titre d’une SpA grave ont ete identifies (groupe temoin n = 2 481), soit un taux de prevalence de la SpA en ALD de 0,18 % [0,17–0,19] dans la population generale. Les comorbidites severes plus frequentes chez les patients atteints de SpA que chez les temoins comprenaient : maladies inflammatoires chroniques de l’intestin (Odds Ratio 15,0 [2,2–6,6–36], hypertension (2,5 [1,6–3,9]), fibrillation auriculaire (4,3 [1,6,9]) et trouble depressif majeur (2,1 [1,3,6]). La depense de sante directe moyenne annuelle per capita etait 3,6 [1–3,3,4] fois plus elevee chez les patients atteints de SpA (6122 € [5838–6406]) que chez les temoins (1682 € [1566–1798]). L’extrapolation de ces chiffres a l’ensemble des patients en France aboutit a un cout total de soins attribuables aux SpA graves de 391 millions € [355–426], dont 53,8 % pour les medicaments. Conclusions Le fardeau considerable des spondyloarthrites graves en France resulte de la forte prevalence de cette maladie, des couts directs eleves et des comorbidites associees.
Published: 2019

24. Heme oxygenase-1—Dependent anti-inflammatory effects of atorvastatin in zymosan-injected subcutaneous air pouch in mice

Author: Bassam Badran, Eva Hamade, May F. Mrad, Charbel A. Mouawad, Aida Habib, Ayad A. Jaffa, Ghewa A. El-Achkar, Roberto Motterlini, Department of Biochemistry and Molecular Genetics [Beyrouth, Liban], American University of Beirut [Beyrouth] (AUB), Équipe 12 [Créteil], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Nehme and Therese Tohme Multiple Sclerosis Center [Beyrouth, Liban] (AUBMC), American University of Beirut Medical Center [Beyrouth, Liban] (AUBMC), American University of Beirut [Beyrouth] (AUB)-American University of Beirut [Beyrouth] (AUB), Laboratory of Cancer Biology and Molecular Immunology [Beyrouth, Liban], Lebanese University [Beirut] (LU), Laboratoire d'Excellence Inflamex [Paris], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), This study has been funded with supports from the National Council for Scientific Research in Lebanon (to AH and EH, 02-05-16), the Medical Practice Plan (MPP to AH), the Faculty of Medicine of the American University of Beirut (to AH), the Ecole Doctorale Des Sciences et Technologie of the Lebanese University (to E.H.), INSERM (To RM), the Université Paris-Est Créteil (to RM)., Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Bodescot, Myriam
Subjects: 0301 basic medicine, Chemokine, Physiology, Atorvastatin, Gene Expression, Pharmacology, Pathology and Laboratory Medicine, Biochemistry, chemistry.chemical_compound, White Blood Cells, 0302 clinical medicine, Spectrum Analysis Techniques, Animal Cells, Immune Physiology, Medicine and Health Sciences, Post-Translational Modification, Immune Response, Innate Immune System, Multidisciplinary, biology, Drugs, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Flow Cytometry, 3. Good health, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, medicine.anatomical_structure, Spectrophotometry, 030220 oncology & carcinogenesis, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Cytophotometry, medicine.symptom, Cellular Types, Mannose receptor, medicine.drug, Research Article, [SDV.IMM] Life Sciences [q-bio]/Immunology, Science, Immune Cells, Immunology, Inflammation, Heme, Research and Analysis Methods, Proinflammatory cytokine, 03 medical and health sciences, Signs and Symptoms, Diagnostic Medicine, medicine, Genetics, Blood Cells, Monocyte, Macrophages, Zymosan, Statins, Biology and Life Sciences, Proteins, Cell Biology, Molecular Development, Heme oxygenase, 030104 developmental biology, chemistry, Immune System, biology.protein, Developmental Biology
Abstract: International audience; Statins exert pleiotropic and beneficial anti-inflammatory and antioxidant effects. We have previously reported that macrophages treated with statins increased the expression of heme oxygenase-1 (HO-1), an inducible anti-inflammatory and cytoprotective stress protein, responsible for the degradation of heme. In the present study, we investigated the effects of atorvastatin on inflammation in mice and analyzed its mechanism of action in vivo. Air pouches were established in 8 week-old female C57BL/6J mice. Atorvastatin (5 mg/kg, i.p.) and/or tin protoporphyrin IX (SnPPIX), a heme oxygenase inhibitor (12 mg/kg, i.p.), were administered for 10 days. Zymosan, a cell wall component of Saccharomyces cerevisiae, was injected in the air pouch to trigger inflammation. Cell number and levels of inflammatory markers were determined in exudates collected from the pouch 24 hours post zymosan injection by flow cytometry, ELISA and quantitative PCR. Analysis of the mice treated with atorvastatin alone displayed increased expression of HO-1, arginase-1, C-type lectin domain containing 7A, and mannose receptor C-type 1 in the cells of the exudate of the air pouch. Flow cytometry analysis revealed an increase in monocyte/macrophage cells expressing HO-1 and in leukocytes expressing MRC-1 in response to atorvastatin. Mice treated with atorvastatin showed a significant reduction in cell influx in response to zymosan, and in the expression of proinflammatory cytokines and chemokines such as interleukin-1α, monocyte chemoattractant protein-1 and prostaglandin E2. Co-treatment of mice with atorvastatin and tin protoporphyrin IX (SnPPIX), an inhibitor of heme oxygenase, reversed the inhibitory effect of statin on cell influx and proinflammatory markers, suggesting a protective role of HO-1. Flow cytometry analysis of air pouch cell contents revealed prevalence of neutrophils and to a lesser extent of monocytes/macrophages with no significant effect of atorvastatin treatment on the modification of their relative proportion. These findings identify HO-1 as a target for the therapeutic actions of atorvastatin and highlight its potential role as an in vivo anti-inflammatory agent.
Published: 2019

25. Mucosal-associated invariant T cells and disease

Author: Toubal, Amine, Nel, Isabelle, Lotersztajn, Sophie, Lehuen, Agnès, Lehuen, Agnès, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Excellence Inflamex [Paris], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The authors are grateful to U. Rogner for critical reading of the manuscript. This work was supported by grants from INSERM, CNRS, Laboratoire d’Excellence consortium Inflamex (grant number ANR-11-IDEX-0005-02) and the Fondation pour la Recherche Médicale (FRM grant numbers DEQ20140329520, to A.L., and DEQ20150331726, to S.L.), EFSD/JDRF/Lilly and EFSD/Lilly (to A.L. and A.T.), Fondation Francophone pour la recherche sur le Diabète (to A.L.), an Aide aux Jeunes Diabétiques fellowship to I.N., and Agence Nationale de la Recherche (ANR OBEMAIT, Provide and Diab1MAIT grants to A.L.)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: [SDV] Life Sciences [q-bio], [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract: International audience; Mucosal-associated invariant T (MAIT) cells are unique innate-like T cells that bridge innate and adaptive immunity. They are activated by conserved bacterial ligands derived from vitamin B biosynthesis and have important roles in defence against bacterial and viral infections. However, they can also have various deleterious and protective functions in autoimmune, inflammatory and metabolic diseases. MAIT cell involvement in a large spectrum of pathological conditions makes them attractive targets for potential therapeutic approaches.
Published: 2019

26. Penetration of the Human Pulmonary Epithelium by Aspergillus fumigatus Hyphae

Author: Rémi Beau, Pierre Mordant, Julien Fernandes, Marina Pretolani, Fatima Hamidi, Amira Boukkerou, Remi Leborgne, Yves Castier, Jean-Paul Latgé, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), Fibrose Inflammation Remodelage [Hôpitaux Universitaires Paris Nord Val de Seine] (DHU FIRE ), Hôpitaux Universitaires Paris Nord Val de Seine, ImagoSeine, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Aspergillus, Institut Pasteur [Paris], Service de Chirurgie Thoracique et Vasculaire [Hôpital Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was funded by grant 'Aspergillus' from Sanofi-Aviesan. The ImagoSeine facility at the Jacques Monod Institute (Paris, France) is supported by the French National Research Agency (ANR-10-INBS-04), 'Investments for the Future' program. The PBI-C2RT, Institut Pasteur (Paris, France) is supported by the French National Research Agency (ANR-10-INBS-04-01 and ANR-11-IDEX-0005-02)., We are grateful to the ImagoSeine facility at the Jacques Monod Institute (Paris), the PBI-CITech, Institut Pasteur (Paris), the Cellular and Tissue imaging plateform of the CRI (Inflammation Research Center), and the Investissement d’Avenir - Program, Laboratoire d’Excellence, INFLAMEX. We also thank Pascal Roux (Imagopole-CITech, Institut Pasteur) for his precious advice and VK Aimanianda and Ian Hooper for a careful revision of this manuscript., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Fernandes, Julien, Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)
Subjects: 0301 basic medicine, Hypha, Cell Culture Techniques, Hyphae, Aspergillosis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Microbiology, Aspergillus fumigatus, Conidium, lung, 03 medical and health sciences, Microscopy, Electron, Transmission, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, A fumigatus, medicine, Humans, Immunology and Allergy, aspergillosis, skin and connective tissue diseases, Cells, Cultured, Actin, ComputingMilieux_MISCELLANEOUS, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Microscopy, Confocal, Lung, biology, Chemistry, fungi, Epithelial Cells, respiratory system, medicine.disease, biology.organism_classification, [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Epithelium, 3. Good health, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, mycology, Respiratory epithelium, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, epithelium
Abstract: Background The airway epithelium is the first barrier interacting with Aspergillus fumigatus conidia after their inhalation, suggesting that this structure functions as point of entry of this fungus to initiate pulmonary aspergillosis. Methods To study epithelial entry by A fumigatus, primary human reconstituted pseudostratified epithelium cultured in air-liquid interface as well as bronchial epithelial cell monolayers were infected with conidia. Results Under these experimental conditions, we found that A fumigatus hyphae traversed the bronchial epithelium through a mechanism involving the recruitment of actin, which formed a tunnel that allows hyphae to enter the cells without disturbing their integrity. Conclusions These findings describe a new mechanism by which A fumigatus hyphae penetrate the airway epithelial barrier and can infect its human host.
Published: 2018

27. TLR4 Receptor Induces 2-AG-Dependent Tolerance to Lipopolysaccharide and Trafficking of CB2 Receptor in Mast Cells

Author: Ulrich Blank, Alfredo Ibarra-Sánchez, Manuela Bratti, Claudia González-Espinosa, Nicolas Charles, Zyanya P Espinosa-Riquer, Shamila Vibhushan, Gabriela Rodríguez-Manzo, Departamento de Farmacobiología [Mexico City, Mexico], Centro de Investigación y de Estudios Avanzados [Mexico City, Mexico], Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Excellence Inflamex [Paris] (Faculté de Médecine Xavier Bichat), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (COMUE) (USPC), This work was supported by the Consejo Nacional de Ciencia y Tecnologia-Agence Nationale de la Recherche (Conacyt-ANR) Grant 188565 (to C.G.-E. and U.B.), Conacyt Grant FC-1122 (to C.G.-E.), and Conacyt Grant 220772 (to G.R.-M.). Z.P.E.-R. received a scholarship from Conacyt (277991) for Ph.D. studies. Conacyt-ANR Grant 188565 and Conacyt Grant 291212 supported an academic exchange period for Z.P.E.-R. at the Université Paris VII., and Blank, Ulrich
Subjects: Lipopolysaccharides, [SDV.IMM] Life Sciences [q-bio]/Immunology, Lipopolysaccharide, medicine.medical_treatment, Immunology, Arachidonic Acids, Glycerides, Receptor, Cannabinoid, CB2, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Lysosomal-Associated Membrane Protein 2, medicine, Cannabinoid receptor type 2, Immune Tolerance, Immunology and Allergy, Animals, Secretion, Mast Cells, Receptor, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Innate immune system, Chemistry, Transcription Factor RelA, rab7 GTP-Binding Proteins, Endocannabinoid system, Cell biology, Toll-Like Receptor 4, Protein Transport, rab GTP-Binding Proteins, TLR4, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), Cannabinoid, 030215 immunology, Endocannabinoids
Abstract: Mast cells (MCs) contribute to the control of local inflammatory reactions and become hyporesponsive after prolonged TLR4 activation by bacterial LPS. The molecular mechanisms involved in endotoxin tolerance (ET) induction in MCs are not fully understood. In this study, we demonstrate that the endocannabinoid 2-arachidonoylglycerol (2-AG) and its receptor, cannabinoid receptor 2 (CB2), play a role in the establishment of ET in bone marrow–derived MCs from C57BL/6J mice. We found that CB2 antagonism prevented the development of ET and that bone marrow–derived MCs produce 2-AG in a TLR4-dependent fashion. Exogenous 2-AG induced ET similarly to LPS, blocking the phosphorylation of IKK and the p65 subunit of NF-κB and inducing the synthesis of molecular markers of ET. LPS caused CB2 receptor trafficking in Rab11-, Rab7-, and Lamp2-positive vesicles, indicating recycling and degradation of the receptor. 2-AG also prevented LPS-induced TNF secretion in vivo, in a MC-dependent model of endotoxemia, demonstrating that TLR4 engagement leads to 2-AG secretion, which contributes to the negative control of MCs activation. Our study uncovers a functional role for the endocannabinoid system in the inhibition of MC-dependent innate immune responses in vivo.
Published: 2018

28. Tomosyn functions as a PKCδ-regulated fusion clamp in mast cell degranulation

Author: Marc Benhamou, Luca Danelli, Nicolas Charles, Joana Vitte, Claudia González-Espinosa, C. Agabriel, Emeline Pacreau, C. Klingebiel, Gaël Ménasché, Marina Macías-Silva, Bárbara Dema, Iris K. Madera-Salcedo, Joëlle Birnbaum, V. Liabeuf, Neeraj Tiwari, Ulrich Blank, Shamila Vibhushan, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Excellence Inflamex [Paris] (Faculté de Médecine Xavier Bichat), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (COMUE) (USPC), Service de dermatologie, vénéreologie et cancérologie cutanée [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire BIOPLUS [Marseille, France], Normal and pathological homeostasis of the immune system (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Instituto de Fisiología Celular [México City, México], Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Departamento de Farmacobiología [Mexico City, Mexico], Centro de Investigación y de Estudios Avanzados [Mexico City, Mexico], Adhésion et Inflammation (LAI), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d’Immunologie [Hôpital La Timone - APHM] (IHU Méditerranée Infection), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), This research project has been supported by the Investissements d’Avenir program (ANR-11-IDEX-0005-02), Sorbonne Paris Cite, and Laboratoire d’Excellence INFLAMEX and by an International Collaboration Grant between Agence Nationale de la Recherche (ANR) France (ANR-12-ISV3-0006-01) to U.B. and Conacyt Mexico (Conacyt-ANR 188565) to C.G.-E. and M.M.-S. The research project has also received funding from the Société Française d’Allergologie 2014 (to U.B.) and 2016 (to G.M.)., ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Blank, Ulrich, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Universidad Nacional Autónoma de México (UNAM), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Microbes évolution phylogénie et infections (MEPHI), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU), and Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, [SDV.IMM] Life Sciences [q-bio]/Immunology, Nerve Tissue Proteins, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Immunoglobulin E, Biochemistry, Cell Degranulation, Exocytosis, R-SNARE Proteins, 03 medical and health sciences, Mice, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Animals, Humans, Mast Cells, Phosphorylation, Receptor, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Cells, Cultured, Retrospective Studies, biology, Chemistry, Kinase, SNARE binding, Qa-SNARE Proteins, Receptors, IgE, Degranulation, Lipid bilayer fusion, Cell Biology, Cell biology, Rats, Vesicular transport protein, Mice, Inbred C57BL, Protein Kinase C-delta, 030104 developmental biology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, 030217 neurology & neurosurgery
Abstract: International audience; Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) family proteins mediate membrane fusion critical for vesicular transport and cellular secretion. Mast cells rely on SNARE-mediated membrane fusion for degranulation stimulated by crosslinking of immunoglobulin E (IgE) bound to the Fcε receptor (FcεRI). We investigated the mechanisms downstream of receptor activation that control degranulation. We found that the SNARE binding protein tomosyn-1 (also known as STXBP5) inhibited FcεRI-stimulated degranulation of mast cells. After mast cell activation, tomosyn-1 was phosphorylated on serine and threonine residues, dissociated from the SNARE protein syntaxin 4 (STX4), and associated with STX3. We identified PKCδ as the major kinase required for tomosyn-1 threonine phosphorylation and for regulation of the interaction with STXs. Incubation with high IgE concentrations increased tomosyn-1 abundance in cultured mast cells. Similarly, in basophils from allergic patients with high amounts of serum IgE, the abundance of tomosyn-1 was increased as compared to that in patients with normal IgE concentrations. Our findings identified tomosyn-1 as an inhibitor of mast cell degranulation that required PKCδ to switch its interaction with STX partners during fusion. We suggest that the IgE-mediated increase in tomosyn-1 abundance in allergic patients may represent a counterregulatory mechanism to limit disease development.Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Published: 2018

29. Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver

Author: Hegde, Pushpa, Weiss, Emmanuel, Paradis, Valérie, Wan, Jinghong, Mabire, Morgane, Sukriti, Sukriti, Rautou, Pierre-Emmanuel, Albuquerque, Miguel, Picq, Olivia, Gupta, Abhishak Chandra, Ferrere, Gladys, Gilgenkrantz, Hélène, Kiaf, Badr, Toubal, Amine, Beaudoin, Lucie, Lettéron, Philippe, Moreau, Richard, Lehuen, Agnès, Lotersztajn, Sophie, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Excellence Inflamex [Paris] (Faculté de Médecine Xavier Bichat), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (COMUE) (USPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Département d'Anesthésie et Réanimation [Hôpital Beaujon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Pathologie [Hôpital Beaujon], Service d'hépatologie [Hôpital Beaujon], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Lehuen, Agnès
Subjects: Adult, Liver Cirrhosis, Male, [SDV.IMM] Life Sciences [q-bio]/Immunology, Macrophages, Science, Cell Count, Middle Aged, Article, Coculture Techniques, Mucosal-Associated Invariant T Cells, Mice, Liver, Non-alcoholic Fatty Liver Disease, Animals, Humans, [SDV.IMM]Life Sciences [q-bio]/Immunology, lcsh:Q, Female, lcsh:Science, Cells, Cultured, Aged
Abstract: Liver fibrosis is the common response to chronic liver injury, and leads to cirrhosis and its complications. Persistent inflammation is a driving force of liver fibrosis progression. Mucosal-associated invariant T (MAIT) cells are non-conventional T cells that display altered functions during chronic inflammatory diseases. Here, we show that circulating MAIT cells are reduced in patients with alcoholic or non-alcoholic fatty liver disease-related cirrhosis while they accumulate in liver fibrotic septa. Using two models of chronic liver injury, we demonstrate that MAIT cell-enriched mice show increased liver fibrosis and accumulation of hepatic fibrogenic cells, whereas MAIT cell-deficient mice are resistant. Co-culture experiments indicate that MAIT cells enhance the proinflammatory properties of monocyte-derived macrophages, and promote mitogenic and proinflammatory functions of fibrogenic cells, via distinct mechanisms. Our results highlight the profibrogenic functions of MAIT cells and suggest that targeting MAIT cells may constitute an attractive antifibrogenic strategy during chronic liver injury., Hepatic fibrosis represents the liver response to chronic injury and can lead to cirrhosis. Here the authors show that mucosal-associated invariant T cells mediate chronic inflammation and fibrogenesis in the liver by inducing a proinflammatory phenotype in macrophages and myofibroblasts and proliferation of the latter.
Published: 2018

30. Non-IgE mediated mast cell activation

Author: Ulrich Blank, Sangeeta Kumari, Yingxin Yu, Frank A. Redegeld, Nicolas Charles, Division of Pharmacology [Utrecht, The Netherlands], Utrecht University [Utrecht]-Utrecht Institute for Pharmaceutical Sciences (UIPS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire d'Excellence Inflamex [Paris] (Faculté de Médecine Xavier Bichat), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (COMUE) (USPC), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la recherche scientifique (CNRS), Paris-diderot University, Investissements d’Avenir programme, Grant/Award Number: ANR-11-IDEX-0005-02, Sorbonne Paris Cité, Laboratoire d’excellence INFLAMEX, Agence Nationale de la Recherche (ANR), Grant/Award Number: JCJC CE17 2015, Chinese Scholarship Council., ANR-11-IDEX-0005-02/10-LABX-0017,INFLAMEX,INSTITUTE OF INFLAMMATORY DISEASES(2011), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Blank, Ulrich, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Afd Pharmacology, and Pharmacology
Subjects: 0301 basic medicine, Chemokine, pattern recognition receptor, substance P, nucleotide oligomerization domain-like receptors, Fc receptor, neurotensin, Receptors, Cytoplasmic and Nuclear, Receptors, Fc, PPAR, 0302 clinical medicine, GPCR, CD81, glucocorticoid receptor, Immunology and Allergy, complement, Mast Cells, Receptor, CD48, Toll-like receptor, biology, aryl hydrocarbon receptor, alarmins, Pattern recognition receptor, retinoic acid-inducible gene-I-like receptors, Cell biology, Cellular Microenvironment, Receptors, Pattern Recognition, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, CD53, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, MAS-related GPCR, free light chain, 03 medical and health sciences, Immune system, sphingosine-1 phosphate, CD63, Animals, Humans, vitamin D receptor, CD151, endothelin receptors, Innate immune system, IL-1, neuropeptides, Immunoglobulin E, CD9, Immunity, Innate, Interleukin 33, ATP, 030104 developmental biology, biology.protein, IL-33, integrins, mast cell, 030215 immunology, CD37
Abstract: International audience; Mast cells (MCs) are innate immune cells that are scattered in tissues throughout the organism being particularly abundant at sites exposed to the environment such as the skin and mucosal surfaces. Generally known for their role in IgE-mediated allergies, they have also important functions in the maintenance of tissue integrity by constantly sensing their microenvironment for signals by inflammatory triggers that can comprise infectious agents, toxins, hormones, alarmins, metabolic states, etc. When triggered their main function is to release a whole set of inflammatory mediators, cytokines, chemokines, and lipid products. This allows them to organize the ensuing innate immune and inflammatory response in tight coordination with resident tissue cells, other rapidly recruited immune effector cells as well as the endocrine and exocrine systems of the body. To complete these tasks, MCs are endowed with a large repertoire of receptors allowing them to respond to multiple stimuli or directly interact with other cells. Here we review some of the receptors expressed on MCs (ie, receptors for Immunoglobulins, pattern recognition receptors, nuclear receptors, receptors for alarmins, and a variety of other receptors) and discuss their functional implication in the immune and inflammatory response focusing on non-IgE-mediated activation mechanisms.© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Published: 2018

31. Granulomatosis with polyangiitis (Wegener granulomatosis): A proteinase-3 driven disease?

Author: Véronique Witko-Sarsat, Nathalie Thieblemont, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), and CCSD, Accord Elsevier
Subjects: Male, 0301 basic medicine, Myeloblastin, Phagocytosis, [SDV]Life Sciences [q-bio], Inflammation, Apoptosis, Autoimmunity, medicine.disease_cause, Sensitivity and Specificity, Antibodies, Antineutrophil Cytoplasmic, 03 medical and health sciences, Proteinase-3, Drug Delivery Systems, Immune system, Rheumatology, Proteinase 3, Humans, Immunologic Factors, Medicine, cardiovascular diseases, ComputingMilieux_MISCELLANEOUS, Anti-neutrophil cytoplasmic antibody, business.industry, Neutrophil, Granulomatosis with Polyangiitis, Dendritic Cells, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Immunology, Female, medicine.symptom, business, Granulomatosis with polyangiitis
Abstract: International audience; Granulomatosis with polyangiitis (GPA, Wegener granulomatosis) is a systemic autoimmune vasculitis that affects small arteries, arterioles, and capillaries, most notably in the kidneys and lungs. In this disease, proteinase-3 (PR3), produced by neutrophils, is targeted by antineutrophil cytoplasmic antibodies (ANCA). Recent work by our group has shown how PR3 impairs the resolution of inflammation and deregulates the immune system. Normally, the clearance of activated neutrophils triggers an anti-inflammatory, pro-resolution process. In patients with GPA, however, macrophages phagocytose apoptotic neutrophils then release massive amounts of pro-inflammatory mediators, notably interleukin-1, thereby generating a pro-inflammatory microenvironment conducive to autoimmunity. This deregulation of immune processes is accompanied with activation of plasmacytoid dendritic cells and with polarization of T-helper-2 (Th2), Th9, and Th17 cells. These recent data highlight the dual role of PR3, both auto-antigenic and auto-inflammatory, thus potentially opening up new therapeutic avenues.
Published: 2018

32. Renal parenchyma impairment characterization in partial unilateral ureteral obstruction in mice with intravoxel incoherent motion-MRI

Author: Ulrich Blank, Michel Peuchmaur, Simon A. Lambert, Miguel Albuquerque, Marianne Alison, Maguelonne Pons, Liza Ali, Benjamin Leporq, Alaa El Ghoneimi, Marie-Laurence Poli Merol, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Excellence Inflamex [Paris] (Faculté de Médecine Xavier Bichat), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (COMUE) (USPC), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), RMN et optique : De la mesure au biomarqueur, Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Chirurgie pédiatrique et urologie [Hôpital Robert Debré - APHP], Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (COMUE) (USPC), Neuroprotection du Cerveau en Développement / Promoting Research Oriented Towards Early Cns Therapies (PROTECT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Radiologie Pédiatrique [AP-HP Hôpital Robert-Debré], Université Paris Diderot - Paris 7 (UPD7)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pathologie [Hôpital Beaujon - APHP], Hôpital Beaujon [AP-HP], Service de Pathologie [Hôpital Robert Debré - APHP], Sorbonne Paris Cité-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Chirurgie Pédiatrique [Reims] (CHU de Reims - American Memorial Hospital (Hôpital des enfants)), Centre Hospitalier Universitaire de Reims (CHU Reims)-American Memorial Hospital (Hôpital des enfants) [Reims], Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, and Paris‐Diderot University, French National Research Agency, Investissements d'Avenir programme, Grant/Award Number: ANR‐11‐IDEX‐0005‐02, Sorbonne Paris Cite, Laboratoire d'excellence INFLAMEX, Association des amis de l'American Memorial Hospital Reims France, Section Française d'Urologie Pédiatrique et de l'Adolescent (SFUPA), ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Blank, Ulrich, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologie pédiatrique (EA_3102), Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)-IFR02, Immunopathologie rénale, récepteurs et inflammation, and Hôpital Robert Debré
Subjects: medicine.medical_specialty, kidney, 030232 urology & nephrology, Urology, Renal function, Scintigraphy, urologic and male genital diseases, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 030218 nuclear medicine & medical imaging, Motion, 03 medical and health sciences, 0302 clinical medicine, hydronephrosis, Fibrosis, partial unilateral ureteral obstruction, Parenchyma, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Animals, Radiology, Nuclear Medicine and imaging, Hydronephrosis, ComputingMilieux_MISCELLANEOUS, Spectroscopy, Intravoxel incoherent motion, intravoxel incoherent motion, Kidney, medicine.diagnostic_test, business.industry, diffusion, medicine.disease, Magnetic Resonance Imaging, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, 3. Good health, Mice, Inbred C57BL, Perfusion, medicine.anatomical_structure, Molecular Medicine, business, Ureteral Obstruction
Abstract: International audience; Ureteropelvic junction obstruction constitutes a major cause of progressive pediatric renal disease. The biological mechanisms underlying the renal response to obstruction can be investigated using a clinically relevant mouse model of partial unilateral ureteral obstruction (pUUO). Renal function and kidney morphology data can be evaluated using renal ultrasound, scintigraphy and uro-magnetic resonance imaging (uro-MRI), but these methods are poorly linked to histological change and not all are quantitative. Here, we propose to investigate pUUO for the first time using an intravoxel incoherent motion diffusion sequence. The aim of this study was to quantitatively characterize impairment of the kidney parenchyma in the pUUO model. This quantitative MRI method was able to assess the perfusion and microstructure of the kidney without requiring the injection of a contrast agent. The results suggest that a perfusion fraction (f) reduction is associated with a decrease in the volume of the renal parenchyma, which could be related to decreased renal vascularization. The latter may occur before impairment by fibrosis and the findings are in accordance with the literature using the UUO mice model and, more specifically, on pUUO. Further investigation is required before this technique can be made available for the diagnosis and management of children with antenatal hydronephrosis and to select the optimal timing of surgery if required.Copyright © 2017 John Wiley & Sons, Ltd.
Published: 2018

33. Mast Cell Degranulation Exacerbates Skin Rejection by Enhancing Neutrophil Recruitment

Author: Ngo Nyekel, Flavie, Pacreau, Emeline, Benadda, Samira, Msallam, Rasha, Åbrink, Magnus, Pejler, Gunnar, Davoust, Jean, Benhamou, Marc, Charles, Nicolas, Launay, Pierre, Blank, Ulrich, Gautier, Gregory, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Laboratoire d'Excellence Inflamex [Paris] (Faculté de Médecine Xavier Bichat), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (COMUE) (USPC), Agency for science, technology and research [Singapore] (A*STAR), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Section of Immunology [Uppsala, Sweden] (Department of Biomedical Sciences and Veterinary Public Health), Swedish University of Agricultural Sciences (SLU)-Veterinary and Animal Science Center [Uppsala, Sweden], Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences (SLU), Department of Medical Biochemistry and Microbiology [Uppsala, Sweden], Uppsala University, This research project has been supported by the Investissements d’Avenir programme ANR-11-IDEX-0005-02, Sorbonne Paris Cite, Laboratoire d’excellence INFLAMEX. This work was also supported by a fellowship grant to Flavie Ngo Nyekel from the Fondation de la Recherche Médicale., ANR-11-IDEX-0005-02/10-LABX-0017,INFLAMEX,INSTITUTE OF INFLAMMATORY DISEASES(2011), Blank, Ulrich, Université Sorbonne Paris Cité - - USPC2011 - ANR-11-IDEX-0005 - IDEX - VALID, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and ANR-11-IDEX-0005,USPC,Université Sorbonne Paris Cité(2011)
Subjects: Graft Rejection, Mice, Knockout, degranulation, skin, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Immunology in the medical area, mast cells, Skin Transplantation, Cell Degranulation, Mice, Neutrophil Infiltration, neutrophils, Immunologi inom det medicinska området, Animals, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Original Research, transplantation
Abstract: Ulrich Blank and Gregory Gautier have contributed equally to this work.; International audience; Recent evidences indicate an important role of tissue inflammatory responses by innate immune cells in allograft acceptance and survival. Here we investigated the role of mast cells (MC) in an acute male to female skin allograft rejection model using red MC and basophil (RMB) mice enabling conditional MC depletion. Kinetic analysis showed that MCs markedly accelerate skin rejection. They induced an early inflammatory response through degranulation and boosted local synthesis of KC, MIP-2, and TNF. This enhanced early neutrophil infiltration compared to a female-female graft-associated repair response. The uncontrolled neutrophil influx accelerated rejection as antibody-mediated depletion of neutrophils delayed skin rejection. Administration of cromolyn, a MC stabilizer and to a lesser extent ketotifen, a histamine type I receptor antagonist, and absence of MCPT4 chymase also delayed graft rejection. Together our data indicate that mediators contained in secretory granules of MC promote an inflammatory response with enhanced neutrophil infiltration that accelerate graft rejection.
Published: 2018

34. IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans

Author: Alzaid, Fawaz, Lagadec, Floriane, Albuquerque, Miguel, Ballaire, Raphaëlle, Orliaguet, Lucie, Hainault, Isabelle, Blugeon, Corinne, Lemoine, Sophie, Lehuen, Agnès, Saliba, David G., Udalova, Irina A., Paradis, Valérie, Foufelle, Fabienne, Venteclef, Nicolas, sophie, lemoine, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), and University of Oxford
Subjects: Liver Cirrhosis, Male, 0301 basic medicine, Apoptosis, Inflammation, Biology, Proinflammatory cytokine, Mice, 03 medical and health sciences, Liver disease, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Nonalcoholic fatty liver disease, medicine, Animals, Humans, Macrophage, Myeloid Cells, Transaminases, Mice, Knockout, Macrophages, Bilirubin, General Medicine, Macrophage Activation, medicine.disease, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Hepatocyte, Interferon Regulatory Factors, Immunology, Hepatocytes, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, medicine.symptom, Hepatic fibrosis, IRF5, Research Article
Abstract: International audience; Hepatic fibrosis arises from inflammation in the liver initiated by resident macrophage activation and massive leukocyte accumulation. Hepatic macrophages hold a central position in maintaining homeostasis in the liver and in the pathogenesis of acute and chronic liver injury linked to fibrogenesis. Interferon regulatory factor 5 (IRF5) has recently emerged as an important proinflammatory transcription factor involved in macrophage activation under acute and chronic inflammation. Here, we revealed that IRF5 is significantly induced in liver macrophages from human subjects developing liver fibrosis from nonalcoholic fatty liver disease or hepatitis C virus infection. Furthermore, IRF5 expression positively correlated with clinical markers of liver damage, such as plasma transaminase and bilirubin levels. Interestingly, mice lacking IRF5 in myeloid cells (MKO) were protected from hepatic fibrosis induced by metabolic or toxic stresses. Transcriptional reprogramming of macrophages lacking IRF5 was characterized by immunosuppressive and antiapoptotic properties. Consequently, IRF5 MKO mice respond to hepatocellular stress by promoting hepatocyte survival, leading to complete protection from hepatic fibrogenesis. Our findings reveal a regulatory network, governed by IRF5, that mediates hepatocyte death and liver fibrosis in mice and humans. Therefore, modulating IRF5 function may be an attractive approach to experimental therapeutics in fibroinflammatory liver disease.
Published: 2016
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35. Critical Evaluation of Sinonasal Disease in 64 Adults with Primary Ciliary Dyskinesia

Author: Emilie Bequignon, Virginie Escabasse, Estelle Escudier, Marie Devars du Mayne, Bruno Crestani, Isabelle Honoré, Laurence Bassinet, Jean-François Papon, Françoise Zerah-Lancner, Marie Legendre, Laurence Dupuy, Bernard Maitre, André Coste, Groupe Henri Mondor-Albert Chenevier, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, CHI Créteil, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biomécanique & Appareil Respiratoire (BAR), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], DHU FIRE Centre de compétence des maladies pulmonaires rares, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Laboratoire d'Excellence INFLAMEX [Paris], Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), and Couvet, Sandrine
Subjects: medicine.medical_specialty, Meatus, Hearing loss, primary ciliary dyskinesia, lcsh:Medicine, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Gastroenterology, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, 0502 economics and business, otorhinolaryngologic diseases, otitis media with effusion, Medicine, Nasal polyps, Nose, Primary ciliary dyskinesia, Kartagener syndrome, business.industry, chronic rhinosinusitis, lcsh:R, 05 social sciences, airway mucociliary clearance, General Medicine, medicine.disease, Hypoplasia, 3. Good health, medicine.anatomical_structure, Otitis, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030228 respiratory system, Agenesis, 050211 marketing, medicine.symptom, business
Abstract: To date, no study precisely described ear, nose and throat (ENT) disease in adults with primary ciliary dyskinesia (PCD) and its relationship with ciliary function/ultrastructure. A retrospective study of standardized ENT data (exam, audiogram, sinus Computed tomography (CT), and bacteriology) was conducted in 64 adults with confirmed PCD who were followed in two ENT reference centers. Rhinorrhoea and hearing loss were the main symptoms. Symptom scores were higher in older patients. Nasal endoscopy was abnormal in all patients except one, showing nasal polyps in one-third of the patients and stagnant nasal mucus secretions in 87.5% of the patients. Sinus CT opacities were mainly incomplete and showed one-third of the patients with sinus hypoplasia and/or agenesis. Middle meatus mainly grew Haemophilus influenzae, Streptoccocus pneumoniae and Pseudomonas aeruginosa. Otitis media with effusion (OME), which is constant in childhood, was diagnosed in less than one-quarter of the patients. In two-thirds of the patients, audiogram showed hearing loss that was sensorineural in half of the patients. ENT disease severity was not correlated with ciliary function and ultrastructure, but the presence of OME was significantly associated with a forced expiratory volume (FEV1) &lt, 70%. Rhinosinusitis is the most common clinical feature of PCD in adults, while OME is less frequent. The presence of active OME in adults with PCD could be a severity marker of lung function and lead to closer monitoring.
Published: 2019

36. Immunosuppressive agents or intravenous immunoglobulin in addition to glucocorticoids in the treatment of Susac syndrome: a French national cohort study.

Author: Kachaner A, Mageau A, Goulenok T, François C, Delory N, Chauveheid MP, Louenan C, Doan S, Halimi C, Klein I, Papo T, and Sacré K
Abstract: Background: Susac syndrome is a rare disease affecting mainly young women and is characterised by an occlusive microvessel disease limited to the brain, retina, and inner ear. No randomised controlled trial has been published or declared as ongoing to investigate treatments for Susac syndrome. We aimed to compare the effect of glucocorticoids given alone or in combination with immunosuppressive agents or intravenous immunoglobulin for the prevention of relapse in patients with Susac syndrome., Methods: The Phenotypic and Etiological Characterization of Susac Syndrome-National Clinical Research Hospital Program study is a prospective national cohort study that started enrolling on Nov 29, 2011, and included all consecutive patients aged 18 years or older with Susac syndrome who were referred to the French reference centre (Department of Internal Medicine, Bichat-Claude Bernard Hospital, Paris). Susac syndrome was defined by either the triad of encephalopathy with typical brain MRI abnormalities, cochleo-vestibular damage, and multiple occlusions of retinal central artery branches, or at least two of the three criteria without any alternative diagnosis. Collected data included fundoscopy, retinal angiography, audiometry, cerebrospinal fluid, brain MRI, and treatment received at diagnosis; months 1, 3, 6, and 12 after diagnosis; and then annually for 5 years or in the case of a relapse. The primary outcome was defined as the first relapse occurring within a 36-month follow-up period from the first day of treatment, characterised by new clinical symptoms or signs, and new abnormalities observed on retinal angiography, audiometry, or brain MRI, necessitating treatment intensification. There was no involvement of people with lived experience at any stage. The study is registered at ClinicalTrials.gov, NCT01481662., Findings: Between Nov 29, 2011, and Dec 2, 2022, 64 patients were included in the study, with a mean age at diagnosis of 35 years (SD 11); 41 (64%) were women and 23 (36%) were men. At diagnosis, 60 patients received glucocorticoids; 40 (63%) of 64 patients received glucocorticoids alone as a first-line therapy while 20 (31%) received glucocorticoids in combination with immunosuppressive agents or intravenous immunoglobulin. Overall, 46 (72%) of 64 patients had a first relapse with a median relapse-free survival time of 3·96 months (95% CI 2·24-16·07). Comparison of relapse-free survival showed no significant difference between the two treatment strategies (hazard ratio [HR] 1·11 [95% CI 0·56-2·17], p=0·76), compared with glucocorticoids alone as the reference group. In patients who first relapsed while treated with glucocorticoids alone, there was no significant difference in second relapse-free survival between those who did or did not receive immunosuppressive agents or intravenous immunoglobulin as a second-line therapy (HR 2·66 [95% CI 0·63-11·18], p=0·18)., Interpretation: The combination of glucocorticoids with immunosuppressive agents or intravenous immunoglobulin did not appear to reduce the risk of Susac syndrome relapse compared with glucocorticoids alone. Our findings did not support the systematic use of immunosuppressive agents in Susac syndrome., Funding: French Ministry of Health., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)
Published: 2024
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37. Rituximab and mycophenolate mofetil in interstitial lung disease (EVER-ILD): 1-year follow-up results of a randomised controlled trial.

Author: Mansy L, Caille A, Reynaud-Gaubert M, Bermudez J, Bonniaud P, Borie R, Brillet PY, Cadranel J, Court-Fortune I, Crestani B, Debray MP, Duprez M, Guillaumot A, Hirschi-Santelmo S, Israel-Biet D, Jouneau S, Juvin K, Kerjouan M, Mankikian J, Marquette CH, Naccache JM, Nunes H, Plantier L, Prevot G, Quetant S, Traclet J, Valentin V, Uzunhan Y, Wémeau-Stervinou L, Cottin V, and Marchand-Adam S
Subjects: Humans, Female, Follow-Up Studies, Male, Middle Aged, Treatment Outcome, Aged, Immunosuppressive Agents therapeutic use, Mycophenolic Acid therapeutic use, Lung Diseases, Interstitial drug therapy, Rituximab therapeutic use
Abstract: Competing Interests: Conflict of interest: R. Borie has received over the past 3 years, outside the submitted work, grants or contracts from Boehringer Ingelheim, consulting fees from Boehringer Ingelheim, Sanofi and Ferrer, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim and Sanofi, and support for attending meetings and/or travel from Boehringer Ingelheim. P. Bonniaud has received over the past 3 years, outside the submitted work, a research grant from AstraZeneca, payment or honoraria for symposia from Sanofi and AstraZeneca, support for attending medical and research meetings from AstraZeneca, Novartis, Sanofi, Boehringer and Stallergene, and personal fees for advisory boards from AstraZeneca, Novartis, Sanofi, GlaxoSmithKline and Boehringer. B. Crestani has received over the past 3 years, outside the submitted work, grants or contracts from Boehringer Ingelheim, consulting fees, payments or honoraria for lectures, presentations, manuscript writing or educational events, support for attending meetings and/or travel from AstraZeneca, BMS, Boehringer Ingelheim, GSK, Novartis, Roche, Sanofi and Chiesi; he has participated in data safety monitoring board or advisory board for BMS, Boehringer Ingelheim, Horizon and Sanofi, and is the president of the board of trustees of the Fondation du Souffle (a French charity). M-P. Debray has received over the past 3 years, outside the submitted work, payments or honoraria for lectures, presentations, manuscript writing or educational events, support for attending meetings and/or travel from Boehringer Ingelheim, GSK and Sanofi. D. Israel-Biet has received over the past 3 years, outside the submitted work, consulting fees and support for attending meetings and/or travel from Boehringer Ingelheim. V. Cottin has received over the past 3 years, outside the submitted work, an unrestricted grant (paid to institution) from Boehringer Ingelheim, consulting fees, payments or honoraria for lectures, presentations, manuscript writing or educational events, support for attending meetings and/or travel from AstraZeneca, Boehringer Ingelheim, BMS/Celgene, CSL (Behring, Vifor), Ferrer/United Therapeutics, GSK, Pliant, PureTech, RedX, Roche, Sanofi, Shionogi and Vifor; he has participated in data safety monitoring boards for Galapagos, Galecto, GSK and Molecure, and has been in an adjudication committee for Fibrogen. S. Quetant has received over the past 3 years, outside the submitted work, support for attending meetings and personal fees for advisory board work from Boehringer Ingelheim. A. Guillaumot has received over the past 3 years, outside the submitted work, honoraria for presentations from Boehringer Ingelheim and support for attending meetings and/or travel from Boehringer Ingelheim, CSL Behring and GSK. S. Hirschi-Santelmo has received over the past 3 years, outside the submitted work, grants or contracts from l'Agence de la biomédecine, honoraria for presentations or expertise from Boehringer Ingelheim, and support for attending meetings and/or travel from CSL Behring and Boehringer Ingelheim. P-Y. Brillet has received over the past 3 years, outside the submitted work, honoraria for lectures from Boehringer Ingelheim and Sanofi, and support for attending a national meeting from Boehringer Ingelheim. S. Marchand-Adam has received over the past 3 years, outside the submitted work, an unrestricted grant (paid to institution) from Boehringer Ingelheim, consulting fees from AstraZeneca and Boehringer Ingelheim, and support for attending meetings from Boehringer Ingelheim. V. Valentin, has received over the past 3 years, outside the submitted work, support for attending meetings and/or travel from Boehringer Ingelheim. Y. Uzunhan has received over the past 3 years, outside the submitted work, grants or contracts from Oxyvie, consulting fees from Boehringer Ingelheim and Pfizer, payments or honoraria for lectures, presentations, manuscript writing or educational events from Sanofi, Boehringer Ingelheim and CSL Vifor, support for attending meetings and/or travel from Oxyvie and Boehringer Ingelheim, and has participated in data safety monitoring boards or advisory boards for Boehringer Ingelheim. The remaining authors have no potential conflicts of interest to disclose.
Published: 2024
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38. Criteria and non-criteria antiphospholipid autoantibodies screening in patients with late pregnancy morbidity: A cross-sectional study.

Author: Gros C, Mageau A, Barral T, Nicaise PR, Saint-Frison MH, Bucau M, Vivier V, Ferre VM, Bourgeois-Moine A, Papo T, Goulenok T, and Sacre K
Subjects: Humans, Female, Pregnancy, Adult, Cross-Sectional Studies, Fetal Growth Retardation immunology, Fetal Growth Retardation blood, Fetal Death, Pre-Eclampsia immunology, Pre-Eclampsia blood, Pregnancy Complications immunology, Pregnancy Complications blood, Antibodies, Antiphospholipid blood, Antibodies, Antiphospholipid immunology, Antiphospholipid Syndrome immunology, Antiphospholipid Syndrome blood
Abstract: Introduction: Antiphospholipid syndrome (APS) is a cause of pregnancy morbidity. We aim to determine the frequency of criteria and non-criteria anti-phospholipid (aPL) autoantibodies in patients admitted for unexplained fetal death (UFD), pre-eclampsia (PE) and/or fetal growth restriction (FGR)., Methods: All consecutive patients with UFD, PE and/or FGR followed in the department of Obstetrics, Bichat Hospital, University of Paris, Paris, between January 2019 and December 2021 were screened. Patients with available serum stored from the index pregnancy were included. Patients with previously known APS or twin pregnancy were excluded. Testing for aPL autoantibodies included anti-cardiolipin (aCL), anti-β2GPI (aβ2GPI), anti-phosphatidylethanolamine (aPE), anti-phosphatidylserine/prothrombin (aPS/PT) IgG/IgM and anti-annexin V IgG. When available, placenta specimens were analyzed by a pathologist blinded to the aPL status. All clinical characteristics, pregnancy features, and comorbidities were extracted from electronic medical records., Results: Overall 167 (32 (28.8-35.7) years) patients with UFD (n = 28; 16.8 %), PE (n = 60; 35.9 %) and/or FGR (n = 105; 62.9 %) were screened for aPL autoantibodies. Moderate titers of aPL autoantibodies were detected in 33 (n = 33/167, 19.8 %) patients. aPL autoantibodies were non-criteria aPE IgG/IgM in most cases (n = 28/33, 84.8 %). aPS/PT IgG/IgM were found in 11 (n = 11/33, 33.3 %) cases and aCL or aβ2GP1 IgG/IgM in 4 (n = 4/33, 12.1 %). Multivariable logistic regression showed that aPL autoantibodies were mostly associated with UFD (OR 4.37 [1.72-11.20], p = 0.002), PE ≤ 34th week of gestation (3.22 [0.86-11.90], p = 0.070) and chronic deciduitis (8.03 [0.89-67.2], p = 0.060) DISCUSSION: The frequency of aPL autoantibodies, mostly aPE, is high in patients with late pregnancy morbidity and may qualify obstetrical APS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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39. Refining urine collection in mice: Development of an innovative urine collection device.

Author: Douté M, Monzali C, Nicoletti A, Caligiuri G, and Clement M
Abstract: Urine collection can be challenging in studies involving small rodents like mice, as the actual methods of collection are anxiogenic and constrain animal welfare while having high variability in the volume of urine collected. To improve the current methods and eventually reduce the impact on the well-being of mice, we developed an innovative 3D-printed urine collection device (UCD). This two-compartment UCD is shaped to fit in classical husbandry cages and allows urine collection by spontaneous urination from two mice housed in their own cage without cross-contamination while enabling potential social interactions. We used our UCD to study the evolution of urinary parameters related to renal functions in a model of antibody-mediated chronic kidney disease. Overall, we report here a time-saving and affordable method for urine collection providing a large amount of uncontaminated urine and which we believe may improve animal welfare in comparison with other methods., Competing Interests: Declaration of conflicting interestsThe authors have no conflicts of interest to declare.
Published: 2024
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40. Outcome and prognosis of isolated carotid vasculitis.

Author: Hankard A, Maalouf G, Laouni J, Espitia O, Agard C, De Boysson H, Aouba A, Sacré K, Papo T, Leroux G, Vautier M, Desbois AC, Domont F, Le Joncour A, Mirouse A, Chiche L, Skaff Y, Gaudric J, Boussouar S, Redheuil A, Bravetti M, Cacoub P, and Saadoun D
Subjects: Humans, Male, Female, Prognosis, Middle Aged, Retrospective Studies, Adult, Takayasu Arteritis diagnosis, Recurrence, Vasculitis diagnosis, Follow-Up Studies, Stroke etiology, Stroke diagnosis, Carotid Stenosis diagnosis, Disease Progression, Giant Cell Arteritis diagnosis
Abstract: Objective: To assess the prognosis and outcome of patients with isolated carotid vasculitis., Methods: We performed a retrospective multicenter study of 36 patients (median age at diagnosis was 37 [IQR 27-45] years and 11 [31 %] patients were men) with initial presentation as isolated carotid vasculitis. Study endpoints included vascular complications, relapses, and progression to large vessel vasculitis (i.e. Giant cell arteritis or Takayasu)., Results: The most frequent involvement was the left internal carotid artery (39 %), and 81 % had stenosis. After a median follow-up of 32 months [IQR 12-96], 21 (58 %) patients had a vascular event, including 31 % of new onset vascular lesions and 25 % of stroke/transient ischemic attack. Patients with stroke had less carotidynia at diagnosis (33 % vs 74 %, p = 0.046), higher significant carotid stenosis (i.e. > 50 %) (89 % vs. 30 %, p = 0.026) and higher severe carotid stenosis (i.e. >70 %) (67 % vs 19 %, p = 0.012), compared to those without stroke. Twenty (52 %) patients experienced relapses. High CRP at diagnosis was associated with relapses (p = 0.022). At the end of follow-up, 21 (58 %) patients were classified as having Takayasu arteritis, 13 (36 %) as isolated carotid vasculitis, and two (6 %) as giant cell arteritis., Conclusion: Carotid vasculitis may occur as a topographically limited lesion and is associated with significant rate of vascular complications., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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41. Sarcoidosis immunopathogenesis - a new concept of maladaptive trained immunity.

Author: Robert M, Yatim N, Sacré K, and Duffy D
Subjects: Humans, Animals, Granuloma immunology, Myeloid Cells immunology, Trained Immunity, Sarcoidosis immunology, Immunity, Innate immunology, Immunologic Memory
Abstract: Sarcoidosis is a chronic immune disease of unknown origin for which we still lack an immunological framework unifying causal agents, host factors, and natural history of disease. Here, we discuss the initial triggers of disease, and how myeloid cells drive granuloma formation and contribute to immunopathogenesis. We highlight recent advances in our understanding of innate immune memory and propose the hypothesis that maladaptive innate immune training connects previous environmental exposure to granuloma maintenance and expansion. Lastly, we consider how this hypothesis may open novel therapeutic avenues, while corticosteroids remain the front-line treatment., Competing Interests: Declaration of interests The authors have no declaration of interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Published: 2024
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42. Risk factors for severe hearing loss in Susac syndrome: A national cohort study.

Author: Peyre M, Mageau A, Henry Feugeas MC, Doan S, Halimi C, Klein I, Goulenok T, François C, Chauveheid MP, Papo T, and Sacré K
Subjects: Humans, Female, Young Adult, Adult, Cohort Studies, Prospective Studies, Immunosuppressive Agents, Risk Factors, Susac Syndrome complications, Susac Syndrome epidemiology, Susac Syndrome diagnosis, Hearing Loss epidemiology, Hearing Loss etiology
Abstract: Background: Nonreversible hearing loss (HL) is the main sequelae of Susac syndrome (SuS). We aimed to identify risk factors for HL in SuS., Methods: The CARESS study is a prospective national cohort study that started in December 2011, including all consecutive patients with SuS referred to the French reference center. The CARESS study was designed with a follow-up including fundoscopy, audiometry, and brain magnetic resonance imaging at 1, 3, 6, and 12 months after diagnosis and then annually for 5 years. The primary outcome was the occurrence at last follow-up of severe HL defined as the loss of 70 dB in at least one ear on audiometry or the need for hearing aids., Results: Thirty-six patients (female 66.7%, median age 37.5 [range 24.5-42.5] years) included in the clinical study were analyzed for the primary outcome. Thirty-three patients (91.7%) had cochleovestibular involvement at SuS diagnosis including HL >20 dB in at least one ear in 25 cases. At diagnosis, 32 (88.9%), 11 (30.6%), and 7 (19.4%) patients had received steroids, intravenous immunoglobulin, and/or immunosuppressive (IS) drugs, respectively. After a median follow-up of 51.8 [range 29.2-77.6] months, 19 patients (52.8%) experienced severe HL that occurred a median of 13 [range 1.5-29.5] months after diagnosis. Multivariable analysis showed that the odds of severe HL were lower in patients who received IS drugs at diagnosis (OR 0.15, 95% CI 0.01-1.07, p = 0.058)., Conclusions: Severe HL in SuS is associated with the absence of IS drugs given at diagnosis. Our findings support the systematic use of IS drugs in SuS., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)
Published: 2024
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43. Myeloperoxidase-specific antineutrophil cytoplasmic antibody-associated vasculitis.

Author: Arnold S, Kitching AR, Witko-Sarsat V, Wiech T, Specks U, Klapa S, Comdühr S, Stähle A, Müller A, and Lamprecht P
Subjects: Humans, Antibodies, Antineutrophil Cytoplasmic immunology, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis immunology, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis drug therapy, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis diagnosis, Peroxidase immunology
Abstract: Myeloperoxidase (MPO)-specific antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-ANCA-associated vasculitis) is one of two major ANCA-associated vasculitis variants characterised by systemic necrotising vasculitis with few or no immune deposits. MPO-ANCA-associated vasculitis predominantly affects small blood vessels and, in contrast to its counterpart proteinase 3-ANCA-associated vasculitis, is generally not associated with granulomatous inflammation. The kidneys and lungs are the most commonly affected organs. The pathogenesis of MPO-ANCA-associated vasculitis is characterised by loss of tolerance to the neutrophil enzyme MPO. This loss of tolerance leads to a chronic immunopathological response where neutrophils become both the target and effector of autoimmunity. MPO-ANCA drives neutrophil activation, leading in turn to tissue and organ damage. Clinical trials have improved the therapeutic approach to MPO-ANCA-associated vasculitis. However, there remains substantial unmet need regarding relapse frequency, toxicity of current treatment, and long-term morbidity. In this Series paper, we present the current state of research regarding pathogenesis, diagnosis, and treatment of MPO-ANCA-associated vasculitis., Competing Interests: Declarations of interest ARK reports grant support from Vifor Pharma, Visterra, and CSL; consulting fees from Visterra, Toleranzia, Variant Bio, and CSL; honoraria for lectures from Vifor Pharma; support for meeting attendance from Vifor Pharma; and is chair of the Australia and New Zealand Vasculitis Society. TW reports grant support from the German Research Society; consulting fees from Bayer, GSK, and Novartis; and has participated on advisory boards for Novartis and Eleva. US reports grant support from AstraZeneca, Bristol Myers Squibb, Genentech, GSK, NorthStar Radioisotopes, and Syneos; consulting fees from Amgen, AstraZeneca, Argenix, Boehringer Ingelheim, and Vifor Pharma; and has participated on advisory boards for AstraZeneca and Boehringer Ingelheim. PL reports grant support from the German Research Society, Federal Ministry of Education and Research, German Society for Rheumatology, John Grube Foundation, and Vifor Pharma; consulting fees from GSK and Vifor Pharma; honoraria for lectures from Bristol Myers Squibb, GSK, Janssen Pharmaceuticals, UCB, and Vifor Pharma; support for meeting attendance from Vifor Pharma; and has participated on advisory boards for GSK and Vifor Pharma. SK reports consulting fees from Galapagos; honoraria for lectures from Galapagos, Pfizer, and AbbVie; support for meeting attendance from Galapagos; and has participated on advisory boards for Galapagos. SC reports grant support from the German Research Society and support for meeting attendance from PMI Excellence Cluster. All other authors report no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Published: 2024
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44. The European Network for IgE-Mediated Autoimmunity and Autoallergy (ENIGMA) initiative.

Author: Kolkhir P, Altrichter S, Badloe FMS, Belasri H, Charles N, De Vriese S, Gutermuth J, Huygen L, Kocatürk E, Kortekaas Krohn I, Muñoz M, Moñino-Romero S, Reber LL, Scheffel J, Steinert C, Xiang YK, and Maurer M
Subjects: Humans, Autoantibodies, Immunoglobulin E, Autoimmunity, Autoimmune Diseases
Published: 2024
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45. The experience of dry mouth and screening for Sjogren's syndrome by the dentist: patient-reported experiences.

Author: Rihab B, Lina EH, Noémie ST, Jean S, and Marjolaine G
Subjects: Humans, Female, Male, Quality of Life, Cross-Sectional Studies, Dentists, Patient Reported Outcome Measures, Sjogren's Syndrome complications, Sjogren's Syndrome diagnosis, Xerostomia diagnosis, Xerostomia etiology
Abstract: Background: One of the main clinical features of Sjögren's Syndrome is oral dryness, which is associated with an increased risk of oral diseases and a lower oral life quality. Dentists have a key role to play in the Sjögren's Syndrome diagnosis and specific management. In parallel, many patients rely on patient associations, which offer opportunities for members to seek information about their disease and share their experiences. We aimed to evaluate patients experience with dry mouth and the importance of dentists in Sjögren's Syndrome diagnosis and its management., Methods: We carried out a cross-sectional survey in 2020 based on a questionnaire drafted in collaboration with clinicians specializing in Sjögren's Syndrome and patient members of a patient association. The survey consisted of 27 questions divided into the six sections: the patient's profile, their experience with dry mouth and treatments used to manage, characteristics of experienced oral-health problems, effects of dry mouth and its consequences on the quality of life, evaluation of the dentist role in the screening of Sjögren's Syndrome, and its management by the dentist. Recruitment was carried out via the patient association's newsletter, website, and social networks. Sjögren's diagnosis was self-reported., Results: One thousand four hundred fifty-eight patients fully responded to the survey. Most respondents were women over 50 and were mainly concerned with primary Sjögren's Syndrome. Overall, 86.97% of respondents reported experiencing frequent or constant dry mouth and 69.01% declared having had oral problems (candidiasis, oral pain, loss or alteration of taste, bad breath, gastro-esophageal reflux). We found a positive correlation between the frequency of dry mouth and each of these disorders and between the frequency of dry mouth and alterations in life quality dimensions. Finally, 74.9% of patients did not report having dry mouth to their dentist prior to being diagnosed with Sjögren's Syndrome and 58% had not been informed about the oral risks associated with it by their dentist and sought information themselves or from their physician., Conclusions: We confirm the significant consequences of dry mouth on oral quality of life, as well as its association with oral health problems. Sjögren's Syndrome screening by dentists should be increased, as well as prevention of the associated oral health risks., (© 2023. The Author(s).)
Published: 2023
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46. Clinical image: atypical calcification of dorsal spine.

Author: Gouze H, Carlier R, Breban M, and Felter A
Abstract: Competing Interests: Competing interests: None declared.
Published: 2023
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47. Editorial: Advances in mast cell physiology and mast cell-driven diseases.

Author: Blank U and Pucillo C
Subjects: Humans, Cell Physiological Phenomena, Mast Cells, Mastocytosis
Abstract: Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision
Published: 2023
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48. Editorial: The fundamental biology of basophils in health and disease.

Author: Pellefigues C and Karasuyama H
Subjects: Humans, Immunoglobulin E, Biology, Basophils, Urticaria
Abstract: Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision
Published: 2023
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49. Management of dental care of patients on immunosuppressive drugs for chronic immune-related inflammatory diseases: a survey of French dentists' practices.

Author: Bourgoin A, Agossa K, Seror R, Fumery M, Radoi L, and Gosset M
Subjects: Humans, Cross-Sectional Studies, Dental Care, Dentists, Immunosuppressive Agents therapeutic use, Surveys and Questionnaires, Antirheumatic Agents, Practice Patterns, Dentists'
Abstract: Objectives: The aim of the study was to provide an overview of the practices of French general dentists (GDs) and specialists (SDs) concerning the management of patients with inflammatory bowel diseases (IBDs), rheumatic inflammatory diseases (IRDs), and vasculitis on biologic disease-modifying antirheumatic drugs (bDMARDs), conventional DMARDs, or immunosuppressants (ISs)., Materials and Methods: An online national cross-sectional survey with 53 questions was developed by a multidisciplinary team including rheumatologists, gastroenterologists and dentists based on their clinical experience. It was refined following a test with nine dentists in private practice and in hospital before being disseminated to the members of French scientific societies and colleges of dentistry teachers over 3 months. Responses of general dentists versus specialists were compared with respect to their experience in managing patients with IRDs or IBDs, knowledge/training, type of invasive procedure performed, management of medical treatment, perioperative oral-care protocols, and frequency of postoperative complications after invasive dental care procedures., Result: In total, 105 practitioners fully completed the survey (participation rate 11.1%). SDs more frequently performed invasive surgical procedures and were more aware of the recommendations of learned societies than GDs. They encountered more post-operative complications for patients on bDMARDs. For both SDs and GDs, most patients were managed without stopping treatment and pre- and postoperative antibiotics were prescribed to more than 75% of patients. When medical treatment was stopped, the decision was made by the prescribing physician., Conclusion: Complications were reported more frequently by SDs when highly invasive procedures were performed on patients under active drug therapy. Certain common procedures, such as scaling and root planing, appear to be safe, regardless of treatment management. However, adapted guidelines for the practice of dentistry are needed to standardize the management of patients on bDMARDS, conventional DMARDs, or ISs., Clinical Relevance: French dentists perform a wide range of oral procedures on patients on bDMARDS, conventional DMARDs, or ISs under antibiotic coverage and antiseptic mouthwashes. SDs reported more postoperative complications after extensive invasive procedures for patients under active drug therapy, despite their greater knowledge of recommendations on how to manage such patients., (© 2023. BioMed Central Ltd., part of Springer Nature.)
Published: 2023
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50. Unexplained fetal death, pre-eclampsia and fetal growth restriction in pregnancy: Who is screened for antiphospholipid syndrome?

Author: Gros C, Barral T, Mageau A, Roland Nicaise P, Vivier V, Papo T, Bourgeois-Moine A, Goulenok T, and Sacre K
Subjects: Pregnancy, Female, Humans, Fetal Growth Retardation diagnosis, Fetal Growth Retardation etiology, Fetal Death etiology, Pregnancy Outcome, Antiphospholipid Syndrome complications, Antiphospholipid Syndrome diagnosis, Pre-Eclampsia diagnosis, Pregnancy Complications
Abstract: Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Published: 2023
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