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11 results on '"Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland]"'

1. Hydrogen Peroxide Affects Growth of S. aureus Through Downregulation of Genes Involved in Pyrimidine Biosynthesis

Author

Buvelot, Hélène, Roth, Myriam, Jaquet, Vincent, Lozkhin, Andrey, Renzoni, Adriana, Bonetti, Eve-Julie, Gaia, Nadia, Laumay, Floriane, Mollin, Michéle, Stasia, Marie-José, Schrenzel, Jacques, François, Patrice, Krause, Karl-Heinz, Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Service of Infectious Diseases [Geneva, Switzerland], Geneva University Hospital (HUG), Service of infectious diseases, Hôpitaux Universitaires de Genève (HUG), CGD Diagnosis and Research Centre (CDiReC), Centre Hospitalier Universitaire [Grenoble] (CHU), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Centre Diagnostic et Recherche sur la Granulomatose septique chronique (CDiReC), CHUGA, University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], and Centre Hospitalier Universitaire Grenoble Alpes (CHU Grenoble Alpes)

Subjects
Staphylococcus aureus, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Immunology, Down-Regulation, hydrogen peroxide, Gene Expression Regulation, Bacterial, S. aureus, pyrimidine metabolism, Pyrimidines, Bacterial Proteins, neutrophils, carA, Immunology and Allergy, Humans, Reactive Oxygen Species, Cells, Cultured, Original Research
Abstract

International audience; Reactive oxygen species (ROS) play a crucial role in the cellular defense against S. aureus , as evidenced by the importance of this pathogen in patients lacking the ROS-generating phagocyte NADPH oxidase NOX2. ROS concentrations required to kill S. aureus in vitro are much higher than those found in the phagosome. We therefore hypothesized that sublethal ROS concentrations may play a role in S. aureus gene dysregulation and investigated the in vitro transcriptomic response of S. aureus to sublethal concentrations of hydrogen peroxide (H 2 O 2 ). A striking observation of these experiments was a coordinated and massive downregulation of genes involved in pyrimidine metabolism. Using transposon insertion mutants, we demonstrated that deletion of carA , a gene involved in pyrimidine synthesis, led to a significant growth defect and to an increased sensitivity of S. aureus to added H 2 O 2 . The phenotype of the carA mutant could be reversed through supplementation with the pyrimidine precursor uracil, or with a multicopy vector encoding carA . As opposed to the impact of ROS on extracellular survival, carA deletion did not affect the intracellular survival in neutrophils. Our results raise the possibility that ROS-dependent downregulation of pyrimidine metabolism might be a survival strategy of S. aureus , allowing colonization through intracellular survival, while decreasing the risk of killing the host through dampened extracellular growth.

Published
2021

2. A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis

Author

Mahdia Benkhoucha, Mashal Claude Ahmed, Dominique Baeten, Romain Marignier, Jose Boucraut, Olivier Casez, Michael Hahne, Jean Boutonnat, Corinne Sonrier, Benoit Manfroi, Laurie Baert, Patrice N. Marche, Nathalie Sturm, Marine Tessier, Patrice H. Lalive, Romain R. Vivès, Bertrand Huard, Cyril Rivat, Catherine Ghezzi, Hans Lassmann, Pascal Schneider, Natalia Popa, Gilda Raguenez, Alexis Broisat, Hugues Lortat-Jacob, Mitra Ahmadi, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Department of Clinical Immunology and Rheumatology [Academic Medical Center, Amsterdam], University of Amsterdam [Amsterdam] (UvA), Institut de biologie structurale (IBS - UMR 5075 ), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Department of Biochemistry [Lausanne], Université de Lausanne (UNIL), University of Vienna [Vienna], Department of Clinical Neurosciences [Geneva, Switzerland], Unit of Neuroimmunology and Neuromuscular Diseases [Geneva, Switzerland] (Division of Neurology), Geneva University Hospitals - HUG [Switzerland]-Geneva University Hospitals - HUG [Switzerland], This work was supported by Grenoble Alpes University (B.H.), the National Institute of Health and Medical Research (B.H.), the Association for Aid to Multiple Sclerosis Research (B.H.), the National Agency for Research (program center of excellence in neurodegeneration obtained within the Grenoble excellence in neurodegeneration network, B.H.), the Swiss National Science Foundation (310030_156961/310030_176256 to PS and 310030_153164/310030_176678 to PL), and the Swiss Multiple Sclerosis Society (P.L.)., Clinical Immunology and Rheumatology, AII - Inflammatory diseases, Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier (INM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Lausanne = University of Lausanne (UNIL), Grenoble Alpes University, the National Institute of Health and Medical Research, the Association for Aid to Multiple Sclerosis Research), the National Agency for Research (program center of excellence in neurodegeneration obtained within the Grenoble excellence in neurodegeneration network, the Swiss National Science Foundation (310030_156961/310030_176256 to PS and 310030_153164/310030_176678 )The Swiss Multiple Sclerosis Society, and MARCHE, Patrice

Subjects
Male, 0301 basic medicine, T-Lymphocytes, Mice, chemistry.chemical_compound, 0302 clinical medicine, B-Cell Activating Factor, Medicine, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Chondroitin Sulfates, Middle Aged, Immunohistochemistry, Interleukin-10, 3. Good health, Interleukin 10, Neurology, Adult, Aged, Animals, Astrocytes/immunology, Astrocytes/metabolism, Astrocytes/pathology, B-Cell Activating Factor/metabolism, Cell Proliferation, Chondroitin Sulfate Proteoglycans/metabolism, Chondroitin Sulfates/metabolism, Cytokines/immunology, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental/immunology, Encephalomyelitis, Autoimmune, Experimental/metabolism, Encephalomyelitis, Autoimmune, Experimental/pathology, Female, Humans, Interleukin-10/immunology, Macrophages/pathology, Multiple Sclerosis/immunology, Multiple Sclerosis/metabolism, Multiple Sclerosis/pathology, T-Lymphocytes/immunology, Tumor Necrosis Factor Ligand Superfamily Member 13/genetics, Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism, Tumor Necrosis Factor Ligand Superfamily Member 13/pharmacology, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, medicine.symptom, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, [SDV.IMM] Life Sciences [q-bio]/Immunology, Tumor Necrosis Factor Ligand Superfamily Member 13, Inflammation, 03 medical and health sciences, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, B-cell activating factor, Autoimmune encephalitis, business.industry, Macrophages, Multiple sclerosis, medicine.disease, 030104 developmental biology, Chondroitin Sulfate Proteoglycans, chemistry, Chondroitin sulfate proteoglycan, Astrocytes, Immunology, Cytokine secretion, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract

International audience; OBJECTIVE:The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.METHODS:APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.RESULTS:APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect.INTERPRETATION:Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.© 2019 American Neurological Association.

Published
2019

3. IL-27-Induced Type 1 Regulatory T-Cells Produce Oxysterols that Constrain IL-10 Production

Author

Vigne , Solenne, Chalmin , Fanny, Duc , Donovan, Clottu , Aurélie S, Apetoh , Lionel, Lobaccaro , Jean-Marc A, Christen , Isabelle, Zhang , Juan, Pot , Caroline, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Department of Pathology and Immunology [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Novartis Institutes for BioMedical Research (NIBR), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Génétique, Reproduction et Développement - Clermont Auvergne ( GReD ), IFR79-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Institutes for BioMedical Research, Novartis, and Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
type 1 regulatory T cells, Epstein–Barr virus-induced G-protein coupled receptor 2 (EBI2), Immunology, autoimmunity, immunometabolism, nuclear hormone liver X receptor, cholesterol 25-hydroxylase, ddc:616.07, CD4+ T cells, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, oxysterols, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), Original Research
Abstract

IF 6.429; International audience; The behaviors of lymphocytes, including CD4(+) T helper cells, are controlled on many levels by internal metabolic properties. Lipid metabolites have recently been ascribed a novel function as immune response modulators and perturbation of steroids pathways modulates inflammation and potentially promotes a variety of diseases. However, the impact of lipid metabolism on autoimmune disease development and lymphocyte biology is still largely unraveled. In this line, oxysterols, oxidized forms of cholesterol, have pleiotropic roles on the immune response aside from their involvements in lipid metabolism. The oxysterols 25-hydroxycholesterol (25-OHC) and 7α,25-dihydroxycholesterol (7α,25-OHC) regulate antiviral immunity and immune cell chemotaxis. However, their physiological effects on adaptive immune response in particular on various subset CD4(+) T lymphocytes are largely unknown. Here, we assessed oxysterol levels in subset of CD4(+) T cells and demonstrated that 25-OHC and transcript levels of its synthesizing enzyme, cholesterol 25-hydroxylase, were specifically increased in IL-27-induced type 1 regulatory T (TR1) cells. We further showed that 25-OHC acts as a negative regulator of TR1 cells in particular of IL-10 secretion via liver X receptor signaling. Not only do these findings unravel molecular mechanisms accounting for IL-27 signaling but also they highlight oxysterols as pro-inflammatory mediators that dampens regulatory T cell responses and thus unleash a pro-inflammatory response.

Published
2017

4. Increased interleukin-27 cytokine expression in the central nervous system of multiple sclerosis patients

Author

Lalive, Patrice, Kreutzfeldt, Mario, Devergne, Odile, Metz, Imke, Bruck, Wolfgang, Merkler, Doron, Pot, Caroline, BMC, BMC, Department of Pathology and Immunology [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Department of Clinical Neurosciences [Geneva, Switzerland], Unit of Neuroimmunology and Neuromuscular Diseases [Geneva, Switzerland] (Division of Neurology), Geneva University Hospitals - HUG [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), 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), Institute of Neuropathology [Göttingen, Germany], University Medical Center Göttingen (UMG), Department of Clinical Neurosciences [Lausanne, Switzerland] (Division of Neurology and Neuroscience Research Center), Laboratories of Neuroimmunology [Lausanne, Switzerland], Lausanne University Hospital-Lausanne University Hospital, P.H.L. received support from the Swiss National Foundation (#310030-153164), D.M. receives support by the Swiss National Science Foundation (310030_173010), and C.P. holds stipendiary professorships of the Swiss National Science Foundation (No. PP00P3_157426). P.H.L., D.M. and C.P. received supports from the Swiss Multiple Sclerosis Society., University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Lausanne University Hospital [Switzerland]-Lausanne University Hospital [Switzerland], Unit of Neuroimmunology and Neuromuscular Diseases [Geneva, Switzerland] ( Division of Neurology ), Department of Pathology and Immunology [Geneva, Switzerland] ( Clinical Pathology Division ), Institut Necker Enfants-Malades (INEM) ( 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 ), University Medical Center Göttingen [Germany], and Department of Clinical Neurosciences [Lausanne, Switzerland] ( Division of Neurology and Neuroscience Research Center )

Subjects
Adult, Central Nervous System, Male, Interleukin-27, Astrocytes/metabolism, Astrocytes/pathology, Central Nervous System/metabolism, Central Nervous System/pathology, Female, Glial Fibrillary Acidic Protein/metabolism, Humans, Interleukin-27/blood, Interleukin-27/cerebrospinal fluid, Interleukin-27/metabolism, Interleukins/metabolism, Middle Aged, Minor Histocompatibility Antigens/metabolism, Multiple Sclerosis/pathology, Oligoclonal Bands/metabolism, Severity of Illness Index, Statistics, Nonparametric, Young Adult, Cerebrospinal fluid, Cytokines, Immunohistochemistry, Multiple sclerosis, [SDV]Life Sciences [q-bio], ddc:616.07, lcsh:RC346-429, Minor Histocompatibility Antigens, Glial Fibrillary Acidic Protein, lcsh:Neurology. Diseases of the nervous system, [ SDV ] Life Sciences [q-bio], Interleukins, Research, Oligoclonal Bands, ddc:616.8, [SDV] Life Sciences [q-bio], Astrocytes
Abstract

Background Multiple sclerosis (MS) is an autoimmune disorder characterized by chronic inflammation, demyelination, and neuronal damage. During autoimmunity, cytokines are important mediators of the inflammation. In this line, interleukin-27 (IL-27) modulates inflammation and can be produced directly at inflammatory sites such as in the joints during rheumatoid arthritis or in the central nervous system (CNS) during MS. While in animal models of MS, treatment with IL-27 decreases the disease severity, its role in humans is not clearly established and it is not known if IL-27 could be detected in the cerebrospinal fluid (CSF) of MS patients. Methods In this study, we measured IL-27 levels using a quantitative enzyme-linked immunosorbent assay in CSF of patients with relapsing remitting multiple sclerosis (RRMS), isolated optic neuritis (ON) and non-inflammatory neurological disease (NIND) as well as in the sera of healthy donors (HD) and RRMS patients undergoing different disease modifying treatments. We further confirmed by immunohistology of patient biopsies the identity of IL-27 producing cells in the brain of active MS lesions. Results We observed that IL-27 levels are increased in the CSF but not in the sera of RRMS compared to HD. We confirmed that IL-27 is expressed in active MS plaques by astrocytes of MS patients. Conclusions Our results point toward a local secretion of IL-27 in the CNS that is increased during autoimmune processes. We propose that local production of IL-27 could sign the induction of a regulatory response that promotes inflammation’s resolution. The effect of new immunomodulatory therapies on cerebral IL-27 production could be used to understand the biology of IL-27 in MS disease.

Published
2017

5. Associations of lower vitamin D concentrations with cognitive decline and long-term risk of dementia and Alzheimer's disease in older adults

Author

Catherine Helmer, Jean-François Dartigues, Cécilia Samieri, Bénédicte M. J. Merle, Cédric Annweiler, Cécile Delcourt, François Herrmann, Catherine Féart, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Rehabilitation and Geriatrics [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Robarts Research Institute [Canada], University of Western Ontario (UWO), Service de Gériatrie [Angers] (Pôle de Neurosciences), Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre de Recherche sur l'Autonomie et la Longévité [CHU Angers] (CeRAL [CHU Angers]), The Three-City Study is conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM), Victor Segalen –Bordeaux2 University and the Sanofi-Synthélabo company. The Fondation pour la Recherche Médicale funded the preparation and beginning of the study. The 3C-Study is also sponsored by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, Ministry of Research-INSERM Program Cohortes et collections de données biologiques, the Fondation Plan Alzheimer (FCS 2009-2012), and the Caisse Nationale pour la Solidarité et l’Autonomie (CNSA). Financial support for 3C-COGINUT project was provided by the French National Research Agency (ANR-06-PNRA-005). Vitamin D assessment was funded by Laboratoires Théa (Clermont-Ferrand, France)., ANR-06-PNRA-0005,COGINUT,COGINUT : Cognition, anti-oxydants, acides gras: approche interdisciplinaire du rôle de la nutrition dans le vieillissement du cerveau(2006), Dupuis, Christine, Programme National de Recherches en Alimentation et Nutrition Humaine (PNRA) - COGINUT : Cognition, anti-oxydants, acides gras: approche interdisciplinaire du rôle de la nutrition dans le vieillissement du cerveau - - COGINUT2006 - ANR-06-PNRA-0005 - PNRA - VALID, University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Centre de Recherche sur l'Autonomie et la Longévité [CHU Angers] (CeRAL [CHU Angers])-Centre Hospitalier Universitaire d'Angers (CHU Angers), and PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Université d'Angers (UA)

Subjects
Male, Gerontology, Pediatrics, medicine.medical_specialty, Epidemiology, Cognitive decline, Kaplan-Meier Estimate, Neuropsychological Tests, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Developmental Neuroscience, Alzheimer Disease, Risk factors in epidemiology, Vitamin D and neurology, medicine, Humans, Dementia, 030212 general & internal medicine, Vitamin D, Prospective cohort study, Aged, Aged, 80 and over, Health Policy, Alzheimer's disease, medicine.disease, Confidence interval, 3. Good health, Psychiatry and Mental health, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Multivariate Analysis, Cohort, ddc:618.97, Etiology, Population study, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), Geriatrics and Gerontology, Cognition Disorders, Psychology, Prospective studies, 030217 neurology & neurosurgery
Abstract

International audience; INTRODUCTION:Hypovitaminosis D has been associated with several chronic conditions; yet, its association with cognitive decline and the risk of dementia and Alzheimer's disease (AD) has been inconsistent.METHODS:The study population consisted of 916 participants from the Three-City Bordeaux cohort aged 65+, nondemented at baseline, with assessment of vitamin D status and who were followed for up to 12 years.RESULTS:In multivariate analysis, compared with individuals with 25(OH)D sufficiency (n = 151), participants with 25(OH)D deficiency (n = 218) exhibited a faster cognitive decline. A total of 177 dementia cases (124 AD) occurred: 25(OH)D deficiency was associated with a nearly three-fold increased risk of AD (hazard ratio = 2.85, 95% confidence interval 1.37-5.97).DISCUSSION:This large prospective study of French older adults suggests that maintaining adequate vitamin D status in older age could contribute to slow down cognitive decline and to delay or prevent the onset of dementia, especially of AD etiology.

Published
2017

6. Open-label, multicentre, dose-escalating phase II clinical trial on the safety and efficacy of tadekinig alfa (IL-18BP) in adult-onset Still’s disease

Author

Peter Lamprecht, Thierry Schaeverbeke, Hendrik Schulze-Koops, Eugen Feist, Jürgen Rech, Bernhard Hellmich, Eduardo Schiffrin, Delphine S. Courvoisier, Jacques Morel, Thierry Martin, Eric Hachulla, Bruno Fautrel, Andrew Sleight, Cem Gabay, Ina Kötter, Mohamed Hamidou, François Spertini, Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Division of Rheumatology [Geneva, Switzerland], Geneva University Hospital, Geneva-Department of Internal Medicine [Genève], Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Service de rhumatologie [CHU Pitié Salpêtrière] (GRC-08 EEMOIS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Division of Immunology and Allergy [Lausanne, Suisse], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Department of Internal Medicine II, University of Tübingen, Service de médecine interne [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de Rhumatologie[Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Lapeyronie, Rhumatologie Bordeaux (SERVICE DE RHUMATOLOGIE), CHU Bordeaux [Bordeaux], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire de Génie des Procédés et Matériaux - EA 4038 (LGPM), CentraleSupélec, Degauque, Nicolas, Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Service de Rhumatologie [CHU Pitié Salpêtrière], 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), and Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen

Subjects
Adult, 0301 basic medicine, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Injections, Subcutaneous, Immunology, Disease, Severity of Illness Index, Drug Administration Schedule, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Team4, Rheumatology, Prednisone, Internal medicine, medicine, Clinical endpoint, Humans, Immunology and Allergy, CRTI, Adverse effect, ComputingMilieux_MISCELLANEOUS, ddc:616, 030203 arthritis & rheumatology, Dose-Response Relationship, Drug, biology, business.industry, C-reactive protein, Interleukin-18, Interleukin, Middle Aged, Antirheumatic Agents/administration & dosage, Antirheumatic Agents/adverse effects, Antirheumatic Agents/therapeutic use, Biomarkers/blood, Female, Intercellular Signaling Peptides and Proteins/administration & dosage, Intercellular Signaling Peptides and Proteins/adverse effects, Intercellular Signaling Peptides and Proteins/therapeutic use, Interleukin-18/blood, Still's Disease, Adult-Onset/drug therapy, Still's Disease, Adult-Onset/immunology, Treatment Outcome, adult onset still’s disease, inflammation, juvenile idiopathic arthritis, 3. Good health, Clinical trial, Institutional repository, 030104 developmental biology, Antirheumatic Agents, biology.protein, Intercellular Signaling Peptides and Proteins, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, Still's Disease, Adult-Onset, Biomarkers, medicine.drug
Abstract

Objectives Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD. Methods In this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study. Results Ten patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria. Conclusions Our results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD. Trial registration number NCT02398435.

Published
2018

7. CFTR inactivation by lentiviral vector-mediated RNA interference and CRISPR-Cas9 genome editing in human airway epithelial cells

Author

Bellec, Jessica, Bacchetta, Marc, Losa, Davide, Anegon, Ignacio, Chanson, Marc, Nguyen, Tuan, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), laboratory of clinical investigation III [Geneva, Switzerland], Geneva University Hospitals - HUG [Switzerland]-University of Geneva [Switzerland], laboratory of clinical investigation III, University of Geneva [Switzerland], Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Université de Genève = University of Geneva (UNIGE), and Le Bihan, Sylvie

Subjects
Cystic Fibrosis, [SDV]Life Sciences [q-bio], Genetic Vectors, Respiratory System, Cystic Fibrosis Transmembrane Conductance Regulator, Gene Expression, Primary cells, Cystic fibrosis, Cell Line, RNA interference, Cell Movement, Humans, Clustered Regularly Interspaced Short Palindromic Repeats, RNA, Small Interfering, CFTR, Cell Proliferation, Genome, ddc:618, Interleukin-8, Lentivirus, Epithelial Cells, Genetic Therapy, [SDV] Life Sciences [q-bio], RNA Interference, Lentiviral vector, CRISPR-Cas9, Biotechnology
Abstract

© 2015 Bentham Science Publishers. Background: Polarized airway epithelial cell cultures modelling Cystic Fibrosis Transmembrane conductance Regulator (CFTR) defect are crucial for CF and biomedical research. RNA interference has proven its value to generate knockdown models for various pathologies. More recently, genome editing using CRISPR-Cas9 artificial endonuclease was a valuable addition to the toolbox of gene inactivation. Methods: Calu-3 cells and primary HAECs were transduced with HIV-1-derived lentiviral vectors (LVV) encoding small hairpin RNA (shRNA) sequence or CRISPR-Cas9 components targeting CFTR alongside GFP. After sorting of GFP-positive cells, CFTR expression was measured by RT-qPCR and Western blot in polarized or differentiated cells. CFTR channel function was assessed in Ussing chambers. Il-8 secretion, proliferation and cell migration were also studied in transduced cells. Results: shRNA interference and CRISPRCas9 strategies efficiently decreased CFTR expression in Calu-3 cells. Strong CFTR knockdown was confirmed at the functional level in CRISPR-Cas9-modified cells. CFTR-specific shRNA sequences did not reduce gene expression in primary HAECs, whereas CRISPR-Cas9-mediated gene modification activity was correlated with a reduction of transepithelial secretion and response to a CFTR inhibitor. CFTR inactivation in the CRISPR-Cas9-modified Calu-3 cells did not affect migration and proliferation but slightly increased basal interleukin-8 secretion. Conclusion: We generated CFTRinactivated cell lines and demonstrated that CRISPR-Cas9 vectorised in a single LVV efficiently promotes CFTR inactivation in primary HAECs. These results provide a new protocol to engineer CF primary epithelia with their isogenic controls and pave the way for manipulation of CFTR expression in these cultures.

Published
2015

8. Cx26 regulates proliferation of repairing basal airway epithelial cells

Author

Marc Bacchetta, S. Huang, Sophie Crespin, Jean-Sylvain Lacroix, Tecla Dudez, Jessica Bellec, P. Tantilipikorn, J. Bou Saab, Marc Chanson, Ludovic Wiszniewski, Brenda R. Kwak, T.H. Nguyen, laboratory of clinical investigation III [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Mahidol University [Bangkok, Thailand], Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Internal Medicine Specialties [Geneva, Switzerland], Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), Division of Otho-Rhino-Laryngology [Geneva, Switzerland], Geneva University Hospitals - HUG [Switzerland], Epithelix SARL [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE), Swiss National Science Foudation (grants 310000_119739 and 310030_134907/1)., Vaincre la Mucoviscidose., Téléthon Action Suisse., Novartis Stiftung für Medizinisch Biologische Forschung., and Le Bihan, Sylvie

Subjects
Population, Proliferation, Kruppel-Like Transcription Factors, Bronchi, Respiratory Mucosa, ddc:616.07, Biology, Biochemistry, Connexins, Cystic fibrosis, Cx26, Kruppel-Like Factor 4, 03 medical and health sciences, 0302 clinical medicine, medicine, otorhinolaryngologic diseases, Humans, Gene silencing, Progenitor cell, Mucilair, education, Cells, Cultured, Gap junctions, Cell Proliferation, 030304 developmental biology, 0303 health sciences, education.field_of_study, ddc:618, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Cell growth, Cell Differentiation, Epithelial Cells, Cell Biology, Epithelium, Cell biology, Connexin 26, medicine.anatomical_structure, KLF4, 030220 oncology & carcinogenesis, Immunology, cardiovascular system, Respiratory epithelium, Immortalised cell line, Repair, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

The recovery of an intact epithelium following injury is critical for restoration of lung homeostasis, a process that may be altered in cystic fibrosis (CF). In response to injury, progenitor cells in the undamaged areas migrate, proliferate and re-differentiate to regenerate an intact airway epithelium. The mechanisms regulating this regenerative response are, however, not well understood. In a model of circular wound injury of well-differentiated human airway epithelial cell (HAEC) cultures, we identified the gap junction protein Cx26 as an important regulator of cell proliferation. We report that induction of Cx26 in repairing HAECs is associated with cell proliferation. We also show that Cx26 is expressed in a population of CK14-positive basal-like cells. Cx26 silencing in immortalized cell lines using siRNA and in primary HAECs using lentiviral-transduced shRNA enhanced Ki67-labeling index and Ki67 mRNA, indicating that Cx26 acts a negative regulator of HAEC proliferation. Cx26 silencing also markedly decreased the transcription of KLF4 in immortalized HAECs. We further show that CF HAECs exhibited deregulated expression of KLF4, Ki67 and Cx26 as well enhanced rate of wound closure in the early response to injury. These results point to an altered repair process of CF HAECs characterized by rapid but desynchronized initiation of HAEC activation and proliferation. This article is part of a Directed Issue entitled: Cystic fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.

Published
2014

9. Pseudomonas aeruginosa-induced apoptosis in airway epithelial cells is mediated by gap junctional communication in a JNK-dependent manner

Author

Pierre Boulanger, Sophie Crespin, Marc Chanson, Marc Bacchetta, Tecla Dudez, T.H. Nguyen, Saw See Hong, Thilo Köhler, Davide Losa, Christian van Delden, Jessica Bellec, Sandrine Morel, laboratory of clinical investigation III [Geneva, Switzerland], Geneva University Hospitals - HUG [Switzerland]-University of Geneva [Switzerland], Service of Infectious Diseases [Geneva, Switzerland], Geneva University Hospital (HUG), Department of Microbiology and Molecular Medicine Geneva [Switzerland], University of Geneva [Switzerland]-School of Medicine, Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], Swiss National Science Foundation Grants 310030_134907/1 and 32473B_140929., Vaincre la Mucoviscidose., Italian Cystic Fibrosis Research Foundation Grant 19/2009 (adopted by Fondazione Ricerca Fibrosi Cistica delegation La Bottega delle Donne)., Fondation pour des Bourses d’Etudes Italo-Suisses, Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), Le Bihan, Sylvie, Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], and Université de Genève = University of Geneva (UNIGE)-School of Medicine

Subjects
Cystic Fibrosis, MAP Kinase Kinase 4, MAP Kinase Signaling System, p38 mitogen-activated protein kinases, Immunology, Cystic Fibrosis Transmembrane Conductance Regulator, Inflammation, Apoptosis, Respiratory Mucosa, Cell Communication, ddc:616.07, Biology, p38 Mitogen-Activated Protein Kinases, Cell Line, Small hairpin RNA, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, medicine, Immunology and Allergy, Humans, Pseudomonas Infections, 030304 developmental biology, ddc:616, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, ddc:618, Innate immune system, Gap Junctions, Epithelial Cells, respiratory system, 3. Good health, Cell biology, Cell culture, 030220 oncology & carcinogenesis, Connexin 43, Pseudomonas aeruginosa, Respiratory epithelium, medicine.symptom, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Chronic infection and inflammation of the airways is a hallmark of cystic fibrosis (CF), a disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The response of the CF airway epithelium to the opportunistic pathogen Pseudomonas aeruginosa is characterized by altered inflammation and apoptosis. In this study, we examined innate immune recognition and epithelial responses at the level of the gap junction protein connexin43 (Cx43) in polarized human airway epithelial cells upon infection by PAO1. We report that PAO1 activates cell surface receptors to elicit an intracellular signaling cascade leading to enhancement of gap junctional communication. Expression of Cx43 involved an opposite regulation exerted by JNK and p38 MAPKs. PAO1-induced apoptosis was increased in the presence of a JNK inhibitor, but latter effect was prevented by lentiviral expression of a Cx43-specific short hairpin RNA. Moreover, we found that JNK activity was upregulated by pharmacological inhibition of CFTR in Calu-3 cells, whereas correction of a CF airway cell line (CF15 cells) by adenoviral expression of CFTR reduced the activation of this MAPK. Interestingly, CFTR inhibition in Calu-3 cells was associated with decreased Cx43 expression and reduced apoptosis. These results indicate that Cx43 expression is a component of the response of airway epithelial cells to innate immune activation by regulating the survival/apoptosis balance. Defective CFTR could alter this equilibrium with deleterious consequences on the CF epithelial response to P. aeruginosa. Copyright © 2014 by The American Association of Immunologists, Inc.

Published
2014

10. Endothelial-specific deletion of connexin40 promotes atherosclerosis by increasing CD73-dependent leukocyte adhesion

Author

F.E.J. Coenjaerts, Brenda R. Kwak, Marc Chanson, Marc Bacchetta, Lucile Miquerol, Isabelle Roth, Zhihong Yang, T. A. B. van Veen, Urban Deutsch, Christos Chadjichristos, Habo J. Jongsma, M.J.A. van Kempen, M. Z. Richani Sarieddine, Tecla Dudez, K.E.L. Scheckenbach, Hema Viswambharan, Bernard Foglia, C. de Wit, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), laboratory of clinical investigation III [Geneva, Switzerland], Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Department of Internal Medicine Specialties [Geneva, Switzerland], and Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division)

Subjects
Pathology, Cell Adhesion/immunology, Connexins/*genetics/metabolism, Vasculitis/immunology/pathology/*physiopathology, 030204 cardiovascular system & hematology, Connexins, Monocytes, Green Fluorescent Proteins/genetics, Transgenic, Mice, 0302 clinical medicine, RNA, Small Interfering, Endothelial dysfunction, 5'-Nucleotidase, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, 0303 health sciences, ddc:618, Cultured, Gap Junctions, 3. Good health, medicine.anatomical_structure, 5'-Nucleotidase/*metabolism, medicine.symptom, Cardiology and Cardiovascular Medicine, Gap Junctions/metabolism, Signal Transduction, Vasculitis, medicine.medical_specialty, Atherosclerosis/immunology/pathology/*physiopathology, Endothelium, Transgene, Cells, Green Fluorescent Proteins, Mice, Transgenic, Inflammation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Small Interfering, Proinflammatory cytokine, 03 medical and health sciences, Physiology (medical), Internal medicine, Cell Adhesion, medicine, Animals, Cell adhesion, 030304 developmental biology, Signal Transduction/immunology, business.industry, Vascular disease, Endothelial Cells/metabolism/*pathology, Monocyte, Endothelial Cells, Monocytes/metabolism/pathology, Atherosclerosis, medicine.disease, Endocrinology, RNA, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background— Endothelial dysfunction is the initiating event of atherosclerosis. The expression of connexin40 (Cx40), an endothelial gap junction protein, is decreased during atherogenesis. In the present report, we sought to determine whether Cx40 contributes to the development of the disease. Methods and Results— Mice with ubiquitous deletion of Cx40 are hypertensive, a risk factor for atherosclerosis. Consequently, we generated atherosclerosis-susceptible mice with endothelial-specific deletion of Cx40 (Cx40del mice). Cx40del mice were indeed not hypertensive. The progression of atherosclerosis was increased in Cx40del mice after 5 and 10 weeks of a high-cholesterol diet, and spontaneous lesions were observed in the aortic sinuses of young mice without such a diet. These lesions showed monocyte infiltration into the intima, increased expression of vascular cell adhesion molecule-1, and decreased expression of the ecto-enzyme CD73 in the endothelium. The proinflammatory phenotype of Cx40del mice was confirmed in another model of induced leukocyte recruitment from the lung microcirculation. Endothelial CD73 is known to induce antiadhesion signaling via the production of adenosine. We found that reducing Cx40 expression in vitro with small interfering RNA or antisense decreased CD73 expression and activity and increased leukocyte adhesion to mouse endothelial cells. These effects were reversed by an adenosine receptor agonist. Conclusions— Cx40-mediated gap junctional communication contributes to a quiescent nonactivated endothelium by propagating adenosine-evoked antiinflammatory signals between endothelial cells. Alteration in this mechanism by targeting Cx40 promotes leukocyte adhesion to the endothelium, thus accelerating atherosclerosis.

Published
2010

11. Combination of Gene Expression Signature and Model for End-Stage Liver Disease Score Predicts Survival of Patients With Severe Alcoholic Hepatitis

Author

Laura Rubbia-Brandt, Karim Abdelrahman, Astrid Marot, Gene Y. Im, Gianluca Bontempi, Yujin Hoshida, Denis Franchimont, Thierry Gustot, Christine Sempoux, Eric Trepo, Delphine Degré, Won-Min Song, Jacques Devière, Nicolas Goossens, Joan Saldarriaga, Swan N. Thung, Charlotte Minsart, Christophe Moreno, Jean Henrion, Antonio Colaprico, Pierre Deltenre, Valerio Lucidi, Pieter Demetter, Venugopalan D. Nair, Laurent Spahr, Naoto Fujiwara, Thomas Sersté, Department of Gastroenterology, Hepatopancreatology, and Digestive Oncology [Brussels, Belgium], Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Laboratory of Experimental Gastroenterology [Brussels, Belgium], Université libre de Bruxelles (ULB), Department of Medicine [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Division of Gastroenterology and Hepatology [Geneva, Switzerland], Geneva University Hospital (HUG), Department of Genetics and Genomic Sciences, Interuniversity Institute of Bioinformatics in Brussels (IB2), Université libre de Bruxelles (ULB)-Vrije Universiteit Brussel (VUB), Machine Learning Group [Brussels, Belgium] (Department d'Informatique), Division of Gastroenterology and Hepatology [Lausanne, Switzerland], Université de Lausanne = University of Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Department of Pathology [Brussels, Belgium], Université libre de Bruxelles (ULB)-Hôpital Erasmes, Department of Clinical Pathology [Lausanne, Switzerland], Lausanne University Hospital-Institute of Pathology [Lausanne, Switzerland], Recanati/Miller Transplantation Institute [New York, NY, USA], Unité d'Hématologie [CH de Jolimont-Lobbes, Belgium], Centre Hospitalier de Jolimont-Lobbes [Haine Saint-Paul, Belgium], Department of Abdominal Surgery [Brussels, Belgium], Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Centre de Chirurgie Hépato-Biliaire de l'ULB [Brussels, Belgium], Department of Pathology and Immunology [Geneva, Switzerland] (Clinical Pathology Division), Université de Genève = University of Geneva (UNIGE)-Geneva University Hospitals - HUG [Switzerland], Department of Neurology [New York, NY, USA], Service d'Hépato-Gastroentérologie [Haine-Saint-Paul, Belgium], Hôpital de Jolimont [Haine-Saint-Paul, Belgium], The study was supported by the Fonds Erasme (Edouard and Suzanne Jacobs Convention), the Belgian Association for the Study of the Liver, and a Research Project (T100914F) from the Fund for Scientific Research-FNRS (F.R.S.-FNRS). Eric Trépo is a Research Associate of the F.R.S.-FNRS and Denis Franchimont is a Research Director of the F.R.S.-FNRS. Nicolas Goossens received funding from the FLAGS and Nuovo-Soldati foundations. Yujin Hoshida is supported by NIH/NIDDK DK099558, European Union ERC-2014-AdG-671231HEPCIR, Irma T. Hirschl Trust, and US Department of Defense (W81XWH-16-1-0363). Antonio Colaprico and Gianluca Bontempi are supported by the BridgeIRIS project funded by INNOVIRIS, Brussels-Capital Region, Brussels, Belgium., European Project: 671231,H2020,ERC-2014-ADG,HEPCIR(2016), UCL - SSS/IREC/MONT - Pôle Mont Godinne, UCL - (MGD) Service de gastro-entérologie, Université de Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Lausanne University Hospital [Switzerland]-Institute of Pathology [Lausanne, Switzerland], University of Geneva [Switzerland]-Geneva University Hospitals - HUG [Switzerland], daulny, anne, and Cell circuits as targets and biomarkers for liver disease and cancer prevention - HEPCIR - - H20202016-01-01 - 2020-12-31 - 671231 - VALID

Subjects
0301 basic medicine, Male, Alcoholic liver disease, Cirrhosis, Time Factors, medicine.medical_treatment, Biopsy, Kaplan-Meier Estimate, Liver transplantation, ddc:616.07, Gastroenterology, Severity of Illness Index, Liver disease, 0302 clinical medicine, Model for End-Stage Liver Disease, Belgium, Adrenal Cortex Hormones, Risk Factors, Oligonucleotide Array Sequence Analysis, ddc:616, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, musculoskeletal, neural, and ocular physiology, Middle Aged, 3. Good health, Phenotype, Treatment Outcome, Liver biopsy, Area Under Curve, 030211 gastroenterology & hepatology, Female, Transcription, Adult, Genetic Markers, medicine.medical_specialty, Alcoholic hepatitis, macromolecular substances, Risk Assessment, Article, Decision Support Techniques, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Proportional Hazards Models, Hepatitis, Hepatology, Ethanol, business.industry, Hepatitis, Alcoholic, Gene Expression Profiling, Reproducibility of Results, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Surgery, MELD, 030104 developmental biology, ROC Curve, nervous system, business, Transcriptome, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; BACKGROUND & AIMS:Patients with severe alcoholic hepatitis (AH) have a high risk of death within 90 days. Corticosteroids, which can cause severe adverse events, are the only treatment that increases short-term survival. It is a challenge to predict outcomes of patients with severe AH. Therefore, we developed a scoring system to predict patient survival, integrating baseline molecular and clinical variables.METHODS:We obtained fixed liver biopsy samples from 71 consecutive patients diagnosed with severe AH and treated with corticosteroids from July 2006 through December 2013 in Brussels, Belgium (derivation cohort). Gene expression patterns were analyzed by microarrays and clinical data were collected for 180 days. We identified gene expression signatures and clinical data that are associated with survival without liver transplantation at 90 and 180 days after initiation of corticosteroid therapy. Findings were validated using liver biopsies from 48 consecutive patients with severe AH treated with corticosteroids, collected from March 2010 through February 2015 at hospitals in Belgium and Switzerland (validation cohort 1) and in liver biopsies from 20 patients (9 received corticosteroid treatment), collected from January 2012 through May 2015 in the United States (validation cohort 2).RESULTS:We integrated data on expression patterns of 123 genes and the model for end-stage liver disease (MELD) scores to assign patients to groups with poor survival (29% survived 90 days and 26% survived 180 days) and good survival (76% survived 90 days and 65% survived 180 days) (P < .001) in the derivation cohort. We named this assignment system the gene signature-MELD (gs-MELD) score. In validation cohort 1, the gs-MELD score discriminated patients with poor survival (43% survived 90 days) from those with good survival (96% survived 90 days) (P < .001). The gs-MELD score also discriminated between patients with a poor survival at 180 days (34% survived) and a good survival at 180 days (84% survived) (P < .001). The time-dependent area under the receiver operator characteristic curve for the score was 0.86 (95% confidence interval 0.73-0.99) for survival at 90 days, and 0.83 (95% confidence interval 0.71-0.96) for survival at 180 days. This score outperformed other clinical models to predict survival of patients with severe AH in validation cohort 1. In validation cohort 2, the gs-MELD discriminated patients with a poor survival at 90 days (12% survived) from those with a good survival at 90 days (100%) (P < .001).CONCLUSIONS:We integrated data on baseline liver gene expression pattern and the MELD score to create the gs-MELD scoring system, which identifies patients with severe AH, treated or not with corticosteroids, most and least likely to survive for 90 and 180 days.

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