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1. Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

Author

Marianna Parlato, Fabienne Charbit‐Henrion, Jie Pan, Claudio Romano, Rémi Duclaux‐Loras, Marie‐Helene Le Du, Neil Warner, Paola Francalanci, Julie Bruneau, Marc Bras, Mohammed Zarhrate, Bernadette Bègue, Nicolas Guegan, Sabine Rakotobe, Nathalie Kapel, Paola De Angelis, Anne M Griffiths, Karoline Fiedler, Eileen Crowley, Frank Ruemmele, Aleixo M Muise, and Nadine Cerf‐Bensussan

Subjects
inflammatory bowel diseases, intestinal phosphatase alkaline, monogenic disease, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract Herein, we report the first identification of biallelic‐inherited mutations in ALPI as a Mendelian cause of inflammatory bowel disease in two unrelated patients. ALPI encodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll‐like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter‐subunit interactions, and heterologous expression in HEK293T cells demonstrated that all ALPI mutations were loss of function. ALPI mutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide‐dependent signalling. Furthermore, ALPI expression was reduced in patients’ biopsies, and ALPI activity was undetectable in ALPI‐deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host–microbiota interactions and restraining host inflammatory responses. These results indicate that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI‐based treatments in intestinal inflammatory disorders.

Published
2018
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2. Gastrointestinal Disorder Associated with Olmesartan Mimics Autoimmune Enteropathy.

Author

Sophie Scialom, Georgia Malamut, Bertrand Meresse, Nicolas Guegan, Nicole Brousse, Virginie Verkarre, Coralie Derrieux, Elizabeth Macintyre, Philippe Seksik, Guillaume Savoye, Guillaume Cadiot, Lucine Vuitton, Lysiane Marthey, Franck Carbonnel, Nadine Cerf-Bensussan, and Christophe Cellier

Subjects
Medicine, Science
Abstract

Background and objectivesAnti-hypertensive treatment with the angiotensin II receptor antagonist olmesartan is a rare cause of severe Sprue-like enteropathy. To substantiate the hypothesis that olmesartan interferes with gut immune homeostasis, clinical, histopathological and immune features were compared in olmesartan-induced-enteropathy (OIE) and in autoimmune enteropathy (AIE).MethodsMedical files of seven patients with OIE and 4 patients with AIE enrolled during the same period were retrospectively reviewed. Intestinal biopsies were collected for central histopathological review, T cell Receptor clonality and flow cytometric analysis of isolated intestinal lymphocytes.ResultsAmong seven olmesartan-treated patients who developed villous atrophy refractory to a gluten free diet, three had extra-intestinal autoimmune diseases, two had antibodies reacting with the 75 kilodalton antigen characteristic of AIE and one had serum anti-goblet cell antibodies. Small intestinal lesions and signs of intestinal lymphocyte activation were thus reminiscent of the four cases of AIE diagnosed during the same period. Before olmesartan discontinuation, remission was induced in all patients (7/7) by immunosuppressive drugs. After interruption of both olmesartan and immunosuppressive drugs in six patients, remission was maintained in 4 but anti-TNF-α therapy was needed in two.ConclusionThis case-series shows that olmesartan can induce intestinal damage mimicking AIE. OIE usually resolved after olmesartan interruption but immunosuppressive drugs may be necessary to achieve remission. Our data sustain the hypothesis that olmesartan interferes with intestinal immuno regulation in predisposed individuals.

Published
2015
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3. Duplication of the IL2RA locus causes excessive IL-2 signaling and may predispose to very early onset colitis

Author

Marianna Parlato, Sandrine Nugteren, D.J. Lindenbergh-Kortleve, Remy Boisgard, R. C. Raatgeep, Nicolas Guegan, Iris H I M Hollink, Nadine Cerf-Bensussan, L M M Costes, Fabienne Charbit-Henrion, M. Luisa Mearin, Johanna C. Escher, Valérie Malan, Jan Krzysztof Nowak, Janneke N. Samsom, Sharon Veenbergen, Maria E. Joosse, Pediatrics, and Clinical Genetics

Subjects
CD4-Positive T-Lymphocytes, 0301 basic medicine, Pancolitis, Immunology, Drug Resistance, Receptors, Antigen, T-Cell, Gene Expression, Lymphocyte Activation, Inflammatory bowel disease, Article, 03 medical and health sciences, 0302 clinical medicine, Gene Duplication, Gene duplication, Humans, Immunology and Allergy, Medicine, Genetic Predisposition to Disease, IL-2 receptor, Age of Onset, Colitis, Alleles, Genetic Association Studies, Chromosomes, Human, Pair 10, business.industry, Interleukin-2 Receptor alpha Subunit, FOXP3, Inflammatory Bowel Diseases, medicine.disease, Immunohistochemistry, 030104 developmental biology, Genetic Loci, Case-Control Studies, Chromosomal region, Cytokines, Interleukin-2, 030211 gastroenterology & hepatology, medicine.symptom, business, CD8, Signal Transduction
Abstract

Single genetic mutations predispose to very early onset inflammatory bowel disease (VEO-IBD). Here, we identify a de novo duplication of the 10p15.1 chromosomal region, including the IL2RA locus, in a 2-year-old girl with treatment-resistant pancolitis that was brought into remission by colectomy. Strikingly, after colectomy while the patient was in clinical remission and without medication, the peripheral blood CD4:CD8 ratio was constitutively high and CD25 expression was increased on circulating effector memory, Foxp3+, and Foxp3neg CD4+ T cells compared to healthy controls. This high CD25 expression increased IL-2 signaling, potentiating CD4+ T-cell-derived IFNγ secretion after T-cell receptor (TCR) stimulation. Restoring CD25 expression using the JAK1/3-inhibitor tofacitinib controlled TCR-induced IFNγ secretion in vitro. As diseased colonic tissue, but not the unaffected duodenum, contained mainly CD4+ T cells with a prominent IFNγ-signature, we hypothesize that local microbial stimulation may have initiated colonic disease. Overall, we identify that duplication of the IL2RA locus can associate with VEO-IBD and suggest that increased IL-2 signaling predisposes to colonic intestinal inflammation.

Published
2021

4. Oncogenetic Landscape Of Lymphomagenesis In Coeliac Disease

Author

Thierry Jo Molina, Ludovic Lhermitte, Christine Bole-Feysot, Georgia Malamut, Elizabeth Macintyre, Morgane Cheminant, Amélie Trinquand, Sophie Kaltenbach, Bruno Tesson, Olivier Hermine, David Sibon, Sofia Berrabah, Patrick Villarese, Christophe Cellier, Sherine Khater, Nicolas Guegan, Sascha Cording, Julie Bruneau, Marc Bras, Bertrand Meresse, Nadine Cerf-Bensussan, Vahid Asnafi, and Michael Dussiot

Subjects
Bortezomib, medicine, Cancer research, Proteasome inhibitor, Biology, medicine.disease, DDX3X, TNFAIP3, Coeliac disease, Exome sequencing, Comparative genomic hybridization, medicine.drug, Lymphoma
Abstract

ObjectiveEnteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of celiac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis.DesignPure populations of RCDII-cells derived from intestinal biopsies (n=9) or sorted from blood (n=2) were analysed by whole exome sequencing, comparative genomic hybridization and RNA-sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=7) were analysed by targeted next-generation sequencing. Moreover, functional in vitro studies and drug testing were performed in RCDII-derived cell lines.Results80% of RCDII and 90% of EATL displayed somatic gain-of-functions mutations in the JAK1-STAT3 pathway, including a remarkable p.G1097 hotspot mutation in the JAK1 kinase-domain in approximately 50% of cases. Other recurrent somatic events were deleterious mutations in NFκB-regulators TNFAIP3 and TNIP3 and potentially oncogenic mutations in TET2, KMT2D and DDX3X. JAK1 inhibitors and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines.ConclusionMutations activating the JAK1-STAT3 pathway appear to be the main drivers of CeD-associated lymphomagenesis. In concert with mutations in negative regulators of NFκB, they may favour the clonal emergence of malignant lymphocytes in the cytokine-rich coeliac intestine. The identified mutations are attractive therapeutic targets to treat RCDII and block progression towards EATL.

Published
2020
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5. Discovery and characterization of a novel humanized anti-IL-15 antibody and its relevance for the treatment of refractory celiac disease and eosinophilic esophagitis

Author

Bertrand Meresse, Olivier Leger, Alex Straumann, Laurence Goffin, Alain Vicari, Nadine Cerf-Bensussan, Yolande Chvatchko, Hans-Uwe Simon, Alain M. Schoepfer, Soheila Josserand, Nicolas Guegan, Shida Yousefi, University of Zurich, and Vicari, Alain P

Subjects
0301 basic medicine, Immunology, 610 Medicine & health, Humanized antibody, Epitope, 03 medical and health sciences, 0302 clinical medicine, Immune system, In vivo, Report, Immunology and Allergy, Medicine, Mode of action, Eosinophilic esophagitis, 2403 Immunology, biology, business.industry, medicine.disease, 10219 Clinic for Gastroenterology and Hepatology, 030104 developmental biology, Interleukin 15, 2723 Immunology and Allergy, biology.protein, 030211 gastroenterology & hepatology, Antibody, business
Abstract

Interleukin-15 (IL-15) is a critical regulator of immune responses, especially at mucosal interfaces within the gastro-intestinal tract. Here, we describe the discovery and characterization of a humanized antibody to IL-15. Data from its epitope and mode of action, cell biology and primate pharmacology, as well as translational studies in human samples and in vivo proof-of-concept experiments in mouse models demonstrate the therapeutic potential of this new antibody targeting IL-15 for refractory celiac disease and eosinophilic esophagitis.

Published
2017
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6. NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: A CELAC study

Author

Nicolas Guegan, Florence Lhospice, Sascha Cording, Amélie Trinquand, Julie Bruneau, Olivier Hermine, Virginie Verkarre, Nicole Brousse, Christophe Cellier, Georgia Malamut, Elizabeth Macintyre, Felipe Suarez, Laurent Frenzel, Vahid Asnafi, Morgane Cheminant, Sherine Khater, Bertrand Meresse, Ambroise Marçais, Nadine Cerf-Bensussan, Tom van Gils, Chris J. J. Mulder, Thierry Jo Molina, Ludovic Lhermitte, C. cile Bonnafous, David Sibon, Anne-Sophie Jannot, Richard Delarue, Laurent Pouyet, Gastroenterology and hepatology, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Département de Pathologie [CHU Necker], Université Sorbonne Paris Cité (USPC)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), 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), VU University Medical Center [Amsterdam], Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), 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 Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris, Mi-mAbs (C/O CIML), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Innate Pharma, Service de gastroenterologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications (ERL 8254), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, MESH: Biopsy / methods, Enteropathy-Associated T-Cell Lymphoma / diagnosis, Entropathy-Associated T-Cell Lymphoma / etiology, Enteropathy-Associated T-Cell Lymphoma / immunology, T cell, Biopsy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Coeliac Disease, Coeliac disease, 03 medical and health sciences, 0302 clinical medicine, Enteropathy-Associated T-Cell Lymphoma, Intestinal mucosa, Intestine, Small, medicine, Cytotoxic T cell, Humans, Intestinal Mucosa, MESH: Enteropathy-Associated T-Cell Lymphoma / pathology, Intestinal Mucosa / immunology, Intestinal Mucosa / pathology, Killer Cells, Natural / immunology, Antibody Targeted Therapy, Cells, Cultured, business.industry, Natural Cytotoxicity Triggering Receptor 1, Gastroenterology, MESH: Natural Cytotoxicity Triggering Receptor 1 / immunology, Antibodies, Monoclonal, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Middle Aged, medicine.disease, NKG2D, Prognosis, 3. Good health, Killer Cells, Natural, Celiac Disease, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Intraepithelial lymphocyte, Enteropathy-associated T-cell lymphoma, Female, France, Gastrointestinal Lymphoma, business, Ex vivo, Biomarkers, Tumour markers
Abstract

ObjectivesPrimary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs).DesignNKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested ex vivo in human primary tumour cells isolated from fresh duodenal biopsies.ResultsNKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL ex vivo.ConclusionNKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.

Published
2019
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7. Efficacy of Ruxolitinib Therapy in a Patient With Severe Enterocolitis Associated With a STAT3 Gain-of-Function Mutation

Author

Marianna, Parlato, Fabienne, Charbit-Henrion, Elie, Abi Nader, Bernadette, Begue, Nicolas, Guegan, Julie, Bruneau, Shérine, Khater, Elizabeth, Macintyre, Capucine, Picard, Rieux-Laucat, Frédéric, Lionel, Le Bourhis, Matthieu, Allez, Olivier, Goulet, Christophe, Cellier, Olivier, Hermine, Nadine, Cerf-Bensussan, and Georgia, Malamut

Subjects
Diarrhea, STAT3 Transcription Factor, Enterocolitis, Article, Young Adult, Pyrimidines, Gain of Function Mutation, Chronic Disease, Nitriles, Exome Sequencing, Humans, Pyrazoles, Female, Protein Kinase Inhibitors
Published
2018

8. Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis

Author

Claudio Romano, Paola De Angelis, Jie Pan, Marc Bras, Anne M. Griffiths, Karoline Fiedler, Paola Francalanci, Marianna Parlato, Nadine Cerf-Bensussan, Mohammed Zarhrate, Frank M. Ruemmele, Eileen Crowley, Aleixo M. Muise, Rémi Duclaux-Loras, Bernadette Bègue, Fabienne Charbit-Henrion, Nicolas Guegan, Julie Bruneau, Sabine Rakotobe, Nathalie Kapel, Marie‐Helene Le Du, Neil Warner, SERRE, Marie-Claude, Laboratory of Intestinal Immunity (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), GENIUS Group, Service de Gastroentérologie, d'hépatologie et nutrition pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Hospital for sick children [Toronto] (SickKids), University of Messina, Department of Pathology, University of Alabama at Birmingham [ Birmingham] (UAB), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Children's Hospital Bambino Gesù IRCCS [Rome], Université Paris Descartes - Paris 5 (UPD5), Service de pathologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme de bioinformatique (UNIV Paris Descartes), Université Paris Descartes - Paris 5 (UPD5)-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), University of Toronto, and Université Sorbonne Paris Cité (USPC)

Subjects
0301 basic medicine, Agonist, Medicine (General), medicine.drug_class, [SDV]Life Sciences [q-bio], Biology, QH426-470, GPI-Linked Proteins, Inflammatory bowel disease, inflammatory bowel diseases, intestinal phosphatase alkaline, Lipid A, 03 medical and health sciences, INTGEN, R5-920, medicine, Genetics, Homeostasis, Humans, Receptor, Loss function, Research Articles, HEK 293 cells, medicine.disease, Alkaline Phosphatase, 3. Good health, Intestines, [SDV] Life Sciences [q-bio], 030104 developmental biology, HEK293 Cells, Metabolism, inflammatory bowel diseases, intestinal phosphatase alkaline, monogenic disease, Molecular Medicine, Immunology, Mutation, Alkaline phosphatase, monogenic disease, Molecular Medicine, Heterologous expression, Genetics, Gene Therapy & Genetic Disease, Digestive System, B3S, Signal Transduction, Research Article
Abstract

International audience; Herein, we report the first identification of biallelic-inherited mutations inALPIas a Mendelian cause of inflammatory bowel disease in two unrelated patients.ALPIencodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that allALPImutations were loss of function.ALPImutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate thatALPImutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.

Published
2018
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9. Development of Double-Action SPF Forming Process by Finite Element Simulation for A380 Part

Author

Olivier Barrau, Gilles Marin, Benoit Marguet, Alain Dupuy, Nicolas Guegan, and Fabien Nazaret

Subjects
Materials science, Computer simulation, Distribution (number theory), business.industry, Mechanical Engineering, Process (computing), Forming processes, Mechanical engineering, Condensed Matter Physics, 3D modeling, Action (physics), Finite element method, Mechanics of Materials, General Materials Science, Development (differential geometry), business
Abstract

The rear part of the APF A380 has a deep drawn shape. In order to develop the forming by SPF process of this part, numerical simulation by finite elements has been performed. Several configurations for 2D and 3D modeling were studied to determine an efficient forming strategy. A double-action solution was chosen. It ensures a satisfactory thickness distribution. This article will deal with the modeling assumptions, the results of individual cases of calculation and comparison with parts obtained at the Airbus plant.

Published
2012
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10. Gastrointestinal Disorder Associated with Olmesartan Mimics Autoimmune Enteropathy

Author

Nicolas Guegan, Sophie Scialom, Nadine Cerf-Bensussan, Coralie Derrieux, Lysiane Marthey, Nicole Brousse, Georgia Malamut, Lucine Vuitton, Philippe Seksik, Virginie Verkarre, Guillaume Cadiot, Franck Carbonnel, Christophe Cellier, Bertrand Meresse, Elizabeth Macintyre, Guillaume Savoye, Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d'hépato-gastro-entérologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Interactions de l'épithelium intestinal et du système immunitaire (UMR_S 793), Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP], Service d'Anatomie et de Cytologie Pathologiques, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], PremUp Foundation, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Sorbonne Universités-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Service hématologie, French group of faecal microbotia transplantation (FGFT), CHU Saint-Antoine [APHP], Service d'Hépato-Gastroentérologie [Rouen], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Université de Reims Champagne-Ardenne (URCA), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Bicêtre, Hépatogastroentérologie, CHU de Bicêtre, Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Interactions de l'épithelium intestinal et du système immunitaire ( UMR_S 793 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Recherche Agronomique ( INRA ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Sorbonne Universités-Université Paris Descartes - Paris 5 ( UPD5 ) -CHI Créteil-Institut de Recherche pour le Développement ( IRD ) -Université Paris-Sud - Paris 11 ( UP11 ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Diderot - Paris 7 ( UPD7 ), French group of faecal microbotia transplantation ( FGFT ), Gastroenterology and nutrition department, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -CHU Saint-Antoine [APHP], Département des maladies de l'appareil digestif, CHU Rouen, Université de Reims Champagne-Ardenne ( URCA ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Université Paris-Sud - Paris 11 ( UP11 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Bicêtre, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Descartes - Paris 5 (UPD5)-CHI Créteil-Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Hépato-Gastroentérologie [CHU Rouen], Hôpital Charles Nicolle [Rouen]-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Institut de Recherche pour le Développement (IRD)-Université Paris-Sud - Paris 11 (UP11)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-CHI Créteil-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and HAL-UPMC, Gestionnaire

Subjects
Adult, Male, Adolescent, Gastrointestinal Diseases, Science, Tetrazoles, Angiotensin II receptor antagonist, Autoimmune enteropathy, Diagnosis, Differential, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, medicine, Humans, Enteropathy, Polyendocrinopathies, Autoimmune, Aged, Multidisciplinary, business.industry, [ SDV.SP.MED ] Life Sciences [q-bio]/Pharmaceutical sciences/Medication, Imidazoles, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Middle Aged, medicine.disease, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 3. Good health, Gastrointestinal disorder, 030220 oncology & carcinogenesis, Immunology, Medicine, Female, [ SDV.MHEP.HEG ] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, 030211 gastroenterology & hepatology, Gluten free, Olmesartan, business, Angiotensin II Type 1 Receptor Blockers, Research Article, medicine.drug
Abstract

International audience; Background and Objectives : Anti-hypertensive treatment with the angiotensin II receptor antagonist olmesartan is a rare cause of severe Sprue-like enteropathy. To substantiate the hypothesis that olmesartan interferes with gut immune homeostasis, clinical, histopathological and immune features were compared in olmesartan-induced-enteropathy (OIE) and in autoimmune enteropathy (AIE).Methods : Medical files of seven patients with OIE and 4 patients with AIE enrolled during the same period were retrospectively reviewed. Intestinal biopsies were collected for central histopathological review, T cell Receptor clonality and flow cytometric analysis of isolated intestinal lymphocytes. Results : Among seven olmesartan-treated patients who developed villous atrophy refractory to a gluten free diet, three had extra-intestinal autoimmune diseases, two had antibodies reacting with the 75 kilodalton antigen characteristic of AIE and one had serum anti-goblet cell antibodies. Small intestinal lesions and signs of intestinal lymphocyte activation were thus reminiscent of the four cases of AIE diagnosed during the same period. Before olmesartan discontinuation, remission was induced in all patients (7/7) by immunosuppressive drugs. After interruption of both olmesartan and immunosuppressive drugs in six patients, remission was maintained in 4 but anti-TNF-α therapy was needed in two.Conclusion : This case-series shows that olmesartan can induce intestinal damage mimicking AIE. OIE usually resolved after olmesartan interruption but immunosuppressive drugs may be necessary to achieve remission. Our data sustain the hypothesis that olmesartan interferes with intestinal immuno regulation in predisposed individuals.

Published
2015
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11. NKP46 EXPRESSION IS A DIAGNOSTIC AND PROGNOSTIC BIOMARKER IN PRIMARY GASTROINTESTINAL T-CELL LYMPHOPROLIFERATIONS. A CELAC NETWORK STUDY

Author

Bertrand Meresse, Elizabeth Macintyre, Ambroise Marçais, Georgia Malamut, Morgane Cheminant, Felipe Suarez, Laurent Frenzel, Amélie Trinquand, F. Lhospice, Nicole Brousse, Nicolas Guegan, Christophe Cellier, Olivier Hermine, Julie Bruneau, C. Bonnafous, Richard Delarue, David Sibon, Vahid Asnafi, Nadine Cerf-Bensussan, Thierry Jo Molina, and Ludovic Lhermitte

Subjects
0301 basic medicine, Cancer Research, Primary (chemistry), business.industry, T cell, Hematology, General Medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, Cancer research, Medicine, 030211 gastroenterology & hepatology, Prognostic biomarker, business

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