Search

Your search keyword '"University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK]"' showing total 8 results
Start Over Author "University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK]" Topic male
8 results on '"University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK]"'

1. Anti-MDA5 juvenile idiopathic inflammatory myopathy: a specific subgroup defined by differentially enhanced interferon-α signalling

Author

Florence Uettwiller, Makoto Miyara, François-Jérôme Authier, Maria José Martin-Niclos, Pierre Quartier, Alice Lepelley, Nicole Fabien, Alexandre Belot, Yanick J. Crow, Alice Hadchouel, Isabelle Melki, Emmanuelle Bourrat, Albert Faye, Darragh Duffy, Theresa Kwon, Brigitte Bader-Meunier, Carolina Uggenti, Sasi Mudumba, Lucile Musset, Gillian I. Rice, Vincent Bondet, Jean-Luc Charuel, Cyril Gitiaux, Naoki Kitabayashi, Cécile Dumaine, Marie-Louise Frémond, Christine Bodemer, Luis Seabra, Sébastien Viel, Plamen Bokov, Mathieu P Rodero, Yves Allenbach, Hervé Devilliers, Ahmed Kheniche, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Paris] (RAISE), AP-HP Hôpital universitaire Robert-Debré [Paris], Service de médecine interne et maladies systémiques (SOC 2) [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Necker - Enfants Malades [AP-HP], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie Translationnelle - Translational Immunology, Institut Pasteur [Paris], Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Pédiatrique des Pathologies du Sommeil [AP-HP Hôpital Robert Debré], Service de Néphrologie pédiatrique [Hôpital Robert Debré, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, Imagine - Institut des maladies génétiques (IMAGINE - U1163), 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), Service de Médecine Interne (SOC 1 et SOC 2) [CHU de Dijon], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), CHU Henri Mondor, Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre de référence national des Maladies Génétiques à Expression Cutanée (MAGEC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), University of Edinburgh, Modélisation et Immunologie pour la Thérapie (CBMIT), Université Paris Descartes - Paris 5 (UPD5), Y.J.C. and D.D. acknowledge support from the ANR (CE17001002) and thank Immunoqure for provision of mAbs for the Simoa assay. I.M. acknowledges support from the Bettencourt Schueler foundation through the Programme Santé-Sciences MD/PhD of Imagine Institute. F.-J.A. and C.G. acknowledge support from the AFM (CE17001002), The work was previously presented at PReS meeting 2018 (O18) and GCOM 2019 (O20), ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche en Myologie, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Henri Mondor [Créteil], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-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)-École normale supérieure de Lyon (ENS de Lyon)-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), Centre de référence national des Maladies Génétiques à Expression Cutanée - National Reference Center for Genodermatoses and Rare Skin Diseases (MAGEC), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Vougny, Marie-Christine, and Investigation des interferonopathies type I humaine - - IFNX2016 - ANR-16-CE17-0010 - AAPG2016 - VALID

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Interferon-Induced Helicase, IFIH1, [SDV.IMM] Life Sciences [q-bio]/Immunology, Adolescent, anti-MDA5 autoantibodies, [SDV]Life Sciences [q-bio], Arthritis, Alpha interferon, Gastroenterology, 03 medical and health sciences, Simoa, 0302 clinical medicine, Rheumatology, Internal medicine, medicine, Humans, interferon alpha, Pharmacology (medical), Prospective Studies, Child, Muscle, Skeletal, Myositis, ComputingMilieux_MISCELLANEOUS, Autoantibodies, Retrospective Studies, 030203 arthritis & rheumatology, Systemic lupus erythematosus, business.industry, interstitial lung disease (ILD), Autoantibody, Interstitial lung disease, Interferon-alpha, Skin ulcer, medicine.disease, 3. Good health, 030104 developmental biology, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, juvenile idiopathic inflammatory myopathies (JIIM), medicine.symptom, business, Signal Transduction
Abstract

Objectives JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). Methods This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. Results Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. Conclusion This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.

Published
2020

2. Type I interferon in patients with systemic autoimmune rheumatic disease is associated with haematological abnormalities and specific autoantibody profiles

Author

John A. Reynolds, Tracy A Briggs, Vincent Bondet, Ben Parker, Ariane L. Herrick, Sahena Haque, Hector Chinoy, Leo A. H. Zeef, Eoghan M. McCarthy, Gillian I. Rice, Sathya Darmalinggam, Ian N. Bruce, Andrew Hayes, Darragh Duffy, Ellen Bruce, Mumtaz Khan, University of Manchester [Manchester], Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Salford Royal NHS Foundation Trust [Salford, UK], This research was funded by the NIHR Manchester Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. This work was also supported by the Centre for Epidemiology Versus Arthritis (grant number 21755). Professor Bruce is an NIHR Senior Investigator and is funded by Versus Arthritis, the National Institute for Health Research Manchester Biomedical Research Centre and the NIHR Manchester Clinical Research Facility. Funding is also acknowledged from the National Institute for Health Research (NIHR) (NIHR Transitional Research Fellowship, Dr. Tracy Briggs, TRF-2016-09-002). This study was also supported by the Medical Research Council (MR/N003322/1). DD acknowledges support from the ANR (CE17001002) and Immunoqure for provision of mAbs for Simoa., Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), and ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016)

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, lcsh:Diseases of the musculoskeletal system, interferon-alpha, autoantibodies, Mucocutaneous zone, Alpha interferon, Autoimmune Diseases, Serology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Rheumatic Diseases, Internal medicine, Humans, Medicine, Whole blood, Autoantibodies, 030203 arthritis & rheumatology, business.industry, Autoantibody, Interferon-alpha, virus diseases, Middle Aged, Systemic autoimmune rheumatic disease, Rheumatology, 3. Good health, 030104 developmental biology, Interferon alpha, Interferon Type I, Cohort, Immunology, Absolute neutrophil count, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, lcsh:RC925-935, Transcriptome, business, Biomarkers, Research Article
Abstract

Objectives To investigate the relationships between interferon alpha (IFNα) and the clinical and serological phenotype of patients with systemic autoimmune rheumatic disease (SARDs) in order to determine whether a distinct subpopulation of patients can be identified. Methods We recruited patients with at least 1 SARD clinical feature and at least 1 SARD-related autoantibody from two NHS Trusts in Greater Manchester. A 6-gene interferon-stimulated gene (ISG) score was calculated in all patients, and in a subgroup, a 30-gene ISG score was produced using NanoString. A digital Single Molecule Array (Simoa) was used to measure plasma IFNα protein. In an exploratory analysis, whole blood RNA sequencing was conducted in 12 patients followed by RT-qPCR confirmation of expression of 6 nucleic acid receptors (NARs) in the whole cohort. Results Sixty three of 164 (38%) patients had a positive ISG score. The 3 measures of IFNα all correlated strongly with each other (p

Published
2019

3. The French version of the HSCL-25 has now been validated for use in primary care

Author

Jean Yves Le Reste, Morgane Guillou-Landreat, Paul Van Royen, Tristan Montier, Harm W.J. van Marwijk, Bernard Le Floch, Florence Gatineau, Patrice Nabbe, Department of general practice [Brest], Soins Primaires, Santé Publique, Registre des cancers de Bretagne Occidentale (SPURBO), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Department of addictology [Brest], Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Division of Population Health, Health Services Research and Primary Care [Manchester, Royaume-Uni], School of Health Sciences [Manchester, Royaume-Uni], Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-University of Manchester [Manchester], Department of Primary and Interdisciplinary Care [Anvers, Belgique], Faculty of Medicine and Health Sciences [Anvers, Belgique], Universiteit Antwerpen [Antwerpen]-Universiteit Antwerpen [Antwerpen], The study had a Grant of 8000 Euros from the European General Practitioners Research Network., Bodescot, Myriam, Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Institut Brestois Santé Agro Matière (IBSAM), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), and Universiteit Antwerpen = University of Antwerpen [Antwerpen]-Universiteit Antwerpen = University of Antwerpen [Antwerpen]

Subjects
Male, Psychometrics, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Pilot Projects, Anxiety, Geographical Locations, Mathematical and Statistical Techniques, 0302 clinical medicine, Surveys and Questionnaires, Outpatients, Medicine and Health Sciences, Medicine, 030212 general & internal medicine, Depression (differential diagnoses), Data Management, Aged, 80 and over, Principal Component Analysis, Multidisciplinary, Depression, Statistics, Middle Aged, 3. Good health, Test (assessment), Europe, Physical Sciences, Engineering and Technology, Female, France, medicine.symptom, Engineering sciences. Technology, Research Article, Clinical psychology, Adult, Computer and Information Sciences, Randomization, Adolescent, Patients, Science, MEDLINE, Research and Analysis Methods, Sensitivity and Specificity, Young Adult, 03 medical and health sciences, Cronbach's alpha, Diagnostic Medicine, Mental Health and Psychiatry, Humans, Translations, Internal validity, Statistical Methods, Primary Care, Aged, Primary Health Care, Mood Disorders, business.industry, Reproducibility of Results, 030227 psychiatry, Health Care, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, People and Places, Human Factors Engineering, Multivariate Analysis, Ergonomics, Human medicine, business, Mathematics
Abstract

Background\ud The Hopkins Symptom Checklist in 25 items (HSCL-25) helps to assess anxiety and depression in Primary Care. Anxiety and depression show considerable overlap in primary care. This self-administrated questionnaire is valid, reliable and ergonomic in the original US version. We have translated it into French. The aim of this study was to estimate the test characteristics of the HSCL-25, in its French version (F-HSCL-25), by comparing it to the Present State Examination-9 French version (F-PSE-9) and by determining its internal validity and dimensions.\ud \ud Method\ud Outpatients from three French General Practice settings (rural, semi-rural and urban) were recruited: approximately 20,000 outpatients among 17 GPs. Two groups were formed: F-HSCL-25 ≥1.75 and F-HSCL-25 1.75 was considered to indicate a clinically relevant level of symptoms of depression and anxiety. In order to obtain two balanced groups, a different method of randomization was chosen for each group. The F-PSE-9 was randomly administered to 1 in 2 patients in the F-HSCL-25 ≥1.75 group, and to 1 in 16 in the (much larger) F-HSCL-25

Published
2019

4. Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173 -activating mutations in 3 children

Author

Frédéric Rieux-Laucat, Didier Bessis, Bruno Charbit, Anne Hulin, Guilhem Cros, Philippe Reix, Darragh Duffy, Thierry Walzer, Muriel Le Bourgeois, Eric Jeziorski, Alexandre Belot, Mathieu P Rodero, Monique Fabre, Christine Bodemer, Yanick J. Crow, Stéphane Blanche, Nihel Khoudour, Nadia Jeremiah, Laureline Berteloot, Bénédicte Neven, Consuelo Modesto Caballero, Gillian I. Rice, Despina Moshous, Alain Fischer, Brigitte Bader-Meunier, Marie-Louise Frémond, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de néphrologie, rhumatologie et dermatologie pédiatriques, Hospices Civils de Lyon (HCL)-Hôpital Mère Enfant, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), University of Manchester [Manchester], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-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)-École normale supérieure de Lyon (ENS de Lyon)-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), Department of Nephrology-Rheumatology-Dermatology Pediatric, Bron, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de dermatologie [CHU de Montpellier], Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], CHU Henri Mondor [Créteil], Vall d'Hebron University Hospital [Barcelona], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Ressources et de Compétences en Mucoviscidose [Lyon] (CRCM [Lyon]), Hospices Civils de Lyon (HCL)-CHU Lyon-Hôpital Renée Sabran [CHU - HCL], Hospices Civils de Lyon (HCL), Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, CHU Henri Mondor, Chaire Médecine expérimentale (A. Fischer), and Davoine, Laure-Hélène

Subjects
0301 basic medicine, Male, Ruxolitinib, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, Pharmacology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, Journal Article, Immunology and Allergy, Medicine, Humans, Child, Preschool, Protein Kinase Inhibitors, ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 030203 arthritis & rheumatology, Mutation, Janus kinase 2, biology, Janus kinase 1, business.industry, Membrane Proteins, Janus Kinase 1, Janus Kinase 2, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, 030104 developmental biology, Membrane protein, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology.protein, Pyrazoles, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, business, medicine.drug
Abstract

International audience

Published
2016

5. Protein Kinase Cδ Deficiency Causes Mendelian Systemic Lupus Erythematosus With B Cell-Defective Apoptosis and Hyperproliferation

Author

Belot, Alexandre, Kasher, Paul R., Trotter, Eleanor W., Foray, Anne-Perrine, Debaud, Anne-Laure, Rice, Gillian I., Szynkiewicz, Marcin, Zabot, Marie-Therese, Rouvet, Isabelle, Bhaskar, Sanjeev S., Daly, Sarah B., Dickerson, Jonathan E., Mayer, Josephine, O'Sullivan, James, Juillard, Laurent, Urquhart, Jill E., Fawdar, Shameem, Marusiak, Anna A., Stephenson, Natalie, Waszkowycz, Bohdan, W Beresford, Michael, Biesecker, Leslie G., C M Black, Graeme, René, Céline, Eliaou, Jean-François, Fabien, Nicole, Ranchin, Bruno, Cochat, Pierre, Gaffney, Patrick M., Rozenberg, Flore, Lebon, Pierre, Malcus, Christophe, Crow, Yanick J., Brognard, John, Bonnefoy, Nathalie, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genetic Medicine, University of Manchester [Manchester]-Faculty of Human and Medical Sciences, Paterson Institute for Cancer Research, University of Manchester [Manchester]-Cancer Research UK, Manchester Centre for Genomic Medicine, St Mary's Hospital-Central Manchester University Hospitals NHS Foundation Trust-Manchester Academic Health Sciences Centre, Centre de Biotechnologie cellulaire, Hospices Civils de Lyon (HCL), Hôpital Edouard Herriot [CHU - HCL], University of Liverpool, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre de Référence des Maladies Rénales Rares, Hospices Civil de Lyon, Oklahoma Medical Research Foundation (OMRF), Université Paris Descartes - Paris 5 (UPD5), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-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)-École normale supérieure de Lyon (ENS de Lyon)-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), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Institut de recherche en cancérologie de Montpellier (IRCM - U896 Inserm - UM1), Université Montpellier 1 (UM1)-CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], and University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester

Subjects
Male, Adult, Adolescent, Mutation, Missense, Apoptosis, Polymorphism, Single Nucleotide, Article, Young Adult, Immune Tolerance, Lupus Erythematosus, Systemic, Humans, Polymorphism, Child, Cell Proliferation, B-Lymphocytes, Hyperplasia, Lupus Erythematosus, Systemic, Homozygote, Genetic Variation, Single Nucleotide, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Protein Kinase C-delta, Mutation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Missense
Abstract

International audience; OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that is assumed to occur via a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. The aim of this study was to identify the cause of an autosomal-recessive form of SLE. METHODS: We studied 3 siblings with juvenile-onset SLE from 1 consanguineous kindred and used next-generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunologic, and functional assays to assess the impact of the identified mutations on B cell biology. RESULTS: We identified a homozygous missense mutation in PRKCD, encoding protein kinase δ (PKCδ), in all 3 affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKCδ (involved in the deletion of autoreactive B cells), leading to resistance to B cell receptor- and calcium-dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKCδ, which exhibit an SLE phenotype and B cell expansion, we observed an increased number of immature B cells in the affected family members and a developmental shift toward naive B cells with an immature phenotype. CONCLUSION: Our findings indicate that PKCδ is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKCδ deficiency represents a novel genetic defect of apoptosis leading to SLE.

Published
2013
Full Text
View/download PDF

6. Mutations in SNORD118 cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts

Author

Elliott H. Sherr, Edward Blair, Charles Marques Lourenço, James O'Sullivan, Imke Metz, Paul R. Kasher, Gabriela M. Baerlocher, Adeline Vanderver, David Cassiman, Himanshu Goel, Nicholas A. Fletcher, Patrick Ferreira, Patrick Revy, Emma Wakeling, Ram L. Kumar, Lieven Lagae, Christopher J. Kershaw, Pierre Landrieu, Andrea Whitney, Calvin Soh, Christine E. G. van Mol, Sakkubai Naidu, John H. Livingston, Geraldine Aubert, H. Stewart, Laurence C. Goosey, Liesbeth De Waele, Kristin W. Barañano, Rosalind J. Jefferson, Axel Panzer, Gerardine Quaghebeur, Raphael Schiffmann, Yanick J. Crow, Hilde Van Esch, Raymond T. O'Keefe, Jill E. Urquhart, Alan Fryer, Mathieu P Rodero, Alex J. Fay, Monika Haubitz, Andrea Berger, Johannes A. Buckard, Cheryl Hemingway, Angela Barnicoat, Sam Griffiths-Jones, Duccio Maria Cordelli, Imelda Hughes, Katrin Õunap, Graham D. Pavitt, Roberta Battini, Yoann Rose, Marjo S. van der Knaap, Sanjeev S. Bhaskar, John Stone, Gillian I. Rice, Marco Henneke, Kanaga R. Sinnathuray, Emma M. Jenkinson, Timothy J. Malpas, Simon G. Williams, Anthony Oojageer, Carolina Uggenti, Rosaline Caumes, Prab Prabhakar, Sarju G. Mehta, Janice E. Brunstrom-Hernandez, Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Manchester [Manchester], Department of Medical Genetics, HMNC Brain Health, Other departments, Jenkinson, Emma M., Rodero, Mathieu P., Kasher, Paul R., Uggenti, Carolina, Oojageer, Anthony, Goosey, Laurence C., Rose, Yoann, Kershaw, Christopher J., Urquhart, Jill E., Williams, Simon G., Bhaskar, Sanjeev S., O'Sullivan, Jame, Baerlocher, Gabriela M., Haubitz, Monika, Aubert, Geraldine, Barañano, Kristin W., Barnicoat, Angela J., Battini, Roberta, Berger, Andrea, Blair, Edward M., Brunstrom-Hernandez, Janice E., Buckard, Johannes A., Cassiman, David M., Caumes, Rosaline, Cordelli, Duccio M., De Waele, Liesbeth M., Fay, Alexander J., Ferreira, Patrick, Fletcher, Nicholas A., Fryer, Alan E., Goel, Himanshu, Hemingway, Cheryl A., Henneke, Marco, Hughes, Imelda, Jefferson, Rosalind J., Kumar, Ram, Lagae, Lieven, Landrieu, Pierre G., Lourenço, Charles M., Malpas, Timothy J., Mehta, Sarju G., Metz, Imke, Naidu, Sakkubai, Õunap, Katrin, Panzer, Axel, Prabhakar, Prab, Quaghebeur, Gerardine, Schiffmann, Raphael, Sherr, Elliott H., Sinnathuray, Kanaga R., Soh, Calvin, Stewart, Helen S., Stone, John, Van Esch, Hilde, Van Mol, Christine E. G., Vanderver, Adeline, Wakeling, Emma L., Whitney, Andrea, Pavitt, Graham D., Griffiths-Jones, Sam, Rice, Gillian I., Revy, Patrick, Van Der Knaap, Marjo S., Livingston, John H., O'Keefe, Raymond T., Crow, Yanick J., Pediatric surgery, and Amsterdam Neuroscience - Cellular & Molecular Mechanisms

Subjects
0301 basic medicine, Male, Genetic Linkage, [SDV]Life Sciences [q-bio], Ribosome biogenesis, medicine.disease_cause, Leukoencephalopathy, Leukoencephalopathie, Cohort Studies, 0302 clinical medicine, Leukoencephalopathies, Exome, Small nucleolar RNA, 610 Medicine & health, Child, ComputingMilieux_MISCELLANEOUS, Genetics, Mutation, Genome, Cysts, Calcinosis, Middle Aged, Phenotype, Child, Preschool, Calcinosi, Female, Sequence Analysis, Human, Adult, Adolescent, Biology, Chromosomes, Cell Line, 03 medical and health sciences, Young Adult, medicine, RNA, Small Nucleolar, Humans, Preschool, Gene, Small Nucleolar, Genome, Human, Pair 17, RNA, Infant, Sequence Analysis, DNA, DNA, Cerebral Small Vessel Diseases, Chromosomes, Human, Pair 17, medicine.disease, Cerebral Small Vessel Disease, 030104 developmental biology, Cyst, Cohort Studie, 030217 neurology & neurosurgery
Abstract

Although ribosomes are ubiquitous and essential for life, recent data indicate that monogenic causes of ribosomal dysfunction can confer a remarkable degree of specificity in terms of human disease phenotype. Box C/D small nucleolar RNAs (snoRNAs) are evolutionarily conserved non-protein-coding RNAs involved in ribosome biogenesis. Here we show that biallelic mutations in the gene SNORD118, encoding the box C/D snoRNA U8, cause the cerebral microangiopathy leukoencephalopathy with calcifications and cysts (LCC), presenting at any age from early childhood to late adulthood. These mutations affect U8 expression, processing and protein binding and thus implicate U8 as essential in cerebral vascular homeostasis.

Published
2016

7. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome

Author

Daphne Heijsman, Rachel Schot, Grazia M.S. Mancini, Scott D. Speer, Frans W. Verheijen, Leontine van Unen, Rob Willemsen, Zhi Li, Johan M. Kros, Femke A.T. de Vries, Grétel Oudesluijs, Aida Bertoli Avella, Dusan Bogunovic, Marije E.C. Meuwissen, Marta Martín-Fernández, Rutger W W Brouwer, Maarten H. Lequin, Irenaeus F.M. de Coo, Yanick J. Crow, Sigrid Tinschert, Wilfred F. J. van IJcken, Jeroen Dudink, Tobias Goldmann, Mark Hermann, Sofija Buta, Wendy Stam, Marco Prinz, Sandra Pellegrini, Li, Zhi, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Medical Faculty Carl Gustav Carus, Technische Universität Dresden = Dresden University of Technology (TU Dresden), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Signalisation des Cytokines, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), institute of neuropathology, University of Freiburg [Freiburg], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Financial support was obtained by NutsOhra Funds project 1203-030 to G.M.S. Mancini. D. Bogunovic is supported by the National Institute of Allergy and Infectious Diseases grant number R00AI106942-02. Z. Li and S. Pellegrini acknowledge institutional support from Institut Pasteur, Centre National de la Recherche Scientifique, and Institut National de la Santé et de la Recherche Médicale. Y.J. Crow acknowledges the European Research Council (GA 309449)., Innsbruck Medical University [Austria] (IMU), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Clinical Genetics, Pathology, Radiology & Nuclear Medicine, Cell biology, Neurology, and Pediatrics

Subjects
Male, 0301 basic medicine, MESH: Signal Transduction, MESH: Interferon Type I, Microcephaly, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Calcinosis, Torch syndrome, Polymicrogyria, Immunology and Allergy, MESH: Endopeptidases, Research Articles, Genetic disorder, Brain, Calcinosis, 3. Good health, MESH: Microglia, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Immunity, Innate, Microglia, medicine.symptom, Ubiquitin Thiolesterase, Signal Transduction, medicine.drug, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Inflammation, Biology, Nervous System Malformations, MESH: Nervous System Malformations, 03 medical and health sciences, MESH: Brain, Autoimmune Diseases of the Nervous System, Endopeptidases, medicine, Journal Article, Humans, [SDV.GEN]Life Sciences [q-bio]/Genetics, Innate immune system, MESH: Humans, Brief Definitive Report, medicine.disease, Immunity, Innate, MESH: Male, MESH: Autoimmune Diseases of the Nervous System, 030104 developmental biology, Human medicine, MESH: Female, Interferon type I, Calcification
Abstract

Meuwissen and collaborators define a novel genetic cause of pseudo-TORCH syndrome, which resembles the sequelae of congenital infection and represents a novel type I interferonopathy., Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.

Published
2016

8. PRKDC mutations associated with immunodeficiency, granuloma, and autoimmune regulator-dependent autoimmunity

Author

Marie Therese Zabot, Jolan E. Walter, Anne Laure Mathieu, Marie Chansel, Gillian I. Rice, Jean-Pierre de Villartay, Luigi D. Notarangelo, Christine Ménétrier-Caux, François Plenat, Nicole Fabien, Brigitte Balme, Kari C. Nadeau, Chantal Rigal, E. Helen Kemp, Annick Lim, Christophe Malcus, Yves Bertrand, Sébastien Viel, Mirjam van der Burg, Despina Moshous, Jacques Bienvenu, A. Phan, Christine Bardin, Catharina Schuetz, Thierry Walzer, Christophe Caux, Capucine Picard, Ana Delgado, David J. Chen, Manish J. Butte, Krisztian Csomos, Isabelle Rouvet, Karin Chen, Jean François Meritet, Alexandre Belot, Héloïse Reumaux, Fanny Fouyssac, Pierre Cochat, Yanick J. Crow, Estelle Verronese, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Manchester Centre for Genomic Medicine (MCGM), Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-St Mary's Hospital Manchester, Service d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Immunology and Inflammatory Diseases [Boston, MA, USA], Harvard Medical School [Boston] (HMS), Department of Microbiology and Immunology [Stanford], Stanford Medicine, Stanford University-Stanford University, University of Texas Southwestern Medical Center, University of Utah School of Medicine [Salt Lake City], Department of Pediatrics and Adolescent Medicine, Universität Ulm - Ulm University [Ulm, Allemagne], Unité Pédiatrique [Jeanne de Flandre], Hôpital Jeanne de Flandre [Lille], Service de Pathologie [CHRU Nancy], Epidémiologie, Pharmacologie, Investigation Clinique, Information médicale, Mère-Enfant (EPICIME), Département de Pathologie [CHU Lyon-Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Sheffield [Sheffield], Hospices Civils de Lyon, Laboratoire d'Immunologie, Groupement Hospitalier Edouard Herriot, 5 Place d'Arsonval, F-69437, Lyon Cedex 03, France, parent, Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris], Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-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)-École normale supérieure de Lyon (ENS de Lyon)-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), Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Institut Pasteur [Paris] (IP), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Manchester Centre for Genomic Medicine, St Mary's Hospital-Central Manchester University Hospitals NHS Foundation Trust-Manchester Academic Health Sciences Centre, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Microbiology and Immunology, Stanford University School of Medicine [CA, USA], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], and Immunology

Subjects
Male, DNA End-Joining Repair, Skin Neoplasms, DCLRE1C, Autoimmunity, DNA-Activated Protein Kinase, medicine.disease_cause, DNA-Dependent Protein Kinase Catalytic Subunit, Immune tolerance, Mice, Immunology and Allergy, DNA-PKcs, B-Lymphocytes, Granuloma, tolerance, PRKDC, recombination-activating gene, V(D)J recombination, Nuclear Proteins, severe combined immunodeficiency, Autoimmune regulator, 3. Good health, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adolescent, Immunology, Biology, Article, Young Adult, Th2 Cells, SDG 3 - Good Health and Well-being, medicine, Immune Tolerance, Animals, Humans, Autoantibodies, Severe combined immunodeficiency, Immunologic Deficiency Syndromes, Th1 Cells, VDJ recombination, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, V(D)J Recombination, Gene Expression Regulation, DNA-dependent protein kinase catalytic subunit, Mutation, Cancer research, Transcription Factors
Abstract

International audience; BACKGROUND: PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase [DNA-PK]) crucial for DNA double-strand break repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. OBJECTIVE: We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. METHODS: Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. RESULTS: We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T~cells displayed a skewed cytokine response typical of TH2 and TH1 but not TH17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in~vitro. The latter defect correlated in~vivo with production of anti-calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1~had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. CONCLUSION: Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.

Published
2015

Catalog

Books, media, physical & digital resources
See catalog results