Author: "Shen, Ying" / Topic: medicine.disease - Searchworks@Jio Institute Digital Library Search Results

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1. Measles Sclerosing Subacute PanEncephalitis (SSPE), an intriguing and ever-present disease: Data, assumptions and new perspectives

Author: A. Gelot, Pierre Lebon, Jean-Laurent Casanova, Shen-Ying Zhang, and J.-J. Hauw
Subjects: Adult, Pediatrics, medicine.medical_specialty, Neurological complication, Fulminant, Disease, Communicable Diseases, Measles, Subacute sclerosing panencephalitis, Measles virus, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, medicine, Humans, 030212 general & internal medicine, Epidemics, Exome sequencing, biology, business.industry, Vaccination, biology.organism_classification, medicine.disease, Neurology, Female, Subacute Sclerosing Panencephalitis, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Background Subacute sclerosing panencephalitis (SSPE) is a rare, non-treatable and fatal neurological complication of measles , still present due to the return of the epidemic linked to the loosening of vaccination policies. Its mechanism remains unexplained. Objective The main objective was to investigate explanatory variables relating to the risk of developing SSPE and its pathophysiology . Methods Literature analysis was focused on different varieties of SSPE: perinatal forms, short-incubation forms similar to acute measles inclusion body encephalitis (MIBE), rapidly evolving forms, forms occurring in the immunosuppressed, adult forms, and family forms. In addition, several studies on the parameters of innate immunity and interferon responses of patients were analyzed. Results Two main data were highlighted: a relationship between the so-called fulminant forms and the prescription of corticosteroids was established. In familial SSPE, two groups were individualized according to the duration of the latency period, prompting an analysis of patient exomes . Conclusion Treatment with corticosteroids should be banned. Knowledge of the genes involved and epigenetics should be useful for understanding the pathophysiology of SSPE and other late-onset neurological infections with RNA viruses .
Published: 2021

2. Molecular and Cellular Dynamics of Aortic Aneurysms Revealed by Single-Cell Transcriptomics

Author: DeBakey, Michael E., Li, Yanming, LeMaire, Scott A., and Shen, Ying H.
Subjects: Cell type, Myocytes, Smooth Muscle, Cell, Computational biology, Biology, Article, Aneurysm, medicine, Animals, Humans, RNA-Seq, Transcription factor, Gene, Aorta, Gene Expression Profiling, Endothelial Cells, RNA, Fibroblasts, medicine.disease, Phenotype, Aortic Aneurysm, medicine.anatomical_structure, Single-Cell Analysis, Transcriptome, Cardiology and Cardiovascular Medicine, Function (biology), Dilatation, Pathologic
Abstract: The aorta is highly heterogeneous, containing many different types of cells that perform sophisticated functions to maintain aortic homeostasis. Recently, single-cell RNA sequencing studies have provided substantial new insight into the heterogeneity of vascular cell types, the comprehensive molecular features of each cell type, and the phenotypic interrelationship between these cell populations. This new information has significantly improved our understanding of aortic biology and aneurysms at the molecular and cellular level. Here, we summarize these findings, with a focus on what single-cell RNA sequencing analysis has revealed about cellular heterogeneity, cellular transitions, communications among cell populations, and critical transcription factors in the vascular wall. We also review the information learned from single-cell RNA sequencing that has contributed to our understanding of the pathogenesis of vascular disease, such as the identification of cell types in which aneurysm-related genes and genetic variants function. Finally, we discuss the challenges and future directions of single-cell RNA sequencing applications in studies of aortic biology and diseases. Graphic Abstract: A graphic abstract is available for this article.
Published: 2021

3. Neuron-intrinsic immunity to viruses in mice and humans

Author: Oliver Harschnitz, Jean-Laurent Casanova, Lorenz Studer, and Shen-Ying Zhang
Subjects: Intrinsic immunity, viruses, Immunology, Central nervous system, Biology, medicine.disease_cause, Article, Mice, Species Specificity, Immunity, medicine, Animals, Humans, Immunology and Allergy, Induced pluripotent stem cell, Disease Resistance, Neurons, Viral encephalitis, medicine.disease, Rats, Toll-Like Receptor 3, Herpes simplex virus, medicine.anatomical_structure, Virus Diseases, Host-Pathogen Interactions, Interferon Type I, TLR3, Central Nervous System Viral Diseases, Disease Susceptibility, Neuron, Biomarkers
Abstract: Viral encephalitis is a major neglected medical problem. Host defense mechanisms against viral infection of the central nervous system (CNS) have long remained unclear. The few previous studies of CNS-specific immunity to viruses in mice in vivo and humans in vitro have focused on the contributions of circulating leukocytes, resident microglial cells and astrocytes, with neurons long considered passive victims of viral infection requiring protection from extrinsic antiviral mechanisms. The last decade has witnessed the gradual emergence of the notion that neurons also combat viruses through cell-intrinsic mechanisms. Forward genetic approaches in humans have shown that monogenic inborn errors of TLR3, IFN-α/β, or snoRNA31 immunity confer susceptibility to herpes simplex virus 1 (HSV-1) infection of the forebrain, whereas inborn errors of DBR1 underlie brainstem infections due to various viruses, including HSV-1. The study of human pluripotent stem cell (hPSC)-derived CNS-resident cells has unraveled known (i.e. TLR3-dependent IFN-α/β immunity) and new (i.e. snoRNA31-dependent or DBR1-dependent immunity) cell-intrinsic antiviral mechanisms operating in neurons. Reverse genetic approaches in mice have confirmed that some known antiviral mechanisms also operate in mouse neurons (e.g. TLR3 and IFN-α/β immunity). The search for human inborn errors of immunity (IEIs) underlying various forms of viral encephalitis, coupled with mouse models in vivo, and hPSC-based culture models of CNS and peripheral nervous system cells and organoids in vitro, should shed further light on the cell-specific and tissue-specific mechanisms of host defense against viruses in the human brain.
Published: 2021

4. A global effort to dissect the human genetic basis of resistance to SARS-CoV-2 infection

Author: Andreakos, Evangelos, Abel, Laurent, Vinh, Donald C., Kaja, Elżbieta, Drolet, Beth A., Zhang, Qian, O’Farrelly, Cliona, Novelli, Giuseppe, Rodríguez-Gallego, Carlos, Haerynck, Filomeen, Prando, Carolina, Pujol, Aurora, Bastard, Paul, Biggs, Catherine M., Bigio, Benedetta, Boisson, Bertrand, Bolze, Alexandre, Bondarenko, Anastasiia, Brodin, Petter, Chakravorty, Samya, Christodoulou, John, Cobat, Aurelié, Condino-Neto, Antonio, Constantinescu, Stefan N., Feldman, Hagit Baris, Fellay, Jacques, Flores, Carlos, Halwani, Rabih, Jouanguy, Emmanuelle, Lau, Yu-Lung, Meyts, Isabelle, Mogensen, Trine H., Okada, Satoshi, Okamoto, Keisuke, Ozcelik, Tayfun, Pan-Hammarström, Qiang, Diego, Rebeca Pérez de, Planas, Anna M., Puel, Anne, Quintana-Murci, Lluis, Renia, Laurent, Resnick, Igor, Sediva, Anna, Shcherbina, Anna, Slaby, Ondrej, Tancevski, Ivan, Turvey, Stuart E., Uddin, K. M. Furkan, van de Beek, Diederik, Zatz, Mayana, Zawadzki, Pawel, Zhang, Shen-Ying, Su, Helen C., Casanova, Jean-Laurent, Spaan, András N., Biomedical Research Foundation of the Academy of Athens (BRFAA), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Department of Medecine [Montréal], McGill University = Université McGill [Montréal, Canada], University of Wisconsin-Madison, Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Trinity College Dublin, University of Rome Tor Vergata, Hospital Universitario de Gran Canaria Dr Negrin, Universidad de las Palmas de Gran Canaria (ULPGC), Ghent University Hospital, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Institució Catalana de Recerca i Estudis Avançats (ICREA), CIBER de Enfermedades Raras (CIBERER), University of British Columbia (UBC), Karolinska Institutet [Stockholm], Emory University [Atlanta, GA], University of Melbourne, Universidade de São Paulo = University of São Paulo (USP), Université Catholique de Louvain = Catholic University of Louvain (UCL), Tel Aviv University (TAU), School of Life Sciences [Lausanne], Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Lausanne = University of Lausanne (UNIL), University of Sharjah (UoS), Department of Paediatrics and Adolescent Medicine [HKU], The University of Hong Kong (HKU), University Hospitals Leuven [Leuven], Department of Microbiology, Immunology and Transplantation [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Aarhus University Hospital, Hiroshima University, Tokyo Medical and Dental University [Japan] (TMDU), Bilkent University [Ankara], Department of Biosciences and Nutrition [Karolinska Insitutet, Sueden] (BioNut), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Collège de France - Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), Agency for science, technology and research [Singapore] (A*STAR), Nanyang Technological University [Singapour], Faculty of Medicine [Brno] (MED / MUNI), Masaryk University [Brno] (MUNI), Leopold Franzens Universität Innsbruck - University of Innsbruck, University of Amsterdam [Amsterdam] (UvA), Adam Mickiewicz University in Poznań (UAM), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), University Medical Center [Utrecht], The Laboratory of Human Genetics of Infectious Diseases is supported by the National Institutes of Health (NIH) (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the French National Research Agency (ANR) under the Investments for the Future program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANR-20-COVI-0003), ANRS-COV05, the Fondation du Souffle, the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM), and the University of Paris. E.A. is supported by research grants from the European Commission’s Horizon 2020 research and innovation program (IMMUNAID, grant no. 779295, CURE, grant no. 767015 and TO_AITION grant no. 848146) and the Hellenic Foundation for Research and Innovation (INTERFLU, no. 1574). C.O.F. is supported in part by the Science Foundation Ireland COVID-19 Program. G.N. is supported by a grant awarded to Regione Lazio (Research Group Projects 2020) no. A0375-2020-36663, GecoBiomark. A.P. is supported in part by the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342) and the CERCA Program/Generalitat de Catalunya. H.S. is supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. A.S. is supported in part by the European Union’s Horizon 2020 research and innovation program (Marie Sklodowska-Curie grant no. 789645)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), Özçelik, Tayfun, Department of Public Health and Cell Biology, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy, Université Paris Cité, Equipe HAL, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé - - GENCOVID2020 - ANR-20-COVI-0003 - COVID-19 - VALID, National Institutes of Health (US), National Center for Advancing Translational Sciences (US), National Human Genome Research Institute (US), Fisher Center for Alzheimer's Research Foundation, Meyer Foundation, Agence Nationale de la Recherche (France), Fondation pour la Recherche Médicale, Pershing Square Foundation, Institut National de la Santé et de la Recherche Médicale (France), Howard Hughes Medical Institute, Rockefeller University, St. Giles Foundation, Université de Paris, European Commission, Hellenic Foundation for Research and Innovation, Science Foundation Ireland, Regione Lazio, Generalitat de Catalunya, and National Institute of Allergy and Infectious Diseases (US)
Subjects: Tuberculosis, autoantibodies, Immunology, Plasmodium vivax, restriction, Disease, Asymptomatic, Risk Assessment, Chemokine receptor, Genetic Heterogeneity, Immunity, Risk Factors, il28b, medicine, Immunology and Allergy, Animals, Humans, PLASMODIUM, Genetic Predisposition to Disease, Disease Resistance, Genetics, biology, Transmission (medicine), SARS-CoV-2, transmission, Autoantibody, COVID-19, virus diseases, deficiency, Protective Factors, hiv-1 infection, biology.organism_classification, medicine.disease, immunity, Phenotype, tuberculosis, Settore MED/03, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Viral infection, Host-Pathogen Interactions, Perspective, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, Infection, individuals, inborn-errors
Abstract: SARS-CoV-2 infections display tremendous interindividual variability, ranging from asymptomatic infections to life-threatening disease. Inborn errors of, and autoantibodies directed against, type I interferons (IFNs) account for about 20% of critical COVID-19 cases among SARS-CoV-2-infected individuals. By contrast, the genetic and immunological determinants of resistance to infection per se remain unknown. Following the discovery that autosomal recessive deficiency in the DARC chemokine receptor confers resistance to Plasmodium vivax, autosomal recessive deficiencies of chemokine receptor 5 (CCR5) and the enzyme FUT2 were shown to underlie resistance to HIV-1 and noroviruses, respectively. Along the same lines, we propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to SARS-CoV-2 infection., The Laboratory of Human Genetics of Infectious Diseases is supported by the National Institutes of Health (NIH) (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the French National Research Agency (ANR) under the Investments for the Future program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANR-20-COVI-0003), ANRS-COV05, the Fondation du Souffle, the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM), and the University of Paris. E.A. is supported by research grants from the European Commission’s Horizon 2020 research and innovation program (IMMUNAID, grant no. 779295, CURE, grant no. 767015 and TO_AITION grant no. 848146) and the Hellenic Foundation for Research and Innovation (INTERFLU, no. 1574). C.O.F. is supported in part by the Science Foundation Ireland COVID-19 Program. G.N. is supported by a grant awarded to Regione Lazio (Research Group Projects 2020) no. A0375-2020-36663, GecoBiomark. A.P. is supported in part by the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342) and the CERCA Program/Generalitat de Catalunya. H.S. is supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. A.S. is supported in part by the European Union’s Horizon 2020 research and innovation program (Marie Sklodowska-Curie grant no. 789645).
Published: 2022

5. Herpes simplex virus encephalitis of childhood: inborn errors of central nervous system cell-intrinsic immunity

Author: Shen-Ying Zhang
Subjects: Intrinsic immunity, Herpesvirus 1, Human, Biology, medicine.disease_cause, Article, 03 medical and health sciences, Central Nervous System Diseases, Immunity, Genetics, medicine, Humans, Genetic Predisposition to Disease, Child, Genetics (clinical), 030304 developmental biology, Immunity, Cellular, 0303 health sciences, Mutation, Viral encephalitis, 030305 genetics & heredity, Herpes Simplex, medicine.disease, Penetrance, Human genetics, Herpes simplex virus, Host-Pathogen Interactions, Immunology, Encephalitis, Herpes Simplex, Encephalitis
Abstract: Herpes simplex virus 1 (HSV-1) encephalitis (HSE) is the most common sporadic viral encephalitis in Western countries. Over the last 15 years, human genetic and immunological studies have provided proof-of-principle that childhood HSE can result from inborn errors of central nervous system (CNS)-specific, cell-intrinsic immunity to HSV-1. HSE-causing mutations of eight genes disrupt known (TLR3-dependent IFN-α/β immunity) and novel (dependent on DBR1 or snoRNA31) antiviral mechanisms. Monogenic inborn errors confer susceptibility to forebrain (TLR3-IFN or snoRNA31) or brainstem (DBR1) HSE. Most of these disorders display incomplete clinical penetrance, with the possible exception of DBR1 deficiency. They account for a small, but non-negligible proportion of cases (about 7%). These findings pave the way for the gradual definition of the genetic and immunological architecture of childhood HSE, with both biological and clinical implications.
Published: 2020

6. A novel small-molecule PI3K/Akt signaling inhibitor, W934, exhibits potent antitumor efficacy in A549 non-small-cell lung cancer

Author: San-Qi Zhang, Hui-Yan Wang, Dong Liang, Yong-Xiao Cao, Hong-Ying Wang, Lei Cao, Shen Ying, and Jin Wang
Subjects: 0301 basic medicine, Cancer Research, Lung Neoplasms, Mice, Nude, Angiogenesis Inhibitors, Antineoplastic Agents, Apoptosis, Small Molecule Libraries, Mice, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, 0302 clinical medicine, Cell Movement, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, medicine, Animals, Humans, Pharmacology (medical), Lung cancer, Protein Kinase Inhibitors, PI3K/AKT/mTOR pathway, Cell Proliferation, Pharmacology, A549 cell, Mice, Inbred BALB C, Akt/PKB signaling pathway, Kinase, Chemistry, Cell Cycle, Cell cycle, HCT116 Cells, medicine.disease, Xenograft Model Antitumor Assays, 030104 developmental biology, Oncology, A549 Cells, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Female, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract: Small-molecule targeted antitumor drugs are considered to be a promising treatment that can improve the efficacy and reduce side effects. PI3K/Akt signaling pathway is constantly activated in various cancers. We recently synthesized a series of novel compounds of PI3K/Akt pathway inhibitors and found the most effective analog to be W934. In this study, we explored the in-vitro and in-vivo antitumor effects of W934 on A549 non-small-cell lung cancer cells and HCT116 colorectal cancer cells. In-vitro assays showed that W934 caused an inhibition of PI3Kα kinase. W934 can significantly suppress the viability of A549 and HCT116 cells with IC50 values of 0.25 and 0.23 μmol/l, respectively. Besides, the inhibitory effects on cell migration, invasion and apoptosis were also observed after treatment of W934 for the indicated hours. According to the cell cycle analysis, W934 caused an inhibition of G0-G1 phase progression and correspondingly decreased the percentage of cells in S and G2-M phases. Results of western blotting indicated that W934 concentration dependently suppressed the activation of the PI3K/Akt pathway. Meanwhile, the in-vivo effect was studied in an A549 xenograft mouse model. Oral administration of W934 inhibited the tumor growth in a dose-dependent manner. Hereby, W934 might be considered as a potential therapeutic drug candidate for non-small-cell lung cancer treatment.
Published: 2019

7. A monocyte/dendritic cell molecular signature of SARS-CoV-2-related multisystem inflammatory syndrome in children with severe myocarditis

Author: Cécile Masson, Aurélien Corneau, Florence Moulin, Ghaith Abdessalem, Pedro Gonçalves, Marianne Leruez, James P. Di Santo, Mathie Lorrot, Julie Toubiana, Julien Haroche, Camille Bruneau, Isabelle Melki, Bruno Charbit, Zahra Belhadjer, Loïc de Pontual, Camille de Cevins, Brigitte Bader Meunier, Alain Fischer, Victor Garcia-Paredes, Brieuc P. Perot, Marine Luka, Damien Bonnet, Quentin Riller, Nikaïa Smith, Slimane Allali, Sonia Meynier, Aude Magérus, Christele Gras Leguen, Shen-Ying Zhang, Olivier Schwartz, Jean-Laurent Casanova, Frédéric Rieux-Laucat, Nicolas Cagnard, Francesco Carbone, Tinhinane Fali, Mélanie Parisot, Mickaël M. Ménager, Maxime Beretta, Mohammed Zarhrate, Christine Bole-Feysot, Vithura Pirabarakan, Ludivine Grzelak, Mehdi Oualha, Darragh Duffy, Laura Barnabei, Hugo Mouquet, Maxime Batignes, Alexandre Boullé, Boris Sorin, Marie-Claude Stolzenberg, Inflammatory Responses and Transcriptomic Networks in diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), 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), Sanofi Aventis R&D [Chilly-Mazarin], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Immunité Innée - Innate Immunity, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Rockefeller University [New York], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital universitaire Robert-Debré [Paris], Université Paris Cité (UPCité), CHU Trousseau [APHP], Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Jean Verdier [AP-HP], Université Paris 13 (UP13), Collège de France (CdF (institution)), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-17-EURE-0013,GENE,Génétique et Epigénétique Nouvelle Ecole(2017), ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), and Université Paris Cité (UPC)
Subjects: Adult, Vascular Endothelial Growth Factor A, Chemokine, Myocarditis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], MIS-C, Monocytes, chemistry.chemical_compound, Viewpoint, scRNA-seq, medicine, otorhinolaryngologic diseases, Humans, Kawasaki Disease, Child, Connective Tissue Diseases, biology, business.industry, SARS-CoV-2, Monocyte, NF-kappa B, COVID-19, General Medicine, Dendritic Cells, Gene signature, medicine.disease, Pathophysiology, Systemic Inflammatory Response Syndrome, Vascular endothelial growth factor, medicine.anatomical_structure, Cytokine, chemistry, TNF-α and NF-κB signaling, Immunology, biology.protein, Cytokines, Tumor necrosis factor alpha, lack of responses to type I and type II IFN secretion, Clinical and Translational Article, Chemokines, myocarditis, business, PIMS-TS
Abstract: Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is generally milder than in adults, but a proportion of cases result in hyperinflammatory conditions often including myocarditis. Methods To better understand these cases, we applied a multiparametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. Plasma cytokine and chemokine levels and blood cellular composition were measured, alongside gene expression at the bulk and single-cell levels. Findings The most severe forms of multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 that resulted in myocarditis were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomics analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis characterized by sustained nuclear factor κB (NF-κB) activity and tumor necrosis factor alpha (TNF-α) signaling and associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type I and type II interferons, hyperinflammation, and response to oxidative stress related to increased HIF-1α and Vascular endothelial growth factor (VEGF) signaling. Conclusions These results provide potential for a better understanding of disease pathophysiology. Funding Agence National de la Recherche (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01; Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010; Laboratoire d’Excellence ‘‘Milieu Intérieur,” grant ANR-10-LABX-69-01; ANR-flash Covid19 “AIROCovid” and “CoVarImm”), Institut National de la Santé et de la Recherche Médicale (INSERM), and the “URGENCE COVID-19” fundraising campaign of Institut Pasteur., Graphical abstract, Context and significance Children with SARS-CoV-2 infection were initially thought to have only mild COVID-19 symptoms. However, several weeks into the first wave of SARS-CoV-2 infections, there was a surge of a postacute pathology called multisystem inflammatory syndrome in children (MIS-C). The authors recruited a cohort of children with suspicion of SARS-CoV-2 infection and uncovered hyperinflammation, hypoxic conditions, exacerbation of TNF-α signaling via NF-κB, and absence of responses to type I and type II IFN secretion in the most severe forms of MIS-C with severe myocarditis. This work led the authors to identify in monocytes and validate in peripheral blood mononuclear cells a molecular signature of 25 genes that allows discrimination of the most severe forms of MIS-C with myocarditis., Multiparametric analysis identifies, in monocytes and dendritic cells, a molecular signature of the most severe forms of multisystem inflammatory syndrome in children caused by SARS-CoV-2 infection. Severe myocarditis is characterized by an excess of TNF-α signaling via NF-κB, hypoxic conditions, and hyperinflammation in the absence of type I and type II interferon responses.
Published: 2021

8. Biochemically deleterious human NFKB1 variants underlie an autosomal dominant form of common variable immunodeficiency

Author: Peng Zhang, Katharina Thoma, Bingnan Lyu, Gulbu Uzel, Juan Li, Boualem Hammadi, András N Spaan, Jamila El Baghdadi, Alexandra F. Freeman, Charlotte Cunningham-Rundles, Yu Zhang, Jean-Laurent Casanova, Claire Fieschi, Franck Rapaport, Jérémie Rosain, Vivien Béziat, Simon J. Pelham, Wei-Te Lei, Anne Puel, Maya Chrabieh, Helen C. Su, V. Koneti Rao, David Hum, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Mélanie Migaud, Anne-Sophie Korganow, Qian Zhang, Aurélie Cobat, Steven M. Holland, Laurent Abel, Vishukumar Aimanianda, Bertrand Boisson, Manfred Fliegauf, Benedetta Bigio, Bodo Grimbacher, Yoann Seeleuthner, Takaki Asano, Carol J Saunders, Shen-Ying Zhang, and Emmanuelle Jouanguy
Subjects: Transcriptional Activation, P50, Immunology, Mutant, Population, Haploinsufficiency, Biology, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Chlorocebus aethiops, medicine, Animals, Humans, Immunology and Allergy, education, Loss function, 030304 developmental biology, Dominance (genetics), Genetics, 0303 health sciences, education.field_of_study, Common variable immunodeficiency, HEK 293 cells, NF-kappa B, NF-kappa B p50 Subunit, medicine.disease, Common Variable Immunodeficiency, HEK293 Cells, Phenotype, COS Cells, 030215 immunology
Abstract: Autosomal dominant (AD) NFKB1 deficiency is thought to be the most common genetic etiology of common variable immunodeficiency (CVID). However, the causal link between NFKB1 variants and CVID has not been demonstrated experimentally and genetically, as there has been insufficient biochemical characterization and enrichment analysis. We show that the cotransfection of NFKB1-deficient HEK293T cells (lacking both p105 and its cleaved form p50) with a κB reporter, NFKB1/p105, and a homodimerization-defective RELA/p65 mutant results in p50:p65 heterodimer–dependent and p65:p65 homodimer–independent transcriptional activation. We found that 59 of the 90 variants in patients with CVID or related conditions were loss of function or hypomorphic. By contrast, 258 of 260 variants in the general population or patients with unrelated conditions were neutral. None of the deleterious variants displayed negative dominance. The enrichment in deleterious NFKB1 variants of patients with CVID was selective and highly significant (P = 2.78 × 10−15). NFKB1 variants disrupting NFKB1/p50 transcriptional activity thus underlie AD CVID by haploinsufficiency, whereas neutral variants in this assay should not be considered causal.
Published: 2021

9. X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

Author: Asano, Takaki, Boisson, Bertrand, Onodi, Fanny, Matuozzo, Daniela, Moncada-Velez, Marcela, Maglorius Renkilaraj, Majistor Raj Luxman, Zhang, Peng, Meertens, Laurent, Bolze, Alexandre, Materna, Marie, Korniotis, Sarantis, Gervais, Adrian, Talouarn, Estelle, Bigio, Benedetta, Seeleuthner, Yoann, Bilguvar, Kaya, Zhang, Yu, Neehus, Anna-Lena, Ogishi, Masato, Pelham, Simon J., Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Soler-Palacín, Pere, Colobran, Roger, Martin-Nalda, Andrea, Rivière, Jacques G., Tandjaoui-Lambiotte, Yacine, Chaïbi, Khalil, Shahrooei, Mohammad, Darazam, Ilad Alavi, Olyaei, Nasrin Alipour, Mansouri, Davood, Hatipoğlu, Nevin, Palabiyik, Figen, Ozcelik, Tayfun, Novelli, Giuseppe, Novelli, Antonio, Casari, Giorgio, Aiuti, Alessandro, Carrera, Paola, Bondesan, Simone, Barzaghi, Federica, Rovere-Querini, Patrizia, Tresoldi, Cristina, Franco, Jose Luis, Rojas, Julian, Reyes, Luis Felipe, Bustos, Ingrid G., Arias, Andres Augusto, Morelle, Guillaume, Kyheng, Christèle, Troya, Jesús, Planas-Serra, Laura, Schlüter, Agatha, Gut, Marta, Pujol, Aurora, Allende, Luis M., Rodriguez-Gallego, Carlos, Flores, Carlos, Cabrera-Marante, Oscar, Pleguezuelo, Daniel E., Pérez de Diego, Rebeca, Keles, Sevgi, Aytekin, Gokhan, Metin Akcan, Ozge, Bryceson, Yenan T., Bergman, Peter, Brodin, Petter, Smole, Daniel, Smith, C. I. Edvard, Norlin, Anna-Carin, Campbell, Tessa M., Covill, Laura E., Hammarström, Lennart, Pan-Hammarström, Qiang, Abolhassani, Hassan, Mane, Shrikant, Marr, Nico, Ata, Manar, Al Ali, Fatima, Khan, Taushif, Spaan, András N., Dalgard, Clifton L., Bonfanti, Paolo, Biondi, Andrea, Tubiana, Sarah, Burdet, Charles, Nussbaum, Robert, Kahn-Kirby, Amanda, Snow, Andrew L., Bustamante, Jacinta, Puel, Anne, Boisson-Dupuis, Stéphanie, Zhang, Shen-Ying, Béziat, Vivien, Lifton, Richard P., Bastard, Paul, Notarangelo, Luigi D., Abel, Laurent, Su, Helen C., Jouanguy, Emmanuelle, Amara, Ali, Soumelis, Vassili, Cobat, Aurélie, Zhang, Qian, Casanova, Jean-Laurent, Al-Muhsen, Saleh, Al-Mulla, Fahd, Anderson, Mark S., Andreakos, Evangelos, Arias, Andrés A., Feldman, Hagit Baris, Belot, Alexandre, Biggs, Catherine M., Bogunovic, Dusan, Bondarenko, Anastasiia, Bousfiha, Ahmed A., Bryceson, Yenan, Bustamante, Carlos D., Butte, Manish J., Chakravorty, Samya, Christodoulou, John, Condino-Neto, Antonio, Constantinescu, Stefan N., Cooper, Megan A., Desai, Murkesh, Drolet, Beth A., El Baghdadi, Jamila, Espinosa-Padilla, Sara, Fellay, Jacques, Franco, José Luis, Froidure, Antoine, Gregersen, Peter K., Haerynck, Filomeen, Hagin, David, Halwani, Rabih, Heath, James R., Henrickson, Sarah E., Hsieh, Elena W.Y., Husebye, Eystein, Imai, Kohsuke, Itan, Yuval, Jarvis, Erich D., Karamitros, Timokratis, Kisand, Kai, Ku, Cheng-Lung, Lau, Yu-Lung, Ling, Yun, Lucas, Carrie L., Maniatis, Tom, Maródi, László, Meyts, Isabelle, Milner, Joshua D., Mironska, Kristina, Mogensen, Trine H., Morio, Tomohiro, Ng, Lisa F.P., O'Farrelly, Cliona, Okada, Satoshi, de Diego, Rebeca Perez, Planas, Anna M., Prando, Carolina, Quintana-Murci, Lluis, Renia, Laurent, Resnick, Igor, Rodríguez-Gallego, Carlos, Sancho-Shimizu, Vanessa, Sediva, Anna, Seppänen, Mikko R.J., Shahrooei, Mohammed, Shcherbina, Anna, Slaby, Ondrej, Tancevski, Ivan, Tangye, Stuart G., Abou Tayoun, Ahmad, Ramaswamy, Sathishkumar, Turvey, Stuart E, Uddin, K M Furkan, Uddin, Mohammed J., van de Beek, Diederik, Vinh, Donald C., von Bernuth, Horst, Zatz, Mayana, Zawadzki, Pawel, Foti, Giuseppe, Bellani, Giacomo, Citerio, Giuseppe, Contro, Ernesto, Pesci, Alberto, Valsecchi, Maria Grazia, Cazzaniga, Marina, Abad, Jorge, Accordino, Giulia, Achille, Cristian, Aguilera-Albesa, Sergio, Aguiló-Cucurull, Aina, Özkan, Esra Akyüz, Roblero Albisures, Jonathan Antonio, Aldave, Juan C, Ramos, Miquel Alfonso, Khan, Taj Ali, Aliberti, Anna, Nadji, Seyed Alireza, Alkan, Gulsum, AlKhater, Suzan A., Allardet-Servent, Jerome, Allende, Luis M, Alonso-Arias, Rebeca, Alshahrani, Mohammed S, Alsina, Laia, Alyanakian, Marie-Alexandra, Borrero, Blanca Amador, Amoura, Zahir, Antolí, Arnau, Arrestier, Romain, Aubart, Mélodie, Auguet, Teresa, Avramenko, Iryna, Aytekin, Gökhan, Azot, Axelle, Bahram, Seiamak, Bajolle, Fanny, Baldanti, Fausto, Baldolli, Aurélie, Ballester, Maite, Barrou, Benoit, Barzagh, Federica, Basso, Sabrina, Bayhan, Gulsum Iclal, Bezrodnik, Liliana, Bilbao, Agurtzane, Blanchard-Rohner, Geraldine, Blanco, Ignacio, Blandinières, Adeline, Blázquez-Gamero, Daniel, Bleibtreu, Alexandre, Bloomfield, Marketa, Bolivar-Prados, Mireia, Borghesi, Alessandro, Borie, Raphael, Botdhlo-Nevers, Elisabeth, Bousfiha, Ahmed A, Bousquet, Aurore, Boutolleau, David, Bouvattier, Claire, Boyarchuk, Oksana, Bravais, Juliette, Briones, M. Luisa, Brunner, Marie-Eve, Bruno, Raffaele, Bueno, Maria Rita P, Bukhari, Huda, Cáceres Agra, Juan José, Capra, Ruggero, Carapito, Raphael, Carrabba, Maria, Casasnovas, Carlos, Caseris, Marion, Cassaniti, Irene, Castelle, Martin, Castelli, Francesco, de Vera, Martín Castillo, Castro, Mateus V, Catherinot, Emilie, Celik, Jale Bengi, Ceschi, Alessandro, Chalumeau, Martin, Charbit, Bruno, Cheng, Matthew P., Clavé, Père, Clotet, Bonaventura, Codina, Anna, Cohen, Yves, Comarmond, Cloé, Combes, Alain, Comoli, Patrizia, Corsico, Angelo G, Coşkuner, Taner, Cvetkovski, Aleksandar, Cyrus, Cyril, Dalmau, David, Danion, François, Darley, David Ross, Das, Vincent, Dauby, Nicolas, Dauger, Stéphane, De Munter, Paul, de Pontual, Loic, Dehban, Amin, Delplancq, Geoffroy, Demoule, Alexandre, Desguerre, Isabelle, Di Sabatino, Antonio, Diehl, Jean-Luc, Dobbelaere, Stephanie, Domínguez-Garrido, Elena, Dubost, Clément, Ekwall, Olov, Bozdemir, Şefika Elmas, Elnagdy, Marwa H, Emiroglu, Melike, Endo, Akifumi, Erdeniz, Emine Hafize, Aytekin, Selma Erol, Lasa, Maria Pilar Etxart, Euvrard, Romain, Fabio, Giovanna, Faivre, Laurence, Falck, Antonin, Fartoukh, Muriel, Faure, Morgane, Arquero, Miguel Fernandez, Ferrer, Ricard, Ferreres, Jose, Francois, Bruno, Fumadó, Victoria, Fung, Kitty S C, Fusco, Francesca, Gagro, Alenka, Solis, Blanca Garcia, Gaussem, Pascale, Gayretli, Zeynep, Gil-Herrera, Juana, Gilardin, Laurent, Gatineau, Audrey Giraud, Girona-Alarcón, Mònica, Cifuentes Godínez, Karen Alejandra, Goffard, Jean-Christophe, Gonzales, Nacho, Gonzalez-Granado, Luis I, González-Montelongo, Rafaela, Guerder, Antoine, Gülhan, Belgin, Gumucio, Victor Daniel, Hanitsch, Leif Gunnar, Gunst, Jan, Hadjadj, Jérôme, Hancerli, Selda, Hariyan, Tetyana, Hatipoglu, Nevin, Heppekcan, Deniz, Hernandez-Brito, Elisa, Ho, Po-ki, Holanda-Peña, María Soledad, Horcajada, Juan P, Hraiech, Sami, Humbert, Linda, Hung, Ivan F N, Iglesias, Alejandro D., Íñigo-Campos, Antonio, Jamme, Matthieu, Arranz, María Jesús, Jimeno, Marie-Thérèse, Jordan, Iolanda, Yüksek, Saliha Kanık, Kara, Yalcin Burak, Karahan, Aydın, Karbuz, Adem, Yasar, Kadriye Kart, Kasapcopur, Ozgur, Kashimada, Kenichi, Demirkol, Yasemin Kendir, Kido, Yasutoshi, Kizil, Can, Kılıç, Ahmet Osman, Klocperk, Adam, Koutsoukou, Antonia, Król, Zbigniew J., Ksouri, Hatem, Kuentz, Paul, Kwan, Arthur M C, Kwan, Yat Wah M, Kwok, Janette S Y, Lagier, Jean-Christophe, Lam, David S Y, Lampropoulou, Vicky, Lanternier, Fanny, LAU, Yu-Lung, Le Bourgeois, Fleur, Leo, Yee-Sin, Lopez, Rafael Leon, Leung, Daniel, Levin, Michael, Levy, Michael, Lévy, Romain, Li, Zhi, Lilleri, Daniele, Bolanos Lima, Edson Jose Adrian, Linglart, Agnes, López-Collazo, Eduardo, Lorenzo-Salazar, José M., Louapre, Céline, Lubetzki, Catherine, Lung, Kwok-Cheung, Luyt, Charles-Edouard, Lye, David C, Magnone, Cinthia, Marchioni, Enrico, Marioli, Carola, Marjani, Majid, Marques, Laura, Pereira, Jesus Marquez, Martín-Nalda, Andrea, Pueyo, David Martínez, Martinez-Picado, Javier, Marzana, Iciar, Mata-Martínez, Carmen, Mathian, Alexis, Matos, Larissa RB, Matthews, Gail V, Mayaux, Julien, McLaughlin-Garcia, Raquel, Meersseman, Philippe, Mège, Jean-Louis, Mekontso-Dessap, Armand, Melki, Isabelle, Meloni, Federica, Meritet, Jean-François, Merlani, Paolo, Akcan, Özge Metin, Mezidi, Mehdi, Migeotte, Isabelle, Millereux, Maude, Million, Matthieu, Mirault, Tristan, Mircher, Clotilde, Mirsaeidi, Mehdi, Mizoguchi, Yoko, Modi, Bhavi P, Mojoli, Francesco, Moncomble, Elsa, Melián, Abián Montesdeoca, Martinez, Antonio Morales, Morandeira, Francisco, Morange, Pierre-Emmanuel, Mordacq, Cléemence, Mouly, Stéphane J, Muñoz-Barrera, Adrián, Nafati, Cyril, Nagashima, Shintaro, Nakagama, Yu, Neven, Bénédicte, Neves, João Farela, Ng, Lisa FP, Ng, Yuk-Yung, Nielly, Hubert, Medina, Yeray Novoa, Cuadros, Esmeralda Nuñez, Ocejo-Vinyals, J. Gonzalo, Okamoto, Keisuke, Oualha, Mehdi, Ouedrani, Amani, Özçelik, Tayfun, Ozkaya-Parlakay, Aslinur, Pagani, Michele, Papadaki, Maria, Parizot, Christophe, Parola, Philippe, Pascreau, Tiffany, Paul, Stéphane, Paz-Artal, Estela, Pedraza, Sigifredo, González Pellecer, Nancy Carolina, Pellegrini, Silvia, de Diego, Rebeca Pérez, Pérez-Fernández, Xosé Luis, Philippe, Aurélien, Picod, Adrien, de Chambrun, Marc Pineton, Piralla, Antonio, Ploin, Dominique, Poissy, Julien, Poncelet, Géraldine, Poulakou, Garyphallia, Pouletty, Marie S, Pourshahnazari, Persia, Qiu-Chen, Jia Li, Quentric, Paul, Rambaud, Thomas, Raoult, Didier, Raoult, Violette, Rebillat, Anne-Sophie, Redin, Claire, Resmini, Léa, Ricart, Pilar, Richard, Jean-Christophe, Rigo-Bonnin, Raúl, Rivet, Nadia, Rivière, Jacques G, Rocamora-Blanch, Gemma, Rodero, Mathieu P, Rodrigo, Carlos, Rodriguez, Luis Antonio, Rodriguez-Palmero, Agustí, Romero, Carolina Soledad, Rothenbuhler, Anya, Roux, Damien, Rovina, Nikoletta, Rozenberg, Flore, Ruch, Yvon, Ruiz, Montse, Ruiz del Prado, Maria Yolanda, Ruiz-Rodriguez, Juan Carlos, Sabater-Riera, Joan, Saks, Kai, Salagianni, Maria, Sanchez, Oliver, Sánchez-Montalvá, Adrián, Sánchez-Ramón, Silvia, Schidlowski, Laire, Schluter, Agatha, Schmidt, Julien, Schmidt, Matthieu, Schuetz, Catharina, Schweitzer, Cyril E, Scolari, Francesco, Seijo, Luis, Seminario, Analia Gisela, Sene, Damien, Seng, Piseth, Senoglu, Sevtap, Seppänen, Mikko, Llovich, Alex Serra, Siguret, Virginie, Siouti, Eleni, Smadja, David M, Smith, Nikaia, Sobh, Ali, Solanich, Xavier, Solé-Violán, Jordi, Soler, Catherine, Sözeri, Betül, Stella, Giulia Maria, Stepanovskiy, Yuriy, Stoclin, Annabelle, Taccone, Fabio, Taupin, Jean-Luc, Tavernier, Simon J, Tello, Loreto Vidaur, Terrier, Benjamin, Thiery, Guillaume, Thorball, Christian, Thorn, Karolina, Thumerelle, Caroline, Tipu, Imran, Tolstrup, Martin, Tomasoni, Gabriele, Toubiana, Julie, Alvarez, Josep Trenado, Triantafyllia, Vasiliki, Trouillet-Assant, Sophie, Tsang, Owen T Y, Tserel, Liina, Tso, Eugene Y K, Tucci, Alessandra, Tüter Öz, Şadiye Kübra, Ursini, Matilde Valeria, Utsumi, Takanori, Uzunhan, Yurdagul, Vabres, Pierre, Valencia-Ramos, Juan, Van Den Rym, Ana Maria, Vandernoot, Isabelle, Velez-Santamaria, Valentina, Zuniga Veliz, Silvia Patricia, Vidigal, Mateus C, Viel, Sébastien, Vilain, Cédric, Vilaire-Meunier, Marie E, Villar-García, Judit, Vincent, Audrey, Vogt, Guillaume, Voiriot, Guillaume, Volokha, Alla, Vuotto, Fanny, Wauters, Els, Wauters, Joost, Wu, Alan K L, Wu, Tak-Chiu, Yahşi, Aysun, Yesilbas, Osman, Yildiz, Mehmet, Young, Barnaby E, Yükselmiş, Ufuk, Zecca, Marco, Zuccaro, Valentina, Jens, Van Praet, Lambrecht, Bart N., Eva, Van Braeckel, Cédric, Bosteels, Levi, Hoste, Eric, Hoste, Bauters, Fré, De Clercq, Jozefien, Cathérine, Heijmans, Hans, Slabbynck, Leslie, Naesens, Florkin, Benoit, Boulanger, Cécile, Vanderlinden, Dimitri, Annereau, Jean-Philippe, Briseño-Roa, Luis, Gribouval, Olivier, Pelet, Anna, Andrejak, Claire, Angoulvant, François, Bachelet, Delphine, Bartoli, Marie, Basmaci, Romain, Behilill, Sylvie, Beluze, Marine, Benkerrou, Dehbia, Bhavsar, Krishna, Bouadma, Lila, Bouchez, Sabelline, Bouscambert, Maude, Cervantes-Gonzalez, Minerva, Chair, Anissa, Chirouze, Catherine, Coelho, Alexandra, Couffignal, Camille, Couffin-Cadiergues, Sandrine, d’Ortenzio, Eric, Debray, Marie-Pierre, Deconinck, Lauren, Deplanque, Dominique, Descamps, Diane, Desvallée, Mathilde, Diallo, Alpha, Diouf, Alphonsine, Dorival, Céline, Dubos, François, Duval, Xavier, Elharrar, Brigitte, Eloy, Philippine, Enouf, Vincent, Esperou, Hélène, Esposito-Farese, Marina, Etienne, Manuel, Devouge, Eglantine Ferrand, Gault, Nathalie, Gaymard, Alexandre, Ghosn, Jade, Gigante, Tristan, Gilg, Morgane, Guedj, Jérémie, Hoctin, Alexandre, Hoffmann, Isabelle, Houas, Ikram, Hulot, Jean-Sébastien, Jaafoura, Salma, Kafif, Ouifiya, Kaguelidou, Florentia, Kali, Sabrina, Khalil, Antoine, Khan, Coralie, Laouénan, Cédric, Laribi, Samira, Le, Minh, Le Hingrat, Quentin, Le Mestre, Soizic, Le Nagard, Hervé, Lescure, François-Xavier, Letrou, Sophie, Levy, Yves, Lina, Bruno, Lingas, Guillaume, Lucet, Jean Christophe, Malvy, Denis, Mambert, Marina, Mentré, France, Meziane, Amina, Mouquet, Hugo, Mullaert, Jimmy, Neant, Nadège, Nguyen, Duc, Noret, Marion, Nseir, Saad, Papadopoulos, Aurélie, Paul, Christelle, Peiffer-Smadja, Nathan, Perpoint, Thomas, Petrov-Sanchez, Ventzislava, Peytavin, Gilles, Pham, Huong, Picone, Olivier, Piquard, Valentine, Puéchal, Oriane, Rabaud, Christian, Rosa-Calatrava, Manuel, Rossignol, Bénédicte, Rossignol, Patrick, Roy, Carine, Schneider, Marion, Su, Richa, Tardivon, Coralie, Tellier, Marie-Capucine, Téoulé, François, Terrier, Olivier, Timsit, Jean-François, Tual, Christelle, Van Der Werf, Sylvie, Vanel, Noémie, Veislinger, Aurélie, Visseaux, Benoit, Wiedemann, Aurélie, Yazdanpanah, Yazdan, Alavoine, Loubna, Behillil, Sylvie, Charpentier, Charlotte, Dechanet, Aline, Ecobichon, Jean-Luc, Frezouls, Wahiba, Houhou, Nadhira, Lehacaut, Jonathan, Lucet, Jean-Christophe, Manchon, Pauline, Nouroudine, Mariama, Quintin, Caroline, Thy, Michael, van der Werf, Sylvie, Vignali, Valérie, Chahine, Abir, Waucquier, Nawal, Migaud, Maria-Claire, Djossou, Félix, Mergeay-Fabre, Mayka, Lucarelli, Aude, Demar, Magalie, Bruneau, Léa, Gérardin, Patrick, Maillot, Adrien, Payet, Christine, Laviolle, Bruno, Laine, Fabrice, Paris, Christophe, Desille-Dugast, Mireille, Fouchard, Julie, Pistone, Thierry, Perreau, Pauline, Gissot, Valérie, Le Goas, Carole, Montagne, Samatha, Richard, Lucie, Bouiller, Kévin, Desmarets, Maxime, Meunier, Alexandre, Lefévre, Benjamin, Jeulin, Hélène, Legrand, Karine, Lomazzi, Sandra, Tardy, Bernard, Gagneux-Brunon, Amandine, Bertholon, Frédérique, Botelho-Nevers, Elisabeth, Kouakam, Christelle, Leturque, Nicolas, Roufai, Layidé, Amat, Karine, Espérou, Hélène, Hendou, Samia, van Agtmael, Michiel, Algera, Anne Geke, Appelman, Brent, van Baarle, Frank, Bax, Diane, Beudel, Martijn, Bogaard, Harm Jan, Bomers, Marije, Bonta, Peter, Bos, Lieuwe, Botta, Michela, de Brabander, Justin, de Bree, Godelieve, de Bruin, Sanne, Buis, David T.P., Bugiani, Marianna, Bulle, Esther, Chouchane, Osoul, Cloherty, Alex, Dijkstra, Mirjam, Dongelmans, Dave A., Dujardin, Romein W.G., Elbers, Paul, Fleuren, Lucas, Geerlings, Suzanne, Geijtenbeek, Theo, Girbes, Armand, Goorhuis, Bram, Grobusch, Martin P., Hafkamp, Florianne, Hagens, Laura, Hamann, Jorg, Harris, Vanessa, Hemke, Robert, Hermans, Sabine M., Heunks, Leo, Hollmann, Markus, Horn, Janneke, Hovius, Joppe W., de Jong, Menno D., Koning, Rutger, Lim, Endry H.T., van Mourik, Niels, Nellen, Jeaninne, Nossent, Esther J., Paulus, Frederique, Peters, Edgar, Pina-Fuentes, Dan A.I., van der Poll, Tom, Preckel, Bennedikt, Prins, Jan M., Raasveld, Jorinde, Reijnders, Tom, de Rotte, Maurits C.F.J., Schinkel, Michiel, Schultz, Marcus J., Schrauwen, Femke A.P., Schuurmans, Alex, Schuurmans, Jaap, Sigaloff, Kim, Slim, Marleen A., Smeele, Patrick, Smit, Marry, Stijnis, Cornelis S., Stilma, Willemke, Teunissen, Charlotte, Thoral, Patrick, Tsonas, Anissa M, Tuinman, Pieter R., van der Valk, Marc, Veelo, Denise, Volleman, Carolien, de Vries, Heder, Vught, Lonneke A., van Vugt, Michèle, Wouters, Dorien, Zwinderman, A. H (Koos), Brouwer, Matthijs C., Wiersinga, W. Joost, Vlaar, Alexander P.J., Tompkins, Miranda F., Alba, Camille, Hupalo, Daniel N., Rosenberger, John, Sukumar, Gauthaman, Wilkerson, Matthew D., Zhang, Xijun, Lack, Justin, Oler, Andrew J., Dobbs, Kerry, Delmonte, Ottavia M., Danielson, Jeffrey J., Bettini, Laura Rachele, D’Angio, Mariella, Beretta, Ilaria, Imberti, Luisa, Sottini, Alessandra, Quaresima, Virginia, Quiros-Roldan, Eugenia, Rossi, Camillo, Children's Hospital, HUS Children and Adolescents, Clinicum, Department of Medicine, UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, AII - Infectious diseases, ANS - Neuroinfection & -inflammation, Neurology, Infectious diseases, Center of Experimental and Molecular Medicine, APH - Aging & Later Life, APH - Global Health, APH - Quality of Care, AII - Amsterdam institute for Infection and Immunity, APH - Health Behaviors & Chronic Diseases, Global Health, APH - Methodology, Graduate School, ACS - Heart failure & arrhythmias, Anesthesiology, ACS - Diabetes & metabolism, APH - Digital Health, APH - Personalized Medicine, ACS - Microcirculation, 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), Laboratory of Human Genetics of Infectious Diseases (Necker Branch - INSERM U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Rockefeller University [New York], Génomes, biologie cellulaire et thérapeutiques (GenCellDi (UMR_S_944)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Helix [San Mateo, CA], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Özçelik, Tayfun, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Pathology, Asano, T., Boisson, B., Onodi, F., Matuozzo, D., Moncada-Velez, M., Renkilaraj, M. R. L. M., Zhang, P., Meertens, L., Bolze, A., Materna, M., Korniotis, S., Gervais, A., Talouarn, E., Bigio, B., Seeleuthner, Y., Bilguvar, K., Zhang, Y., Neehus, A. -L., Ogishi, M., Pelham, S. J., Le Voyer, T., Rosain, J., Philippot, Q., Soler-Palacin, P., Colobran, R., Martin-Nalda, A., Riviere, J. G., Tandjaoui-Lambiotte, Y., Chaibi, K., Shahrooei, M., Darazam, I. A., Olyaei, N. A., Mansouri, D., Hatipoglu, N., Palabiyik, F., Ozcelik, T., Novelli, G., Novelli, A., Casari, G., Aiuti, A., Carrera, P., Bondesan, S., Barzaghi, F., Rovere-Querini, P., Tresoldi, C., Franco, J. L., Rojas, J., Reyes, L. F., Bustos, I. G., Arias, A. A., Morelle, G., Kyheng, C., Troya, J., Planas-Serra, L., Schluter, A., Gut, M., Pujol, A., Allende, L. M., Rodriguez-Gallego, C., Flores, C., Cabrera-Marante, O., Pleguezuelo, D. E., Diego, R. P. D., Keles, S., Aytekin, G., Akcan, O. M., Bryceson, Y. T., Bergman, P., Brodin, P., Smole, D., Smith, C. I. E., Norlin, A. -C., Campbell, T. M., Covill, L. E., Hammarstrom, L., Pan-Hammarstrom, Q., Abolhassani, H., Mane, S., Marr, N., Ata, M., Ali, F. A., Khan, T., Spaan, A. N., Dalgard, C. L., Bonfanti, P., Biondi, A., Tubiana, S., Burdet, C., Nussbaum, R., Kahn-Kirby, A., Snow, A. L., Bustamante, J., Puel, A., Boisson-Dupuis, S., Zhang, S. -Y., Beziat, V., Lifton, R. P., Bastard, P., Notarangelo, L. D., Abel, L., Su, H. C., Jouanguy, E., Amara, A., Soumelis, V., Cobat, A., Zhang, Q., Casanova, J. -L., Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Génomes, biologie cellulaire et thérapeutiques (GenCellDi (U944 / UMR7212)), Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHU Amiens-Picardie, French COVID cohort study group, The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, Rockefeller University, the St. Giles Foundation, the NIH (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at the George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01) and the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project, the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the European Union’s Horizon 2020 Research and Innovation Program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir–Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, Fondation du Souffle, Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM, and the University of Paris. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (RECOVER WP 6). The Neurometabolic Diseases Laboratory received funding from the European Union’s Horizon 2020 Research and Innovation Program (EasiGenomics grant no. 824110 COVID-19/PID12342). A.P., R.P.d.D., C.R.-G., and C.F. were funded by Instituto de Salud Carlos III (COV20_01333 and COV20_01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1, AEI/FEDER, UE), Fundación DISA (OA18/017), and Cabildo Insular de Tenerife (CGIEU0000219140 and 'Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19'). The laboratories of G.N. and A.N. were supported by a grant awarded to Regione Lazio (PROGETTI DI GRUPPI DI RICERCA 2020) no. A0375-2020-36663, GecoBiomark. A. Amara’s laboratory was supported by ANR under the 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the FRM (EQU202003010193), ANR (ANR-20-COVI-000 project IDISCOVR and ANR-20-CO11-0004 project FISHBP), and the University of Paris (Plan de Soutien Covid-19: RACPL20FIR01-COVID-SOUL). This work was supported, in part, by the Division of Intramural Research, NIAID, NIH (grants 1ZIAAI001265 to H.C.S. and ZIA AI001270 to L.D.N.). The G.C. laboratory was supported by the Italian Ministry of Health (grant COVID-2020-12371617) and the intramural COVID Host Genetics program. The J.L.F. laboratory was supported, in part, by the Coopération Scientifique France-Colciencias (ECOS-Nord/COLCIENCIAS/MEN/ICETEX, 806-2018) and Colciencias contract 713-2016 (no. 111574455633). The V.S. laboratory was supported by ANR DENDRISEPSIS (ANR-17-CE15-0003) and ANR APCOD (ANR-17-CE15-0003-01), a Fast Grant from the Mercatus Center, FRM, University of Paris PLAN D’URGENCE COVID19. The N.M. laboratory was supported by Sidra Medicine (SDR400048) and the Qatar National Research Fund (grant No. NPRP9-251-3-045). A.-L.N. was supported by the Bettencourt Schueller Foundation and the International PhD program of the Imagine Institute. P. Bergman and C.I.E.S received support from the Center for Medical Innovation (CIMED), the Swedish Medical Research Council and the Stockholm County Council (ALF-project). Part of this work was generated within the European Reference Network for rare primary immunodeficiency, autoinflammatory and autoimmune diseases (RITA)., Members of French COVID Cohort Study Group: Laurent Abel1, Claire Andrejak2, François Angoulvant3, Delphine Bachelet4, Marie Bartoli5, Romain Basmaci6, Sylvie Behilill7, Marine Beluze8, Dehbia Benkerrou9, Krishna Bhavsar4, Lila Bouadma4, Sabelline Bouchez10, Maude Bouscambert11, Minerva Cervantes-Gonzalez4, Anissa Chair4, Catherine Chirouze12, Alexandra Coelho13, Camille Couffignal4, Sandrine Couffin-Cadiergues14, Eric d’Ortenzio5, Marie-Pierre Debray4, Lauren Deconinck4, Dominique Deplanque15, Diane Descamps4, Mathilde Desvallée16, Alpha Diallo5, Alphonsine Diouf13, Céline Dorival9, François Dubos17, Xavier Duval4, Brigitte Elharrar18, Philippine Eloy4, Vincent Enouf7, Hélène Esperou14, Marina Esposito-Farese4, Manuel Etienne19, Eglantine Ferrand Devouge19, Nathalie Gault4, Alexandre Gaymard11, Jade Ghosn4, Tristan Gigante20, Morgane Gilg20, Jérémie Guedj21, Alexandre Hoctin13, Isabelle Hoffmann4, Ikram Houas14, Jean-Sébastien Hulot22, Salma Jaafoura14, Ouifiya Kafif4, Florentia Kaguelidou23, Sabrina Kali4, Antoine Khalil4, Coralie Khan16, Cédric Laouénan4, Samira Laribi4, Minh Le4, Quentin Le Hingrat4, Soizic Le Mestre5, Hervé Le Nagard24, François-Xavier Lescure4, Sophie Letrou4, Yves Levy25, Bruno Lina11, Guillaume Lingas24, Jean Christophe Lucet4, Denis Malvy26, Marina Mambert13, France Mentré4, Amina Meziane9, Hugo Mouquet7, Jimmy Mullaert4, Nadège Neant24, Duc Nguyen26, Marion Noret27, Saad Nseir17, Aurélie Papadopoulos14, Christelle Paul5, Nathan Peiffer-Smadja4, Thomas Perpoint28, Ventzislava Petrov-Sanchez5, Gilles Peytavin4, Huong Pham4, Olivier Picone6, Valentine Piquard4, Oriane Puéchal29, Christian Rabaud30, Manuel Rosa-Calatrava11, Bénédicte Rossignol20, Patrick Rossignol30, Carine Roy4, Marion Schneider4, Richa Su4, Coralie Tardivon4, Marie-Capucine Tellier4, François Téoulé9, Olivier Terrier11, Jean-François Timsit4, Christelle Tual31, Sarah Tubiana4, Sylvie Van Der Werf7, Noémie Vanel32, Aurélie Veislinger31, Benoit Visseaux4, Aurélie Wiedemann25, Yazdan Yazdanpanah4, ANR-17-CE15-0003,DENDRISEPSIS,Analyse systémique des cellules présentatrices d'antigène dans le sepsis humain(2017), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), Asano, T, Boisson, B, Onodi, F, Matuozzo, D, Moncada-Velez, M, Maglorius Renkilaraj, M, Zhang, P, Meertens, L, Bolze, A, Materna, M, Korniotis, S, Gervais, A, Talouarn, E, Bigio, B, Seeleuthner, Y, Bilguvar, K, Zhang, Y, Neehus, A, Ogishi, M, Pelham, S, Le Voyer, T, Rosain, J, Philippot, Q, Soler-Palacín, P, Colobran, R, Martin-Nalda, A, Rivière, J, Tandjaoui-Lambiotte, Y, Chaïbi, K, Shahrooei, M, Darazam, I, Olyaei, N, Mansouri, D, Hatipoğlu, N, Palabiyik, F, Ozcelik, T, Novelli, G, Novelli, A, Casari, G, Aiuti, A, Carrera, P, Bondesan, S, Barzaghi, F, Rovere-Querini, P, Tresoldi, C, Franco, J, Rojas, J, Reyes, L, Bustos, I, Arias, A, Morelle, G, Christèle, K, Troya, J, Planas-Serra, L, Schlüter, A, Gut, M, Pujol, A, Allende, L, Rodriguez-Gallego, C, Flores, C, Cabrera-Marante, O, Pleguezuelo, D, de Diego, R, Keles, S, Aytekin, G, Akcan, O, Bryceson, Y, Bergman, P, Brodin, P, Smole, D, Smith, C, Norlin, A, Campbell, T, Covill, L, Hammarström, L, Pan-Hammarström, Q, Abolhassani, H, Mane, S, Marr, N, Ata, M, Al Ali, F, Khan, T, Spaan, A, Dalgard, C, Bonfanti, P, Biondi, A, Tubiana, S, Burdet, C, Nussbaum, R, Kahn-Kirby, A, Snow, A, Bustamante, J, Puel, A, Boisson-Dupuis, S, Zhang, S, Béziat, V, Lifton, R, Bastard, P, Notarangelo, L, Abel, L, Su, H, Jouanguy, E, Amara, A, Soumelis, V, Cobat, A, Zhang, Q, and Casanova, J
Subjects: Male, SUBSETS, [SDV]Life Sciences [q-bio], Penetrance, REDUNDANT, COVID-19 (Malaltia), 0302 clinical medicine, Resposta immunitària, 80 and over, Medicine and Health Sciences, Medicine, Young adult, Child, X-linked recessive inheritance, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, 0303 health sciences, education.field_of_study, PYOGENIC BACTERIAL-INFECTIONS, virus diseases, Genetic Diseases, X-Linked, HUMANS, General Medicine, Middle Aged, PROTECTIVE IMMUNITY, 3. Good health, Pedigree, Settore MED/03, Immune System Diseases, Genetic Diseases, Child, Preschool, Cohort, medicine.symptom, SINGLE-STRANDED RNA, Adult, Adolescent, Aged, Alleles, COVID-19, Humans, Infant, Toll-Like Receptor 7, Young Adult, Immunology, Population, Asymptomatic, Article, 03 medical and health sciences, HOST-DEFENSE, Immune response, Allele, Preschool, education, 030304 developmental biology, TOLL-LIKE RECEPTORS, business.industry, RECOGNITION, Proteins, X-Linked, medicine.disease, Pneumonia, 3121 General medicine, internal medicine and other clinical medicine, PLASMACYTOID DENDRITIC CELLS, business, Proteïnes, 030215 immunology
Abstract: Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract. Funding: The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, Rockefeller University; the St. Giles Foundation; the NIH (R01AI088364), the National Center for Advancing Translational Sciences (NCATS); NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866); a Fast Grant from Emergent Ventures; Mercatus Center at the George Mason University; the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956); the Meyer Foundation; the JPB Foundation; the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01) and the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID); the French Foundation for Medical Research (FRM) (EQU201903007798); the FRM and ANR GENCOVID project, the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AABIFNCOV (ANR-20-CO11-0001) projects; the European Union’s Horizon 2020 Research and Innovation Program under grant agreement no. 824110 (EASI-genomics). The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (RECOVER WP 6). The Neurometabolic Diseases Laboratory received funding from the European Union’s Horizon 2020 Research and Innovation Program (EasiGenomics grant no. 824110 COVID-19/PID12342). A.P., R.P.d.D., C.R.-G., and C.F. were funded by Instituto de Salud Carlos III (COV20_01333 and COV20_01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, UE), Fundación DISA (OA18/017), and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). The laboratories of G.N. and A.N. were supported by a grant awarded to Regione Lazio (PROGETTI DI GRUPPI DI RICERCA 2020) no. A0375-2020-36663, GecoBiomark. A. Amara’s laboratory was supported by ANR under the “Investments for the Future” program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the FRM (EQU202003010193), ANR (ANR-20-COVI-000 project IDISCOVR and ANR-20-CO11-0004 project FISHBP), and the University of Paris (Plan de Soutien Covid-19: RACPL20FIR01-COVID-SOUL). This work was supported, in part, by the Division of Intramural Research, NIAID, NIH (grants 1ZIAAI001265 to H.C.S. and ZIA AI001270 to L.D.N.). The G.C. laboratory was supported by the Italian Ministry of Health (grant COVID-2020-12371617) and the intramural COVID Host Genetics program. The J.L.F. laboratory was supported, in part, by the Coopération Scientifique France-Colciencias (ECOS-Nord/COLCIENCIAS/MEN/ICETEX; 806-2018) and Colciencias contract 713-2016 (no. 111574455633). The V.S. laboratory was supported by ANR DENDRISEPSIS (ANR-17-CE15-0003) and ANR APCOD (ANR-17-CE15-0003-01), a Fast Grant from the Mercatus Center, FRM, University of Paris PLAN D’URGENCE COVID19. The N.M. laboratory was supported by Sidra Medicine (SDR400048) and the Qatar National Research Fund (grant No. NPRP9-251-3-045)
Published: 2021

10. Insufficient type I IFN immunity underlies life-threatening COVID-19 pneumonia

Author: Jean-Laurent Casanova, Paul Bastard, Emmanuelle Jouanguy, Qian Zhang, Shen-Ying Zhang, Laurent Abel, and Aurélie Cobat
Subjects: 0106 biological sciences, 0301 basic medicine, Disease, 01 natural sciences, Virus, 03 medical and health sciences, Immunity, Interferon, Medicine, Humans, Gene, business.industry, SARS-CoV-2, Autoantibody, COVID-19, General Medicine, Pneumonia, medicine.disease, 030104 developmental biology, Immunology, Interferon Type I, business, Interferon type I, 010606 plant biology & botany, medicine.drug
Abstract: We established the COVID Human Genetic Effort (www.covidhge.com) to discover the human genetic and immunological bases of the vast interindividual clinical variability between humans infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We found that about 3% of patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia were ill because of inborn errors of genes controlling type I interferon (IFN)-dependent immunity (which controls influenza virus), and at least 10% of patients with life-threatening COVID-19 pneumonia had neutralizing auto-Abs against some of the 17 individual type I IFNs. These findings indicate that impaired type I IFN immunity underlies life-threatening COVID-19 pneumonia in at least 13% of patients. These discoveries pave the way for further research into unexplained severe cases, and provide a rationale for preventing and treating the disease in individuals at risk, with recombinant type I IFNs.Nous avons créé le COVID Human Genetic Effort (www.covidhge.com) afin de découvrir les bases génétiques et immunologiques expliquant l’immense variabilité clinique interindividuelle entre les humains infectés par le nouveau coronavirus 2 du syndrome respiratoire aigu sévère (SRAS-CoV-2). Nous avons découvert qu’environ 3% des patients atteints de pneumonie sévère à coronavirus 2019 (COVID-19) menaçant leur pronostic vital étaient malades en raison de défauts génétiques dans les gènes contrôlant l’immunité dépendant de la voie de l’interféron (IFN) de type I (qui contrôle le virus de la grippe), et qu’au moins 10% de ces patients avaient des auto-anticorps neutralisants contre certains des 17 IFN de type I. Ces résultats indiquent qu’un défaut de l’immunité dépendante des IFN de type I est à l’origine de la sévérité de la pneumopathie à COVID-19 chez au moins 13% des patients. Ces découvertes ouvrent la voie à d’autres recherches sur des cas graves inexpliqués de COVID-19 et sont un argument en faveur de l’utilisation d’IFNs de type I recombinants pour la prévention et le traitement de la maladie chez les personnes à risque.
Published: 2021

11. SARS-CoV-2-related MIS-C:A key to the viral and genetic causes of Kawasaki disease?

Author: Sancho-Shimizu, Vanessa, Brodin, Petter, Cobat, Aurélie, Biggs, Catherine M., Toubiana, Julie, Lucas, Carrie L., Henrickson, Sarah E., Belot, Alexandre, Haddad, Elie, Beland, Kathie, Pujol, Aurora, Schlüter, Agatha, Planas-Serra, Laura, Aguilera-Albesa, Sergio, Valencia-Ramos, Juan, Rodríguez-Palmero, Agustí, Gut, Marta, Rivière, Jacques G., Colobran, Roger, Soler-Palacin, Pere, Rodriguez-Gallego, Carlos, Perez De Diego, Rebeca, Flores, Carlos, Alsina, Laia, Blazquez-Gamero, Daniel, Jordan, Iolanda, Keles, Sevgi, Emiroglu, Melike, Akcan, Ozge Metin, Alkan, Gulsum, Aytekin, Selma Erol, Gul, Yahya, Tüter Öz, Şadiye Kübra, Bozdemir, Sefika Elmas, Bayhan, Gulsum Iclal, Yüksek, Saliha Kanık, Parlakay, Aslınur Özkaya, Gülhan, Belgin, Yahşi, Aysun, Kilic, Ahmet Osman, Karbuz, Adem, Erdeniz, Emine Hafize, Özkan, Esra Akyüz, Orbak, Zerrin, Aydemir, Şehnaz, Celik, Jale Bengi, Kandemir, Bahar, Aytekin, Gökhan, Kapakli, Hasan, Yarar, Volkan, Yosunkaya, Alper, Vatansev, Hulya, Aytekin, Caner, Torun, Selda Hancerli, Nepesov, Serdar, Coskuner, Taner, Sözeri, Betül, Demirkol, Yasemin Kendir, Kasapcopur, Ozgur, Yıldız, Mehmet, Sevketoglu, Esra, Hatipoğlu, Nevin, Özçelik, Tayfun, Yesilbas, Osman, Gayretli Aydin, Zeynep Gökçe, Sediva, Anna, Klocperk, Adam, Bloomfield, Marketa, Meyts, Isabelle, Delafontaine, Selket, Haerynck, Filomeen, Hoste, Levi, Shahrooei, Mohammad, Marque, Laura, Neves, João Farela, Novelli, Giuseppe, Novelli, Antonio, Aiuti, Alessandro, Casari, Giorgio, Bousfiha, Amed Aziz, Almuhsen, Saleh Zaid, Sobh, Ali, Gagro, Alenka, Bajolle, Fanny, Bonnet, Damien, Lebon, Pierre, Lei, Weite, Lee, Danyel, Seeleuthner, Yoann, Zhang, Peng, Maglorius, Majistor, Philippot, Quentin, Pelham, Simon, Bastard, Paul, Zhang, Qian, Jouanguy, Emmanuelle, Puel, Anne, Herberg, Jethro, Kuijpers, Taco W, Bellos, Evangelos, Kaforou, Myrsini, Menikou, Stephanie, Pan-Hammarström, Qiang, Hammarström, Lennart, Abolhassani, Hassan, Bryceson, Yenan, Condino-Neto, Antonio, Prando, Carolina, Bando, Silvia Yumi, Cavalcanti, Andre, Fellay, Jacques, Blanchard-Hohner, Giradine, Mansouri, Davood, Mahmoudi, Shima, Boyarchuk, Oksana, Volokha, Alla, Bondarenko, Anastasiia, Stepanovskiy, Yuriy, Mogensen, Trine, van de Beek, Diederik, Andreakos, Evangelos, Papadaki, Maria, Abou Tayoun, Ahmad, Halwani, Rabih, Al-Mulla, Fahd, Franco, José Luis, Lau, Yu-Lung, Kwan, Mike, Imai, Kohsuke, Okada, Satoshi, Bolze, Alexandre, Butte, Manish J., Hsieh, Elena, Drolet, Beth A, Arkin, Lisa, Itan, Yuval, Maniatis, Tom, Arditi, Moshe, Cooper, Megan, Schmitt, Erica, Chakravorty, Samya, Anderson, Mark S., Su, Helen C., Notarangelo, Luigi D., MIS-C@CHGE, [missing], Tangye, Stuart G., Milner, Joshua D., Levin, Michael, Abel, Laurent, Bogunovic, Dusan, Casanova, Jean-Laurent, Zhang, Shen-Ying, Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département de Pédiatrie et maladies infectieuses [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), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, Institut Pasteur [Paris] (IP), 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), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Service de cardiologie pédiatrique [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), Université Paris Cité (UPCité), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Funded by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (R01AI088364 to J.-L. Casanova and S.-Y. Zhang, R01AI148963, R01AI151029, and R01AI150300 to D. Bogunovic, K08AI135091 to S.E. Henrickson, R21AI144315-02S1 to C.L. Lucas), the National Center for Advancing Translational Sciences, National Institutes of Health Clinical and Translational Science Award program (UL1 TR001866), the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (UM1HG006504 and U24HG008956), Institut National de la Santé et de la Recherche Médicale and Université de Paris, the French National Research Agency (ANR) Résilience-Covid-19 grant GenMIS-C, the ANR 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the ANR project AABIFNCOV (ANR-20-CO11-0001), the French Foundation for Medical Research (EQU201903007798), the French Foundation for Medical Research and ANR GENCOVID project, the ANRSCOV05 project, the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, UK Research and Innovation Future Leader’s Fellowship (MR/S032304/1), the NIHR Imperial Biomedical Research Centre at Imperial College Healthcare NHS Trust (70931), the Burroughs Wellcome Fund Career Awards for Medical Scientists, the Clinical Immunology Society, the American Academy of Allergy Asthma and Immunology, the Michael Smith Foundation for Health Research, the National Health and Medical Research Council of Australia, and the University of New South Wales Sydney COVID Rapid Response Initiative (to S.G. Tangye)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), Imperial College BRC, Imperial College Healthcare NHS Trust- BRC Funding, and UKRI Future Leader's Fellowship
Subjects: 0301 basic medicine, viruses, Systemic Inflammatory Response Syndrome/epidemiology, Genome-wide association study, CHILDREN, COVID-19 (Malaltia), Pathogenesis, 0302 clinical medicine, hemic and lymphatic diseases, INFECTION, Medicine and Health Sciences, Immunology and Allergy, 030212 general & internal medicine, skin and connective tissue diseases, Child, 11 Medical and Health Sciences, COVID-19/epidemiology, Pediatria, Malaltia de Kawasaki, Systemic Inflammatory Response Syndrome, Settore MED/03, Inflammation Mediators/blood, Perspective, Cytokines, SHOCK, medicine.symptom, Inflammation Mediators, Lymphohistiocytosis, Hemophagocytic/genetics, congenital, hereditary, and neonatal diseases and abnormalities, HUMAN CORONAVIRUS NL63, SUSCEPTIBILITY LOCI, MULTISYSTEM INFLAMMATORY SYNDROME, Inflammation/etiology, Immunology, Innate Immunity and Inflammation, Inflammation, Biology, Mucocutaneous Lymph Node Syndrome, Cytokines/blood, Models, Biological, Lymphohistiocytosis, Hemophagocytic, SARS-CoV-2/immunology, 03 medical and health sciences, Immune system, Immunity, CORONARY ANEURYSMS, medicine, otorhinolaryngologic diseases, Immunodeficiency, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Pandemics, SARS-CoV-2, Mucocutaneous Lymph Node Syndrome/epidemiology, COVID-19, biochemical phenomena, metabolism, and nutrition, medicine.disease, Systemic inflammatory response syndrome, 030104 developmental biology, Etiology, Kawasaki disease, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, PIMS-TS, Biomarkers, Human Disease Genetics, Genètica, Biomarkers/blood, Genome-Wide Association Study
Abstract: SARS-CoV-2 is the trigger of MIS-C, which suggests that other viruses may trigger different forms of Kawasaki disease. The discovery of inborn errors of immunity underlying MIS-C would facilitate that of inborn errors of immunity to viruses underlying Kawasaki disease., Multisystem inflammatory syndrome in children (MIS-C) emerged in April 2020 in communities with high COVID-19 rates. This new condition is heterogenous but resembles Kawasaki disease (KD), a well-known but poorly understood and clinically heterogenous pediatric inflammatory condition for which weak associations have been found with a myriad of viral illnesses. Epidemiological data clearly indicate that SARS-CoV-2 is the trigger for MIS-C, which typically occurs about 1 mo after infection. These findings support the hypothesis of viral triggers for the various forms of classic KD. We further suggest that rare inborn errors of immunity (IEIs) altering the immune response to SARS-CoV-2 may underlie the pathogenesis of MIS-C in some children. The discovery of monogenic IEIs underlying MIS-C would shed light on its pathogenesis, paving the way for a new genetic approach to classic KD, revisited as a heterogeneous collection of IEIs to viruses.
Published: 2021

12. A monocyte/dendritic cell molecular signature of SARS-CoV2-related multisystem inflammatory syndrome in children (MIS-C) with severe myocarditis

Author: Ludivine Grzelak, Maxime Beretta, Slimane Allali, Aude Magérus, Hugo Mouquet, Maxime Batignes, Isabelle Melki, Olivier Schwartz, Quentin Riller, Mehdi Oualha, Nicolas Cagnard, Christine Bole-Feysot, Camille de Cevins, James P. Di Santo, Christele Gras Leguen, Florence Moulin, Jean-Laurent Casanova, Cécile Masson, Aurélien Corneau, Damien Bonnet, Vithura Pirabarakan, Mickaël M. Ménager, Camille Bruneau, Brieuc P. Perot, Francesco Carbone, Darragh Duffy, Mohammed Zarhrate, Marie-Claude Stolzenberg, Alexandre Boullé, Mélanie Parisot, Boris Sorin, Ghaith Abdessalem, Alain Fischer, Marianne Leruez, Julie Toubiana, Victor Garcia-Paredes, Mathie Lorrot, Loïc de Pontual, Zahra Belhadjer, Bruno Charbit, Tinhinane Fali, Marine Luka, Nikaïa Smith, Brigitte Bader Meunier, Shen-Ying Zhang, Sonia Meynier, Fredéric Rieux Laucat, Julien Haroche, Pedro Gonçalves, Laura Barnabei, Inflammatory Responses and Transcriptomic Networks in diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - 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), Sanofi Aventis R&D [Chilly-Mazarin], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunité Innée - Innate Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Rockefeller University [New York], Service d'immuno-hématologie pédiatrique [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), Service d'Immunologie [CHU Pitié-Salpétrière], 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), AP-HP Hôpital universitaire Robert-Debré [Paris], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département des urgences pédiatriques [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), Laboratoire de Virologie [CHU Necker], Département de Pédiatrie et maladies infectieuses [CHU Necker], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Collège de France (CdF (institution)), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, The study was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), by the 'URGENCE COVID-19' fundraising campaign of Institut Pasteur, by the Atip-Avenir, Emergence ville de Paris program and fond de dotation Janssen Horizon and by government grants managed by the Agence National de la Recherche as part of the 'Investment for the Future' program (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01, Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010, Laboratoire d’Excellence ‘‘Milieu Intérieur', grant ANR-10-LABX-69-01), the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), the Agence National de la Recherche (ANR-flash Covid19 'AIROCovid' to FRL and 'CoVarImm' to DD and JDS), and by the FAST Foundation (French Friends of Sheba Tel Hashomer Hospital). The LabTech Single Cell@Imagine is supported by the Paris Region and the 'Investissements d’avenir' program through the 2019 ATF funding – Sésame Filières PIA (Grant N°3877871). CdC is the recipient of a CIFRE-PhD (Sanofi). L.B. was a recipient of an Imagine institute PhD international program supported by the Fondation Bettencourt Schueller. L.B. was also supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) and is part of the Université de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its 'Investments for the Future' program. S.M. was a recipient of an INSERM and Institut Imagine post-doctorat program supported by the Fondation pour la Recherche Médicale (FRM N°SPF20170938825). NS was a recipient of the Pasteur-Roux-Cantarini Fellowship. VGP obtained an Imagine international PhD fellowship program supported by the Fondation Bettencourt Schueller. BPP is the recipient of an ANRS post-doctoral fellowship., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-20-COVI-0022,AIROCovid19,Analyse Omics de la réponse immune aigue au cours de l'infection à Covid19: rationnel moléculaire pour un traitement ciblé(2020), ANR-17-EURE-0013,GENE,Génétique et Epigénétique Nouvelle Ecole(2017), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), 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), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0303 health sciences, Chemokine, Myocarditis, biology, business.industry, Monocyte, Dendritic cell, Gene signature, medicine.disease_cause, medicine.disease, Pathophysiology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, biology.protein, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, business, Oxidative stress, 030304 developmental biology
Abstract: SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis, characterized by sustained NF-κB activity, TNF-α signaling, associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1α and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology.
Published: 2021

13. Polyclonal expansion of TCR Vb 21.3 + CD4 + and CD8 + T cells is a hallmark of multisystem inflammatory syndrome in children

Author: Olivier Dauwalder, David Klatzmann, Marie Duperril, Marion Moreews, Christine Lombard, Behrouz Kassai, Fanny Bajolle, Jean-Laurent Casanova, Anne-Laure Mathieu, Guillaume Monneret, Magali Perret, Rémi Pescarmona, Aurélie Portefaix, Jacqueline Marvel, Laurent Abel, Christophe Malcus, Tiphaine Louazon, Anne Moulin-Zinsch, Mehdi Mezidi, Lisa Giovannini-Chami, Omran Allatif, Hugues Patural, Thierry Walzer, Emilie Chopin, Francois Vandenesh, Encarnita Mariotti-Ferrandiz, Fabienne Venet, Céline Dupieux, Valérie Launay, Paul Bastard, Sophie Trouillet-Assant, Jean-Christophe Richard, Olivier Thaunat, Shen-Ying Zhang, Marine Villard, Samira Khaldi-Plassart, Kahina Saker, Alexandre Belot, Sophia Djebali, Marlène Dreux, Alicia Bellomo, Isabelle Rouvet, Robin Pouyau, Etienne Javouhey, Margaux Guerder, Sonia Teyssedre, Valérie Dubois, Kenz Le Gouge, Hugues Flodrops, Jean-Marie De Guillebon, 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), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l’enfant / National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children [Lyon] (RAISE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hôpital Edouard Herriot [CHU - HCL], Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre National de Reference des Staphylocoques, Université de Lyon, Centre hospitalier de Valence, Hôpital Louis Pradel [CHU - HCL], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), CIC CHU Lyon (inserm), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), 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), Rockefeller University [New York], Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Hôpital de la Croix-Rousse [CHU - HCL], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), 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)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-16-RHUS-0001,iMAP,iMAP(2016), Référent HAL, 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), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, T cell, [SDV]Life Sciences [q-bio], Immunology, T-cell receptor, Toxic shock syndrome, General Medicine, Human leukocyte antigen, Biology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Antigen, medicine, Cytotoxic T cell, 030212 general & internal medicine, Cytokine storm, CD8
Abstract: International audience; Multisystem inflammatory syndrome in children (MIS-C) is a delayed and severe complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease (KD) and toxic shock syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared with 16 KD, 58 TSS, and 42 coronavirus disease 2019 (COVID-19) cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFN-γ, sCD25, MCP1, and IL-1RA) in MIS-C, TSS, and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of patients with MIS-C and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3 + T cells from patients with MIS-C expressed high levels of HLA-DR, CD38, and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS, and acute COVID-19.
Published: 2021

14. Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines

Author: Stephen J. Seligman, Serkan Belkaya, Ruben Pholien, Ismail Reisli, Johan Neyts, Yoann Seeleuthner, Leen Moens, Afshin Shirkani, Scott Drutman, Charles M. Rice, Lazaro Lorenzo-Diaz, Isabelle Meyts, Margaret R. MacDonald, Emersom Ciclini Mesquita, Dick Zijlmans, Denise Cristina de Souza Matos, Nicholas Hernandez, Sheila Maria Barbosa de Lima, Maria de Lourdes de Sousa Maia, Alain Lefevre-Utile, Dirk Jochmans, Paul J. Hertzog, Tamiris Azamor da Costa Barros, Marilda M. Siqueira, Esra Hazar Sayar, Hans Heinrich Hoffmann, Xavier Bossuyt, Nico Marr, Qian Zhang, Patrícia Mouta Nunes de Oliveira, Laura Pöyhönen, Emmanuelle Jouanguy, Giorgia Bucciol, Andrea Jurado, Shen-Ying Zhang, Aurélie Cobat, Robbert Boudewijns, Hassan Rokni-Zadeh, Jérémie Le Pen, Ekaterini Goudouris, Rik Gijsbers, Ian Tietjen, Chibuzo U Enemchukwu, Reinaldo de Menezes Martins, Laurent Abel, Majid Changi-Ashtiani, Jean-Laurent Casanova, Mohammad Shahrooei, Mana Momenilandi, and Akira Homma
Subjects: Male, 0301 basic medicine, Adolescent, Measles-Mumps-Rubella Vaccine, Measles Vaccine, Immunology, Inheritance Patterns, Yellow fever vaccine, Receptor, Interferon alpha-beta, Rubella, Measles, Article, 03 medical and health sciences, 0302 clinical medicine, Immunity, medicine, Humans, Immunology and Allergy, Child, Research Articles, Alleles, business.industry, Yellow Fever Vaccine, Yellow fever, Infant, medicine.disease, Virology, Pedigree, 3. Good health, Vaccination, 030104 developmental biology, Interferon Type I, Mutation, Female, Mutant Proteins, Measles vaccine, business, Signal Transduction, 030215 immunology, medicine.drug
Abstract: We describe two unrelated patients with inherited IFNAR1 deficiency who suffered from life-threatening infections following measles or yellow fever virus vaccination and were otherwise healthy., Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients’ fibroblast phenotypes are rescued with WT IFNAR1. Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.
Published: 2019

15. Efficacy and safety of CT-guided percutaneous pulsed radiofrequency treatment of the Gasserian ganglion in patients with medically intractable idiopathic trigeminal neuralgia

Author: Ren Hao, Luo Fang, Meng Lan, Shen Ying, and Jia Zipu
Subjects: safety, medicine.medical_specialty, Percutaneous, efficacy, pulsed radiofrequency, 03 medical and health sciences, 0302 clinical medicine, Pharmacotherapy, Refractory, 030202 anesthesiology, Trigeminal neuralgia, Medicine, Case Series, Journal of Pain Research, Prospective cohort study, trigeminal neuralgia, Pulsed radiofrequency, business.industry, medicine.disease, Surgery, Ganglion, Anesthesiology and Pain Medicine, medicine.anatomical_structure, Pulsed Radiofrequency Treatment, business, 030217 neurology & neurosurgery
Abstract: Meng Lan,* Jia Zipu,* Shen Ying, Ren Hao, Luo Fang Department of Anesthesiology and Pain Management, Beijing Tiantan Hospital, Capital Medical University, Beijing, PR China*These authors contributed equally to this workBackground: There is a lack of prospective studies for the long-term results of percutaneous pulsed radiofrequency (PRF) of the Gasserian ganglion in the treatment of patients with medically refractory trigeminal neuralgia (TN).Methods and results: We prospectively observed the outcomes of 28 idiopathic TN patients (between July 2013 and July 2016) who received CT-guided percutaneous PRF treatment of the Gasserian ganglion. All of the patients had stopped responding to drug therapy before PRF treatment. The effective treatment standard was a reduction in the pain numeric rating scale (NRS) by≥50% after the procedure. The postoperative NRS score decreased gradually from preoperative 7.6±0.8 months to 1.5±2.4, 0.2±0.4, 0.2±0.4, 0.1±0.4, and 0.1±0.4 at 1, 3, and 6 months and 1 and 2 years after the PRF treatment. The response rates at 1, 3, and 6 months were 85.7%, and the rates at 12 months and 2 years were maintained at 78.6%. No serious side effects were observed.Conclusion: CT-guided PRF invention is an effective and safe technique for medically intractable idiopathic TN patients. This minimally invasive alternative treatment has the potential as a first-line therapy for TN. Keywords: trigeminal neuralgia, pulsed radiofrequency, efficacy, safety
Published: 2018

16. Superantigenic TCR Vbeta 21.3 signature in Multisystem Inflammatory Syndrome in Children

Author: Encarnita Mariotti-Ferrandiz, Marlène Dreux, Kenz Le Gouge, Aurélie Portefaix, Anne-Moulin-Zinsch, Alexandre Belot, Emilie Chopin, Marie Duperril, Marion Moreews, Hugues Patural, Thierry Walzer, Jean-Christophe Richard, Anne-Laure Mathieu, Robin Pouyau, Etienne Javouhey, Olivier Thaunat, Valérie Dubois, Hugues Flodrops, Behrouz Kassai, Marine Villard, Alicia Bellomo, Laurent Abel, Fabienne Venet, Samira Khaldi-Plassart, Sophia Djebali, David Klatzmann, Jacqueline Marvel, Sonia Teyssedre, Céline Dupieux, Tiphaine Louazon, Lisa Giovannini-Chami, Sophie Trouillet-Assant, Christine Lombard, Francois Vandenesh, Mehdi Mezidi, Shen-Ying Zhang, Guillaume Monneret, Jean-Laurent Casanova, Magali Perret, Rémi Pescarmona, Margaux Guerder, Paul Bastard, Christophe Malcus, and Isabelle Rouvet
Subjects: business.industry, medicine.medical_treatment, T cell, Toxic shock syndrome, medicine.disease, Cytokine release syndrome, Cytokine, medicine.anatomical_structure, Immune system, Immunology, medicine, Cytotoxic T cell, Interferon gamma, business, CD8, medicine.drug
Abstract: ObjectivesMultiple Inflammatory Syndrome in Children (MIS-C) is the most severe pediatric form of COVID-19 and occurs in previously healthy children. MIS-C combines features of Kawasaki disease and Toxic Shock Syndrome (TSS).MethodsChildren with suspected MIS-C were included within the first week of diagnosis and a large scale immunoassay was performed to determein the immunologic signature of these patients.ResultsWe characterized the immunological profile of 27 MIS-C cases in comparison with 4 KD and 4 TSS cases. Similarly to TSS, an increase of serum inflammatory cytokines (IL-6, TNF-a, CD25s) was observed in MIS-C contrasting with low expression of HLA-DR monocytes, a feature often associated with immune paralysis. Expansions of T cells expressing the Vβ21.3 T cell receptor β chain variable region were detected in both CD4 and CD8 subsets in almost 50% of patients and Vβ21.3-positive T cells expressed high level of HLA-DR highlighting their specific activation. TCR sequencing uncovered the polyclonal nature of the Vβ 21.3+ population. SARS-CoV2 antigene-specific production of interferon gamma in T cells was not increased in MIS-C T cells compared to COVID-19 patients suggesting the antigen-specific immune response in MIS-C patients is not pivotal to the manifestation.ConclusionsOur findings argue in favor of a strong activation of the immune system related to a superantigenic immune response in MIS-C with a specific polyclonal Vβ21.3 T cell expansion.Key messagesWhat is already known about this subject ?MIS-C occurs 3-5 weeks after acute SARS-CoV2 infection and overlap features of Toxic Shock syndrome and Kawasaki disease.MIS-C appears different in term of cytokine and autoantibodies generation from KD with subtle signs of T cells activationWhat does this study add?This study demonstrates that Vβ21.3+ CD4 and CD8 T cells are highly increased in about 50% of MIS-C and distinctive of the Vβ2+ expansion observed in toxic shock syndrome in This reflects a specific T cell activation and cytokine release syndrome similar to toxic shock syndromeHow mich this impact on clinical practice or future developments?Vβ21.3+ signature can be available on a short term basis by flowcytometry and represents a signature of the MIS-C.As for TSS, immunomodulating therapies may revert the superantigenic activation and resolve this life threatening pediatric condition.
Published: 2021

17. Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

Author: Jeremy Manry, Eduardo J. Garcia Reino, Taushif Khan, Romain Lévy, Mary Hasek, Jérémie Rosain, Yoann Seeleuthner, Isabelle Meyts, Lazaro Lorenzo, Laurent Abel, Zhi Li, Omar AbuZaitun, Shai Shrot, Paul Bastard, Jean-Laurent Casanova, Bertrand Boisson, Emmanuelle Jouangy, Flore Rozenberg, Nicholas Hernandez, Raz Somech, Benedetta Bigio, Shen-Ying Zhang, Mélodie Aubart, Vivien Béziat, Nico Marr, Jie Chen, Rik Gijsbers, Peng Zhang, Jacinta Bustamante, Qian Zhang, Yoon-Seung Lee, Sandra Pellegrini, Aurélie Cobat, Soraya Boucherit, Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Sidra Medicine [Doha, Qatar], Service d'immuno-hématologie pédiatrique [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), Chaim Sheba Medical Center, Kfar Saba and Sackler School of Medicine, Service de neurochirurgie pédiatrique [CHU Necker], Faculté de Médecine et Médecine Dentaire [UCLouvain], Université Catholique de Louvain = Catholic University of Louvain (UCL), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Hamad Bin Khalifa University (HBKU), Precision Immunology Institute [New-York] (PrIISM), Icahn School of Medicine at Mount Sinai [New York] (MSSM), CHU Necker - Enfants Malades [AP-HP], Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), This work was conducted in the two branches of the Laboratory of Human Genetics of Infectious Diseases, and was funded in part by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Clinical and Translational Science Award (CTSA) program, grant UL1TR001866, NIH grants R01AI088364, R01NS072381 and R21AI151663, the National Vaccine Program Office of the US Department of Health and Human Services grant VSRNV000006, grants from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), the ANR grants IEIHSEER (ANR-14-CE14-0008-01), SEAeHostFactors (ANR-18-CE15-0020-02), and CNSVIRGEN (ANR-19-CE15-0009-01), the French Foundation for Medical Research (FRM) (EQU201903007798), the Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, and the St. Giles Foundation. PB was supported by the French Foundation for Medical Research (FRM, EA20170638020) and the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller). JR was supported by the Inserm PhD program ('poste d’accueil Inserm'). JM was supported by ANR grants BURULIGEN (ANR-12-BSV3-0013-01) and MYCOPARADOX (ANR-16-CE12-0023)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle?(2014), ANR-18-CE15-0020,SEAe-HostFactors,Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est(2018), and ANR-19-CE15-0009,CNSVIRGEN,Déficits immunitaires innés dans les infections sévères du tronc cérébral(2019)
Subjects: Male, 0301 basic medicine, Untranslated region, Adolescent, [SDV]Life Sciences [q-bio], Immunology, Herpesvirus 1, Human, Receptor, Interferon alpha-beta, Biology, medicine.disease_cause, Rubella, 03 medical and health sciences, Exon, 0302 clinical medicine, Immunity, medicine, Humans, MESH: Receptor, Interferon alpha-beta, MESH: Interferons, Innate immunity, MESH: Adolescent, Infectious disease, MESH: Humans, MESH: Encephalitis, Herpes Simplex, MESH: Child, Preschool, General Medicine, medicine.disease, Virology, MESH: Male, MESH: Herpesvirus 1, Human, HEK293 Cells, 030104 developmental biology, Herpes simplex virus, Tyrosine kinase 2, Child, Preschool, 030220 oncology & carcinogenesis, MESH: HEK293 Cells, Cytokines, Encephalitis, Herpes Simplex, Interferons, Viral disease, Encephalitis, Research Article, Genetic diseases
Abstract: International audience; Inborn errors of TLR3-dependent IFN-α/β– and IFN-λ–mediated immunity in the CNS can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/β and IFN-λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3′-UTR of the last exon of IFNAR1, who died of HSE at the age of 2 years. An older cousin died following vaccination against measles, mumps, and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe, viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient’s fibroblasts and EBV-B cells did not respond to IFN-α2b or IFN-β, in terms of STAT1, STAT2, and STAT3 phosphorylation or the genome-wide induction of IFN-stimulated genes. The patient’s fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-α2b or IFN-β. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This viral disease occurred in natural conditions, unlike those previously reported in other patients with IFNAR1 or IFNAR2 deficiency. This experiment of nature indicates that IFN-α/β are essential for anti–HSV-1 immunity in the CNS
Published: 2021

18. Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1

Author: Lucy Bizien, Eystein S. Husebye, Edwin Carter, Maria Pavlova, Jérémie Rosain, Fanny Vuoto, Bénédicte Neven, Thomas DiMaggio, Monica M. Schmitt, Agnès Linglart, Luigi D. Notarangelo, Kai Kisand, Adrian Gervais, Michail S. Lionakis, Mark S. Anderson, Olov Ekwall, Nathalie Cheikh, Sébastien Humbert, Yulia Rodina, Olivier Hermine, Pierre Rohrlich, Lucia Ghizzoni, Romain Lévy, Anya Rothenbuhler, Tom Le Voyer, Paul Bastard, Laurent Abel, Brigite Mignot, Anna-Lena Neehus, Sebastian Ochoa, Steven M. Holland, Helen C. Su, Quentin Philippot, Emmanuelle Jouanguy, Karine Faure, Martin Mcintyre, Mélanie Migaud, Elana Shaw, Maria Kareva, Arthur Pavot, Aurélie Comte, Nelli Y Kann, Elise M. N. Ferré, Anna Shcherbina, Katarina Trebušak Podkrajšek, Alyssa James, Leila S. Sozaeva, Lars Breivik, Yanick J. Crow, Primož Kotnik, Guglielmo Beccuti, Stefan Berg, Nizar Mahlaoui, Tadej Battelino, Gérard Thiriez, Anne Puel, Alain Coaquette, Cécile Goujard, Marie-Louise Frémond, Shen-Ying Zhang, Jean-Laurent Casanova, Lindsey B. Rosen, Peter D. Burbelo, Anna Kolodkina, and Elizaveta Orlova
Subjects: 0301 basic medicine, Male, Autoimmunity, Disease, medicine.disease_cause, Medical and Health Sciences, law.invention, 0302 clinical medicine, law, Immunology and Allergy, 030212 general & internal medicine, Young adult, Child, Polyendocrinopathies, Autoimmune, Lung, education.field_of_study, Middle Aged, Intensive care unit, Infectious Diseases, Autoimmune polyendocrine syndrome, Interferon Type I, Pneumonia & Influenza, Female, Adult, medicine.medical_specialty, Adolescent, Immunology, Population, Innate Immunity and Inflammation, Autoimmune Disease, Infectious Disease and Host Defense, 03 medical and health sciences, Young Adult, Rare Diseases, Clinical Research, Internal medicine, medicine, Humans, education, Autoantibodies, business.industry, SARS-CoV-2, Prevention, Autoantibody, Brief Definitive Report, COVID-19, Pneumonia, medicine.disease, 030104 developmental biology, Polyendocrinopathies, business, Autoimmune
Abstract: Patients with autoimmune polyendocrine syndrome type-1 (APS-1) have circulating auto-Abs neutralizing most type I interferons. These auto-Abs can underlie life-threatening COVID-19 pneumonia in the general population. The authors report 22 APS-1 patients infected with SARS-CoV-2, including 15 (68%) who developed life-threatening disease., Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti–IFN-β and another anti–IFN-ε, but none had anti–IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
Published: 2021

19. A Monocyte/Dendritic Cell Molecular Signature of SARS-CoV-2 Related Multisystem Inflammatory Syndrome in Children (MIS-C) with Severe Myocarditis

Author: Camille de Cevins, Marine Luka, Nikaia Smith, Sonia Meynier, Aude Magérus, Francesco Carbone, Victor Garcia-Paredes, Laura Barnabei, Maxime Batignes, Alexandre Boullé, Marie-Claude Stolzenberg, Brieuc P. Pérot, Bruno Charbit, Tinhinane Fali, Vithura Pirabarakan, Boris Sorin, Quentin Riller, Ghaith Abdessalem, Maxime Beretta, Ludivine Grzelak, Pedro Goncalves, James Di Santo, Hugo Mouquet, Olivier Schwartz, Mohammed Zarhrate, Mélanie Parisot, Christine Bole-Feysot, Cécile Masson, Nicolas Cagnard, Aurelien Corneau, Camille Bruneau, Shen-Ying Zhang, Jean-Laurent Casanova, Brigitte Bader Meunier, Julien Haroche, Isabelle Melki, Mathie Lorrot, Mehdi Oualha, Florence Moulin, Damien Bonnet, Zahra Belhadjer, Mariane Leruez, Slimane Allali, Christele Gras Leguen, Loic de Pontual, Pediatric-Biocovid Study Group, Alain Fischer, Darragh Duffy, Frederic Rieux-Laucat, Julie Toubiana, and Mickaël Mathieu Ménager
Subjects: Gynecology, medicine.medical_specialty, Myocarditis, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Monocyte, education, Ethics committee, medicine.disease, medicine.anatomical_structure, Medicine, VEGF signaling, business
Abstract: SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis, characterized by sustained NF-κ B activity, TNF-α signaling, associated with decreased gene expression of NF-κ B inhibitors. We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1α and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology. Funding: The study was supported by the Institut National de la Sante et de la Recherche Medicale (INSERM), by the “URGENCE COVID-19” fundraising campaign of Institut Pasteur, by the Atip-Avenir, Emergence ville de Paris program and fond de dotation Janssen Horizon and by government grants managed by the Agence National de la Recherche as part of the “Investment for the Future” program (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01, Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010, Laboratoire d’Excellence ‘‘Milieu Interieur”, grant ANR-10-LABX-69-01), the Centre de Reference Deficits Immunitaires Hereditaires (CEREDIH), the Agence National de la Recherche (ANR-flash Covid19 “AIROCovid” to FRL and “CoVarImm” to DD and JDS), and by the FASTFoundation (French Friends of Sheba Tel Hashomer Hospital). The LabTech Single-Cell@Imagine is supported by the Paris Region and the “Investissements d’avenir” program through the 2019 ATF funding – Sesame Filieres PIA (Grant N°3877871).CdC is the recipient of a CIFRE-PhD (Sanofi). L.B. was a recipient of an Imagine institute PhD international program supported by the Fondation Bettencourt Schueller. L.B. was also supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) and is part of the Universite de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its“Investments for the Future” program. S.M. was a recipient of an INSERM and Institut Imagine post-doctorat program supported by the Fondation pour la Recherche Medicale (FRMN°SPF20170938825). NS was a recipient of the Pasteur-Roux-Cantarini Fellowship. VGP obtained an Imagine international PhD fellowship program supported by the Fondation Bettencourt Schueller. BPP is the recipient of an ANRS post-doctoral fellowship. Conflict of Interest: DD, FRL, JT and MMM are listed as inventors on a patent application related to this technology (European Patent Application no. EP21305197, entitled “Methods of predicting multisystem inflammatory syndrome (MIS-C) with severe myocarditis in subjects suffering from a SARS-CoV-2 infection”). Ethical Approval: The study was approved by the Ethics Committee (Comite de Protection des Personnes Ouest IV, n° DC-2017-2987).
Published: 2021

20. Life-Threatening COVID-19: Defective Interferons Unleash Excessive Inflammation

Author: Shen-Ying Zhang, Helen C. Su, Luigi D. Notarangelo, Aurélie Cobat, Alexandre Bolze, Jean-Laurent Casanova, Qian Zhang, Paul Bastard, Covid Human Genetic Effort, Emmanuelle Jouanguy, and Laurent Abel
Subjects: Inflammation, 2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), SARS-CoV-2, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Autoantibody, COVID-19, General Medicine, Disease, medicine.disease, Pneumonia, Interferon Type I, Immunology, Epidemiology, Commentary, medicine, Humans, medicine.symptom, business, Autoantibodies
Abstract: The risk of life-threatening COVID-19 pneumonia increases sharply after 65 years of age, but other epidemiological risk factors, genetic or otherwise, are modest. Various rare monogenic inborn errors of type I interferons (IFNs) underlie critical disease, and neutralizing autoantibodies against type I IFNs account for at least 10% of critical cases.
Published: 2020
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21. Molecular Diagnosis of Panel-Based Next-Generation Sequencing Approach and Clinical Symptoms in Patients With Glycogen Storage Disease: A Single Center Retrospective Study

Author: Lin Qian, Zheng Bixia, Zhang Zhihua, Cheng Weixia, Liu Zhi-feng, Zheng Yucan, Jin Yu, and Shen Ying
Subjects: 0301 basic medicine, medicine.medical_specialty, media_common.quotation_subject, Nonsense, Single Center, Pediatrics, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, glycogen storage disease, Internal medicine, Hypothesis and Theory, Gene duplication, Medicine, Missense mutation, Glycogen storage disease, splice, panel, media_common, variants, uncooked cornstarch, business.industry, lcsh:RJ1-570, lcsh:Pediatrics, Retrospective cohort study, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, next-generating sequencing, Pediatrics, Perinatology and Child Health, business
Abstract: Aim: The aim of this study was to investigate the clinical utility of panel-based next-generation sequencing (NGS) in the diagnostic approach of glycogen storage disease (GSD).Methods: We performed a retrospective review of the 32 cases with suspected GSDs between April 2013 and November 2019 through panel-based NGS, clinical and biochemical data and long-term complications.Results: Of the 32 clinical cases, we identified 41 different variants, including 24 missense (58.5%), one synonymous (2.4%), three nonsense (8%), one splice (2.4%), four frameshift (9.8%), one deletion (2.4%), four insertions (9.8%), two deletion-insertion (4.9%) and one duplication(2.4%), of which 13(31.7%) were previously unreported in the literature. In addition, patients with different types of GSDs showed important differences in biochemical parameters (i.e., CK, rGGT, TG, and UA).Conclusions: The panel-based NGS played an important diagnostic role in the suspicious GSDs patients, especially in the mild phenotype and ruled out detectable pathologic conditions. Besides, differences between our GSDs patients reflect biochemical heterogeneity.
Published: 2020

22. Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine

Author: Yoann Seeleuthner, Marie Materna, Aurélie Cobat, Luigi D. Notarangelo, Quentin Philippot, Hans-Heinrich Hoffmann, Tom Le Voyer, Adrian Gervais, Rui Yang, Flore Rozenberg, Marwa Chbihi, Charles M. Rice, Ralph Huits, Steven M. Holland, Johannes Schäfer, Jean-Laurent Casanova, Tamiris Azamor, Ana Paula Dinis Ano Bom, Lindsey B. Rosen, Lazaro Lorenzo, Lucia V Erazo, Jérémie Rosain, Maya Chrabieh, Qian Zhang, Patrícia Mouta Nunes de Oliveira, Shen-Ying Zhang, Joseph D. Miller, Eleftherios Michailidis, Günther Slesak, Maria de Lourdes de Sousa Maia, Deborah Araújo da Conceição, Laurent Abel, Rafi Ahmed, Vivien Béziat, Margaret R. MacDonald, Lucy Bizien, Bali Pulendran, Paul Bastard, Emmanuelle Jouanguy, Akira Homma, Ekaterini Goudouris, Stephen J. Seligman, Anne Puel, Helen C. Su, and Mohamed Jeljeli
Subjects: 0301 basic medicine, Adult, Male, Adolescent, Immunology, Innate Immunity and Inflammation, Yellow fever vaccine, Receptor, Interferon alpha-beta, Vaccines, Attenuated, Virus, Autoimmune Diseases, 03 medical and health sciences, 0302 clinical medicine, medicine, Immunology and Allergy, Humans, Immunodeficiency, Adverse effect, Aged, Autoantibodies, Attenuated vaccine, biology, business.industry, SARS-CoV-2, Yellow fever, Yellow Fever Vaccine, Genetic Diseases, Inborn, Brief Definitive Report, COVID-19, Interferon-alpha, Middle Aged, medicine.disease, Antibodies, Neutralizing, Vaccination, Pneumonia, 030104 developmental biology, HEK293 Cells, 030220 oncology & carcinogenesis, biology.protein, Female, Antibody, Yellow fever virus, business, Human Disease Genetics, medicine.drug
Abstract: Yellow fever virus live attenuated vaccine can rarely cause life-threatening disease. Inherited IFNAR1 deficiency was previously reported in one patient. Here, we report a patient with inherited IFNAR2 deficiency and three other patients with neutralizing auto-antibodies against type I IFNs., Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine–associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.
Published: 2020

23. Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis

Author: Virpi Glumoff, Harri Rusanen, Johanna Lehtonen, Minna Kraatari, Lazaro Lorenzo, Terhi Partanen, Pirjo Åström, Jie Chen, Mikko Seppänen, Veli-Jukka Anttila, Outi Kuismin, Heikki Kauma, Michaela K. Bode, Olli Vapalahti, Jean-Laurent Casanova, Shen-Ying Zhang, Timo Hautala, Tytti Vuorinen, Antti Vaheri, Nina Hautala, Janna Saarela, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Medicum, Helsinki One Health (HOH), HUSLAB, Veterinary Microbiology and Epidemiology, Veterinary Biosciences, Olli Pekka Vapalahti / Principal Investigator, Viral Zoonosis Research Unit, Department of Virology, Helsinki University Hospital Area, HUS Inflammation Center, Doctoral Programme in Clinical Research, Infektiosairauksien yksikkö, Janna Saarela / Principal Investigator, Children's Hospital, HUS Children and Adolescents, Clinicum, and Department of Medicine
Subjects: 0301 basic medicine, Orthohantavirus, Encephalomyelitis, viruses, encephalitis, hantavirus, Loss of heterozygosity, Pathogenesis, 0302 clinical medicine, Immunology and Allergy, Encephalitis, Viral, 030212 general & internal medicine, Cells, Cultured, Exome sequencing, virus diseases, 3. Good health, DEFICIENCY, Original Article, Disease Susceptibility, Encephalitis, EXPRESSION, Heterozygote, Hantavirus Infections, Immunology, central nervous system infections, HYPOPITUITARISM, Cell Line, 03 medical and health sciences, genetic diseases, Immunity, medicine, Humans, Genetic Predisposition to Disease, Allele, Alleles, Hantavirus, PUUMALA VIRUS-INFECTION, business.industry, Fibroblasts, medicine.disease, Virology, 030104 developmental biology, HEMORRHAGIC-FEVER, Toll-like receptor 3, 3121 General medicine, internal medicine and other clinical medicine, Mutation, RNA, business, primary immunodeficiency diseases
Abstract: Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses. Electronic supplementary material The online version of this article (10.1007/s10875-020-00834-2) contains supplementary material, which is available to authorized users.
Published: 2020

24. microRNA-1271-5p/TIAM1 suppresses the progression of ovarian cancer through inactivating Notch signaling pathway

Author: Yi-Chao Liu, Feng-Juan Han, Guo Ying, Yan-Hong Wang, Shao-Xuan Liu, Shen Ying, Yang Yu, Jia-Yue Xu, and Jia Li
Subjects: 0301 basic medicine, Notch pathway, Notch signaling pathway, Biology, Transfection, lcsh:Gynecology and obstetrics, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Cyclin D1, Downregulation and upregulation, Ovarian cancer, microRNA, medicine, Humans, T-Lymphoma Invasion and Metastasis-inducing Protein 1, miR-1271-5p, HES1, lcsh:RG1-991, Ovarian Neoplasms, Gene knockdown, Research, Obstetrics and Gynecology, Prognosis, medicine.disease, MicroRNAs, 030104 developmental biology, Oncology, Cell behavior, 030220 oncology & carcinogenesis, Disease Progression, Cancer research, NUMB, Female, Signal Transduction
Abstract: Objective Ovarian cancer (OC) has been regarded as the most malignant gynecological neoplasm and often confers grave outcomes owing to the frequent metastasis and high recurrence. A previous study has demonstrated that miR-1271-5p is implicated in OC progression, however, the possible mechanism of it remains unknown. The purpose of this investigation was to explore how miR-1271-5p regulates the progression of OC. Methods Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were employed to analyze the differentially expressed miRNAs or genes as well as their corresponding prognostic values. miR-1271-5p expression in OC cells was examined by qRT-PCR. Cell counting kit 8 (CCK-8), colony formation, and transwell tests were conducted to evaluate the proliferation, migration and invasion potentials. Bioinformatics prediction and luciferase activity analysis were utilized to predict and verify the target gene of miR-1271-5p. Western blot assay was carried out to measure protein expression. Results miR-1271-5p was significantly decreased in OC and its down-regulation was associated with the grave outcome of OC patients. Upregulation of miR-1271-5p inhibited cell viability, but miR-1271-5p knockdown promoted the proliferation of OC cells. TIAM1 was a direct target gene of miR-1271-5p and expressed in OC tissues at higher level. High expression of TIAM1 induced the poorer prognosis of patients with OC. Further functional analyses showed that the suppressive role of miR-1271-5p on OC cell malignant behaviors was overturned by the upregulation of TIAM1. The protein levels of Cyclin D1, HES1, NOTCH and NUMB were remarkably changed due to the abnormal expression of miR-1271-5p and TIAM1. Conclusion To sum up, miR-1271-5p inhibits proliferation, invasion and migration of OC cells by directly repressing TIAM1 to inactivate the Notch signaling pathway, which provides an alternative therapeutic candidate for the advancement of OC treatment.
Published: 2020

25. Involvement of Differentially Expressed microRNAs in the PEGylated Liposome Encapsulated 188Rhenium-Mediated Suppression of Orthotopic Hypopharyngeal Tumor

Author: Shen-Ying Wan, Min-Ying Lin, Chih-Hsien Chang, Yi Jang Lee, Ting-Wen Chen, Muh Hwa Yang, and Bing-Ze Lin
Subjects: Colorectal cancer, Pharmaceutical Science, 188Re-liposome, Capsules, Biology, Article, Analytical Chemistry, Polyethylene Glycols, lcsh:QD241-441, 03 medical and health sciences, Mice, 0302 clinical medicine, lcsh:Organic chemistry, In vivo, Cell Line, Tumor, Drug Discovery, microRNA, medicine, Animals, Humans, Physical and Theoretical Chemistry, Survival rate, 030304 developmental biology, Radioisotopes, 0303 health sciences, Hypopharyngeal Neoplasms, hypopharyngeal cancer, repeated therapy, NGS, Organic Chemistry, Hypopharyngeal cancer, medicine.disease, Survival Analysis, Fold change, Gene Expression Regulation, Neoplastic, MicroRNAs, Rhenium, Chemistry (miscellaneous), 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Liposomes, Cancer research, Molecular Medicine, Signal transduction
Abstract: Hypopharyngeal cancer (HPC) accounts for the lowest survival rate among all types of head and neck cancers (HNSCC). However, the therapeutic approach for HPC still needs to be investigated. In this study, a theranostic 188Re-liposome was prepared to treat orthotopic HPC tumors and analyze the deregulated microRNA expressive profiles. The therapeutic efficacy of 188Re-liposome on HPC tumors was evaluated using bioluminescent imaging followed by next generation sequencing (NGS) analysis, in order to address the deregulated microRNAs and associated signaling pathways. The differentially expressed microRNAs were also confirmed using clinical HNSCC samples and clinical information from The Cancer Genome Atlas (TCGA) database. Repeated doses of 188Re-liposome were administrated to tumor-bearing mice, and the tumor growth was apparently suppressed after treatment. For NGS analysis, 13 and 9 microRNAs were respectively up-regulated and down-regulated when the cutoffs of fold change were set to 5. Additionally, miR-206-3p and miR-142-5p represented the highest fold of up-regulation and down-regulation by 188Re-liposome, respectively. According to Differentially Expressed MiRNAs in human Cancers (dbDEMC) analysis, most of 188Re-liposome up-regulated microRNAs were categorized as tumor suppressors, while down-regulated microRNAs were oncogenic. The KEGG pathway analysis showed that cancer-related pathways and olfactory and taste transduction accounted for the top pathways affected by 188Re-liposome. 188Re-liposome down-regulated microRNAs, including miR-143, miR-6723, miR-944, and miR-136 were associated with lower survival rates at a high expressive level. 188Re-liposome could suppress the HPC tumors in vivo, and the therapeutic efficacy was associated with the deregulation of microRNAs that could be considered as a prognostic factor.
Published: 2020

26. Human inborn errors of immunity to herpes viruses

Author: Trine H. Mogensen, Vivien Béziat, Emmanuelle Jouanguy, Stuart G. Tangye, Shen-Ying Zhang, and Jean-Laurent Casanova
Subjects: 0301 basic medicine, viruses, Immunology, Context (language use), Asymptomatic, Article, 03 medical and health sciences, 0302 clinical medicine, Immunity, medicine, Immunology and Allergy, Humans, Herpesviridae, Pneumonitis, Innate immune system, business.industry, Genetic Diseases, Inborn, Immunologic Deficiency Syndromes, Herpesviridae Infections, biochemical phenomena, metabolism, and nutrition, medicine.disease, Acquired immune system, Immunity, Innate, 030104 developmental biology, TLR3, medicine.symptom, business, Encephalitis, 030215 immunology
Abstract: Infections with any of the nine human herpes viruses (HHV) can be asymptomatic or life-threatening. The study of patients with severe diseases caused by HHVs, in the absence of overt acquired immunodeficiency, has led to the discovery or diagnosis of various inborn errors of immunity. The related inborn errors of adaptive immunity disrupt α/β T-cell rather than B-cell immunity. Affected patients typically develop HHV infections in the context of other infectious diseases. However, this is not always the case, as illustrated by inborn errors of SAP-dependent T-cell immunity to EBV-infected B cells. The related inborn errors of innate immunity disrupt leukocytes other than T and B cells, non-hematopoietic cells, or both. Patients typically develop only a single type of infection due to HHV, although, again, this is not always the case, as illustrated by inborn errors of TLR3 immunity resulting in HSV1 encephalitis in some patients and influenza pneumonitis in others. Most severe HHV infections in otherwise healthy patients remains unexplained. The forward human genetic dissection of isolated and syndromic HHV-driven illnesses will establish the molecular and cellular basis of protective immunity to HHVs, paving the way for novel diagnosis and management strategies.
Published: 2020

27. Severe Acute Flaccid Myelitis Associated With Enterovirus in Children: Two Phenotypes for Two Evolution Profiles?

Author: Delphine Sterlin, Charles Joris Roux, Flore Rozenberg, Mélodie Aubart, Florence Moulin, Isabelle Schuffenecker, Audrey Mirand, Nathalie Boddaert, Cyril Gitiaux, Marianne Leruez-Ville, Shen-Ying Zhang, Nathalie Bach, Manoelle Kossorotoff, Isabelle Desguerre, Denise Antona, Raphael Levy, Lucile Musset, Jean Bergounioux, 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 Paris Cité (UPCité), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Hôpital Raymond Poincaré [AP-HP], Hôpital Cochin [AP-HP], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Bailly, Jean-Luc
Subjects: Pediatrics, medicine.medical_specialty, Weakness, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Myelitis, macromolecular substances, medicine.disease_cause, lcsh:RC346-429, 03 medical and health sciences, myelitis, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, 0302 clinical medicine, Anterior Horn Cell, children, EV-D68, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine, 030212 general & internal medicine, lcsh:Neurology. Diseases of the nervous system, Original Research, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, business.industry, enterovirus, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Spinal cord, Acute flaccid myelitis, 3. Good health, Poliomyelitis, EV-A71, medicine.anatomical_structure, Neurology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Enterovirus, Neurology (clinical), Brainstem, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: International audience; Acute flaccid myelitis (AFM) is an acute paralysis syndrome defined by a specific inflammation of the anterior horn cells of the spinal cord. From 2014, worrying waves of life-threatening AFM consecutive to enterovirus infection (EV-D68 and EV-A71) have been reported. We describe 10 children displaying an AFM with an EV infection, the treatments performed and the 1 to 3-years follow-up. Two groups of patients were distinguished: 6 children (“polio-like group”) had severe motor disability whereas 4 other children (“brainstem group”) displayed severe brainstem weakness requiring ventilation support. Electrodiagnostic studies (n = 8) support the presence of a motor neuronopathy associated to myelitis. The best prognosis factor seems to be the motor recovery after the first 4 weeks of the disease.
Published: 2020

28. Herpes simplex virus 2 encephalitis in a patient heterozygous for a TLR3 mutation

Author: Terhi Partanen, Outi Kuismin, Minna Kraatari, Pirjo Åström, Laura Tervonen, Usko Huuskonen, Timo Hautala, Lazaro Lorenzo, Mikko Seppänen, Satu Winqvist, Jie Chen, Janna Saarela, Jean-Laurent Casanova, Tytti Vuorinen, Johanna Lehtonen, Shen-Ying Zhang, Virpi Glumoff, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, HUSLAB, Janna Saarela / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Children's Hospital, HUS Children and Adolescents, Clinicum, Department of Medicine, Infektiosairauksien yksikkö, and HUS Inflammation Center
Subjects: 0301 basic medicine, medicine.disease_cause, 3124 Neurology and psychiatry, Temporal lobe, White matter, 03 medical and health sciences, 0302 clinical medicine, Immunity, Interferon, medicine, Clinical/Scientific Notes, Genetics (clinical), business.industry, 3112 Neurosciences, 1184 Genetics, developmental biology, physiology, medicine.disease, 3. Good health, 030104 developmental biology, Herpes simplex virus, Hemiparesis, medicine.anatomical_structure, Immunology, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Encephalitis, medicine.drug, Altered level of consciousness
Abstract: Susceptibility to herpes simplex virus type 1 (HSV-1) encephalitis (HSE-1) in otherwise healthy individuals, in the course of primary infection, can be caused by single-gene inborn errors of Toll-like receptor 3 (TLR3) dependent, interferon (IFN)-alpha/beta-mediated immunity,(1,2) or by single-gene inborn errors of snoRNA31.(3) These variations underlie infections of the forebrain, whereas mutations of DBR1 underlie infections of the brainstem.(3) HSV-2 encephalitis (HSE-2) is typically observed in neonates, albeit also rarely in older children and adults.(4) Its manifestations include altered level of consciousness, cranial neuropathies or more extensive brainstem encephalitis, hemiparesis, hemisensory loss, and permanent neurologic deficit.(4) MRI in HSE-2 may show normal findings, nonspecific white matter, orbitofrontal, mesial temporal lobe, or brainstem lesions. Inborn errors of immunity underlying HSE-2 have not been described. Non
Published: 2020

29. T-cell Responses to HSV-1 in Persons Who Have Survived Childhood Herpes Simplex Encephalitis

Author: Lazaro Lorenzo, Lichen Jing, Mariliis Ott, Jean-Laurent Casanova, Shen-Ying Zhang, and David M. Koelle
Subjects: CD4-Positive T-Lymphocytes, 0301 basic medicine, Microbiology (medical), Enzyme-Linked Immunospot Assay, Adolescent, viruses, T cell, Mucocutaneous zone, Herpesvirus 1, Human, Human leukocyte antigen, CD8-Positive T-Lymphocytes, Article, Virus, Cohort Studies, Epitopes, Viral Proteins, 03 medical and health sciences, Blood serum, Immunity, medicine, Humans, Child, business.industry, Infant, medicine.disease, Virology, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, Child, Preschool, Pediatrics, Perinatology and Child Health, Encephalitis, Herpes Simplex, business, Encephalitis, CD8
Abstract: Background Herpes simplex encephalitis (HSE) after primary herpes simplex virus (HSV)-1 infection can occur in children due to inborn errors of cell-intrinsic immunity in the central nervous system. Paradoxically, symptomatic mucocutaneous HSV-1 recurrences are rare survivors of childhood HSE. T-cell-acquired immunity is thought to be involved in control of recurrent mucocutaneous HSV infection. We thus tested HSV-1-specific immunity in HSE survivors. Methods We obtained serum and peripheral blood mononuclear cells (PBMCs) from participants a median of 13.5 years after HSE. HSV-1 and HSV-2 IgG was detected by type-specific immunoblot. PBMCs from subjects passing quality control criteria were tested using enzyme-linked immunospot assay for CD4 interferon-γ responses with an HSV-1 lysate and for CD8 responses using pooled synthetic HSV-1 peptide CD8 T-cell epitopes. Healthy adult PBMCs were used to standardize assays and as comparators. Results All participants were HSV-1 seropositive. Most (23/24) HSE survivors had human leukocyte antigen class I types matching the human leukocyte antigen restriction of the pooled peptides. We detected HSV-specific CD8 T-cell responses in 14 of 24 (58%) HSE survivors and in 9 of 9 healthy HSV-1 seropositive adults. HSV-specific CD4 T-cell responses were present in all 5 HSE subjects tested and in 8 of 9 healthy adults. Response magnitudes were overlapping between subject groups. Conclusions The defects in cell-intrinsic immunity leading to failure to control primary central nervous system HSV-1 infection do not preclude the acquisition of specific immunity or the control of recurrent mucocutaneous HSV infections. The rarity and lack of severe or recurrent mucocutaneous HSV infection in survivors of childhood HSE corresponds with intact adaptive T-cell immunity.
Published: 2017

30. How About P300 in Patients with Depression in China: Review of Results from Some Chinese Meta- Analysis

Author: Shen Ying, Ma Yongchun, Chen Zhenxin, Jin Weidong, Gao Zhhan, Ren Zhibin, Chen Fengpei, and Zhu Jianfeng
Subjects: Rehabilitation, business.industry, Cognitive Neuroscience, medicine.medical_treatment, Neuropsychology, Cognition, medicine.disease, Mental health, Atomic and Molecular Physics, and Optics, Quality of life (healthcare), Developmental Neuroscience, Meta-analysis, Medicine, Major depressive disorder, business, Depression (differential diagnoses), Clinical psychology
Abstract: The depression are a common mental disorders in China. It's morbidity is about 4. 0/100, which influence Chinese people's mental health. The Chinese psychiatrists carry out many studies about depression in aetiologyi¼Œtherapeuticsi¼Œprophylaxis and rehabilitation. The study of P 300 in patients with depression are one of those studies, and also generated some studies about relationship between P300 and depression. These studies include : (1) features of depression patients, (2) effects of antidepressants on P300 in patients with depression, (3) relationship between P300 and depression symptoms, (4) relationship between P300 and cognitive impairment, (5) treatment effective prediction role of P300 in patients with depression. (6) P300 aid in the differential diagnosis of subtype of depression. These results will be reviewed and assessed in our review. Major depressive disorder is a serious mental disorder that profoundly affects an individual's quality of life. Although the aetiology underlying this disorder remain unclear, an increasing attention has been focused on the pathophysiological changes, regardless of etiology or outcome, which are associated with depression (Yang et al., 2015). The existence of such a link is indeed conducive to the study of the etiology of depression and the initiation of therapeutic. P300 also was studied widely in depression as a index of cognitive function, because most of patients with depression often are company with cognitive impairment. P300 waveform is the most widely used component of event-related brain potential (ERP), which is related to cognitive information processing, including working memory, attention and executive function. As an electrophysiological indicator of cognitive activity, P300 is non-invasive, inexpensive, convenient, and free of cultural and educational bias. Because of its high temporal resolution, P300 is more sensitive to cognitive changes than traditional neuropsychological tests and can provide insight into cognitive processes.
Published: 2019

31. Severe influenza pneumonitis in children with inherited TLR3 deficiency

Author: Mary Hasek, Isabelle Meyts, Michael D. Keller, Flore Rozenberg, Fabien G. Lafaille, Priya Luthra, Lazaro Lorenzo, Marie Celard, Jie Chen, Eduardo J. Garcia Reino, Tatiana Kochetkov, Laurent Abel, Catherine Vedrinne, Yuval Itan, Olivier Gilliaux, Hye Kyung Lim, Soraya Boucherit, Benedetta Bigio, Jordan S. Orange, Nicholas Hernandez, Nicolas Goudin, Paul Bastard, Sarah X.L. Huang, Hans-Willem Snoeck, Jean-Laurent Casanova, Michael J. Ciancanelli, Gaspard Kerner, Kerry Dobbs, Shen-Ying Zhang, Luigi D. Notarangelo, Qian Zhang, and Adolfo García-Sastre
Subjects: 0301 basic medicine, Male, viruses, NF-KAPPA-B, Inheritance Patterns, STAT2 DEFICIENCY, Research & Experimental Medicine, medicine.disease_cause, RIG-I, 0302 clinical medicine, Fatal Outcome, Loss of Function Mutation, Influenza A virus, Immunology and Allergy, Child, Lung, Research Articles, virus diseases, hemic and immune systems, Penetrance, 3. Good health, VIRUS ENCEPHALITIS, Protein Transport, Medicine, Research & Experimental, Child, Preschool, Female, Life Sciences & Biomedicine, Encephalitis, STRUCTURAL BASIS, Heterozygote, HERPES-SIMPLEX ENCEPHALITIS, Immunology, Induced Pluripotent Stem Cells, Mutation, Missense, chemical and pharmacologic phenomena, DOUBLE-STRANDED-RNA, PANDEMIC INFLUENZA, Article, 03 medical and health sciences, Immunity, Influenza, Human, medicine, Humans, Alleles, Pneumonitis, Science & Technology, business.industry, TOLL-LIKE RECEPTOR-3, Infant, Newborn, Infant, Heterozygote advantage, Epithelial Cells, Pneumonia, Fibroblasts, medicine.disease, Toll-Like Receptor 3, 030104 developmental biology, Poly I-C, IRF7, Interferons, business, 030217 neurology & neurosurgery, GROWTH-RETARDATION
Abstract: The authors report three unrelated children with inherited TLR3 deficiency, impaired TLR3-dependent, IFN-α/β– and/or -λ–mediated, pulmonary epithelial cell–intrinsic immunity to influenza A virus, and life-threatening influenza pneumonitis., Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients’ iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN–mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.
Published: 2018

32. Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency

Author: Man Chun Leung, Laurent Abel, Bertrand Boisson, Jeffrey Danielson, Huie Jing, Susie S.Y. Huang, Vimel Rattina, Serkan Belkaya, Lisa S. Mathew, Nicholas Hernandez, Yanick J. Crow, Silvia Giliani, Stephen J. Elledge, Michael J. Ciancanelli, Yoann Rose, Damien Chaussabel, Lazaro Lorenzo-Diaz, Tanwir Habib, Isabelle Melki, Qian Zhang, Helen C. Su, Jean-Laurent Casanova, Shen-Ying Zhang, Marie-Noëlle Lebras, Luigi D. Notarangelo, Nico Marr, Stéphanie Boisson-Dupuis, Mathieu P Rodero, Scott Drutman, Naoki Kitabayashi, Tomasz Kula, Cécile Dumaine, Anais Boulai, Stéphane Blanche, 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), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sidra Medicine [Doha, Qatar], Imagine - Institut des maladies génétiques (IMAGINE - U1163), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Immunology, Pneumonia, Viral, Interferon alpha-2, medicine.disease_cause, Virus, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Immunity, Influenza, Human, Influenza A virus, medicine, Immunology and Allergy, Gene silencing, Humans, STAT1, Research Articles, Alleles, ComputingMilieux_MISCELLANEOUS, biology, Homozygote, virus diseases, Infant, medicine.disease, Orthomyxoviridae, Virology, Interferon-Stimulated Gene Factor 3, gamma Subunit, 3. Good health, Pneumonia, 030104 developmental biology, Viral replication, 030220 oncology & carcinogenesis, biology.protein, Female
Abstract: We report a child with inherited, complete IRF9 deficiency who suffered from life-threatening influenza pneumonitis. IRF9 deficiency disrupts the activation of ISGF3 and impairs but does not abolish cellular responses to type I IFNs, as some ISGs are induced., Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient’s cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient’s cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV.
Published: 2018

33. Lethal Influenza in Two Related Adults with Inherited GATA2 Deficiency

Author: Edgar de Borges de Oliveira, María Teresa Martínez-Saavedra, M López-Rodríguez, Michael J. Ciancanelli, Inmaculada Casas, Carlos Rodríguez-Gallego, Jose M. Ferrer, Ithaisa Sologuren, Felipe Rodríguez de Castro, Cristina Bilbao, Roger Colobran, Miguel Andújar-Sánchez, Mónica Martínez-Gallo, José Pestano, Jean-Laurent Casanova, Estefanía Herrera-Ramos, Shen-Ying Zhang, Jordi Solé-Violán, Mercedes Álvarez Fernández, C. Perez, Carmen Oleaga-Quintas, Nieves Franco, E. Betancor, Jacinta Bustamante, and José Juan Ruiz-Hernández
Subjects: 0301 basic medicine, Male, GATA2 Deficiency, Immunology, DNA Mutational Analysis, Viremia, Disease, medicine.disease_cause, Article, Immunophenotyping, immunological memory, Pathogenesis, 03 medical and health sciences, Immune system, Fatal Outcome, Influenza, Human, GATA2, Influenza A virus, medicine, Immunodeficiency, influenza A virus, Immunology and Allergy, Humans, Young adult, business.industry, H1N1, medicine.disease, Lymphocyte Subsets, 3. Good health, Pedigree, GATA2 Transcription Factor, 030104 developmental biology, Mutation, Cytokines, Female, business, Biomarkers
Abstract: The pathogenesis of life-threatening influenza A virus (IAV) disease remains elusive, as infection is benign in most individuals. We studied two relatives who died from influenza. We Sanger sequenced GATA2 and evaluated the mutation by gene transfer, measured serum cytokine levels, and analyzed circulating T- and B-cells. Both patients (father and son, P1 and P2) died in 2011 of H1N1pdm IAV infection at the ages of 54 and 31 years, respectively. They had not suffered from severe or moderately severe infections in the last 17 (P1) and 15 years (P2). A daughter of P1 had died at 20 years from infectious complications. Low B-cell, NK- cell, and monocyte numbers and myelodysplastic syndrome led to sequence GATA2. Patients were heterozygous for a novel, hypomorphic, R396L mutation leading to haplo-insufficiency. B- and T-cell rearrangement in peripheral blood from P1 during the influenza episode showed expansion of one major clone. No T-cell receptor excision circles were detected in P1 and P3 since they were 35 and 18 years, respectively. Both patients presented an exuberant, interferon (IFN)-γ-mediated hypercytokinemia during H1N1pdm infection. No data about patients with viremia was available. Two previously reported adult GATA2-deficient patients died from severe H1N1 IAV infection; GATA2 deficiency may predispose to life-threatening influenza in adulthood. However, a role of other genetic variants involved in immune responses cannot be ruled out. Patients with GATA2 deficiency can reach young adulthood without severe infections, including influenza, despite long-lasting complete B-cell and natural killer (NK) cell deficiency, as well as profoundly diminished T-cell thymic output.
Published: 2017

34. Computerized tomography-guided sphenopalatine ganglion pulsed radiofrequency treatment in 16 patients with refractory cluster headaches: Twelve- to 30-month follow-up evaluations

Author: Shen Ying, Meng Lan, Ji Nan, Lu Jingjing, Wang Tao, and Luo Fang
Subjects: Adult, Male, medicine.medical_specialty, Percutaneous, Adolescent, medicine.medical_treatment, Cluster Headache, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Radiofrequency thermocoagulation, Refractory, medicine, Humans, Pain Management, 030212 general & internal medicine, business.industry, Cluster headache, General Medicine, Middle Aged, medicine.disease, Ablation, Pulsed Radiofrequency Treatment, Surgery, Ganglion, medicine.anatomical_structure, Surgery, Computer-Assisted, Female, Neurology (clinical), Headaches, medicine.symptom, Tomography, X-Ray Computed, business, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Background Sphenopalatine ganglion percutaneous radiofrequency thermocoagulation treatment can improve the symptoms of cluster headaches to some extent. However, as an ablation treatment, radiofrequency thermocoagulation treatment also has side effects. Objective To preliminarily evaluate the efficacy and safety of a non-ablative computerized tomography-guided pulsed radiofrequency treatment of sphenopalatine ganglion in patients with refractory cluster headaches. Methods We included and analysed 16 consecutive cluster headache patients who failed to respond to conservative therapy from the Pain Management Center at the Beijing Tiantan Hospital between April 2012 and September 2013 treated with pulsed radiofrequency treatment of sphenopalatine ganglion. Results Eleven of 13 episodic cluster headaches patients and one of three chronic cluster headaches patient were completely relieved of the headache within an average of 6.3 ± 6.0 days following the treatment. Two episodic cluster headache patients and two chronic cluster headache patients showed no pain relief following the treatment. The mean follow-up time was 17.0 ± 5.5 months. All patients enrolled in this study showed no treatment-related side effects or complications. Conclusion Our data show that patients with refractory episodic cluster headaches were quickly, effectively and safely relieved from the cluster period after computerized tomography-guided pulsed radiofrequency treatment of sphenopalatine ganglion, suggesting that it may be a therapeutic option if conservative treatments fail.
Published: 2015

35. Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis

Author: Soraya Boucherit, Damien Bonnet, Lazaro Lorenzo, Raphaelle Quint, Serkan Belkaya, Laurent Abel, Aurélie Cobat, Yuval Itan, Fanny Bajolle, Amy R Kontorovich, Cecile Stoven, Minji Byun, Shen-Ying Zhang, Bruce D. Gelb, Sylvie Di Filippo, Rebecca Josowitz, Sonia Mulero-Navarro, and Jean-Laurent Casanova
Subjects: 0301 basic medicine, Male, Pathology, medicine.medical_specialty, Myocarditis, Viral Myocarditis, viruses, Induced Pluripotent Stem Cells, Cardiomyopathy, 030204 cardiovascular system & hematology, Compound heterozygosity, Virus, TNNI3, 03 medical and health sciences, 0302 clinical medicine, Immunity, Interferon, Medicine, Humans, Myocytes, Cardiac, business.industry, medicine.disease, Enterovirus B, Human, Toll-Like Receptor 3, 030104 developmental biology, STAT1 Transcription Factor, Case-Control Studies, Immunology, Host-Pathogen Interactions, Female, Cardiology and Cardiovascular Medicine, business, Cardiomyopathies, medicine.drug
Abstract: Background Myocarditis is inflammation of the heart muscle that can follow various viral infections. Why children only rarely develop life-threatening acute viral myocarditis (AVM), given that the causal viral infections are common, is unknown. Genetic lesions might underlie such susceptibilities. Mouse genetic studies demonstrated that interferon (IFN)-α/β immunity defects increased susceptibility to virus-induced myocarditis. Moreover, variations in human TLR3, a potent inducer of IFNs, were proposed to underlie AVM. Objectives This study sought to evaluate the hypothesis that human genetic factors may underlie AVM in previously healthy children. Methods We tested the role of TLR3-IFN immunity using human induced pluripotent stem cell-derived cardiomyocytes. We then performed whole-exome sequencing of 42 unrelated children with acute myocarditis (AM), some with proven viral causes. Results We found that TLR3- and STAT1-deficient cardiomyocytes were not more susceptible to Coxsackie virus B3 (CVB3) infection than control cells. Moreover, CVB3 did not induce IFN-α/β and IFN-α/β-stimulated genes in control cardiomyocytes. Finally, exogenous IFN-α did not substantially protect cardiomyocytes against CVB3. We did not observe a significant enrichment of rare variations in TLR3- or IFN-α/β-related genes. Surprisingly, we found that homozygous but not heterozygous rare variants in genes associated with inherited cardiomyopathies were significantly enriched in AM-AVM patients compared with healthy individuals (p = 2.22E-03) or patients with other diseases (p = 1.08E-04). Seven of 42 patients (16.7%) carried rare biallelic (homozygous or compound heterozygous) nonsynonymous or splice-site variations in 6 cardiomyopathy-associated genes (BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3). Conclusions Previously silent recessive defects of the myocardium may predispose to acute heart failure presenting as AM, notably after common viral infections in children.
Published: 2016

36. Effectiveness of Low Glycemic Index Diet Consultations Through a Diet Glycemic Assessment App Tool on Maternal and Neonatal Insulin Resistance: A Randomized Controlled Trial

Author: Zhang, Yi, Wang, Liping, Yang, Wenhong, Niu, Dayan, Li, Chunying, Wang, Liling, Gu, Ping, Xia, Yingqian, Shen, Ying, Yan, Juhua, Zhao, Qian, Mu, Kai, and Yan, Weili
Subjects: Adult, Male, China, medicine.medical_specialty, Child Health Services, Health Informatics, Information technology, Overweight, law.invention, Insulin resistance, Randomized controlled trial, law, insulin resistance, Internal medicine, Glycemic load, medicine, overweight, Humans, Maternal Health Services, Referral and Consultation, Glycemic, Original Paper, Pregnancy, business.industry, Infant, Newborn, T58.5-58.64, medicine.disease, Mobile Applications, Gestational diabetes, Glycemic index, Glycemic Index, randomized controlled trial, Female, pregnancy, Public aspects of medicine, RA1-1270, medicine.symptom, business, Diet Therapy
Abstract: BackgroundLow glycemic index (LGI) diet has shown to be effective in reducing maternal and neonatal complications in high-risk pregnancies. ObjectiveThis trial aimed to examine the effectiveness of individualized LGI diet consultations based on the accurate diet glycemic load (GL) assessment tool on maternal and neonatal insulin resistance levels and diet behavior changes in overweight and obese pregnant women. MethodsOverweight and obese pregnant women were recruited before 16 weeks of gestation and randomized to the LGI diet arm or the control arm. All participants received standard dietary education according to the Chinese Dietary Guide for Pregnant Women. In the intervention arm, additional individualized dietary GL assessments were performed using an app and instructions of lowering diet glycemic index (GI) to achieve LGI diet were provided by a clinical dietitian at early, middle, and late gestation. Primary outcomes were serum insulin at late gestation, incidence of gestational diabetes mellitus (GDM) for mothers, and cord blood C-peptide level of neonates. ResultsIn total, 400 subjects were randomized and received different interventions. There were no significant differences in maternal serum insulin levels (13.2 [9.3−13.2] uU/mL vs 12.4 [10.5−12.4] uU/mL), incidence of GDM (45 [22.5%] vs 43 [21.5%]), or cord blood C-peptide levels (mean 0.9ng/mL [SD 0.7] vs mean 0.8ng/mL [SD 0.6]) in the intervention group compared with the controls. The diet GI at late gestation was similar (mean 63.2 [SD 10.4] vs mean 64.3 [SD 10.4]), whereas greater diet fiber intake was observed in the intervention group (mean 11.6 grams [SD 8.0] vs mean 9.0 grams [SD 5.6]; P=.006). Adherence measurements did not significantly differ between 2 groups. ConclusionsIndividualized LGI diet consultations for overweight and obese pregnant women failed to make a significant difference in maternal or neonatal insulin resistance compared with the standard gestational diet consultation. Trial RegistrationClinicalTrials.gov NCT01628835; http://clinicaltrials.gov/ct2/show/NCT01628835 (Archived by WebCite at http://www.webcitation.org/77LHgWP0k)
Published: 2019

37. Fourteen (14) cases of acute focal bacterial nephritis in children

Author: Shen Ying, Zhang Guiju, Meng Fanying, Jiao Liping, Fan Jianfeng, Zhou Nan, and Chen Zhi
Subjects: medicine.medical_specialty, Pediatrics, business.industry, Urinary system, Vascular malformation, Plant Science, medicine.disease, Microbiology, Vesicoureteral reflux, Pyuria, Surgery, Infectious Diseases, Nephromegaly, medicine, Etiology, medicine.symptom, Fever of unknown origin, business, Nephritis
Abstract: To investigate clinical features, laboratory, and imaging characters in Chinese children, we conducted a retrospective study on 14 children with acute focal bacterial nephritis (AFBN) admitted in Beijing Children’s Hospital during January 2005 to December 2009. Six girls and eight boys with a mean age of 4.7 years (range: 0.3-11.4 years) were followed up on average 1.7 years (range: 0.5-3.5 years). Leukocyturia was found in 10/14 children. Urine cultures were positive in 10/14 cases; E. coli was the most common cause of AFBN. A combination of nephromegaly and focal mass was found in 11/14 patients. Urinary tract anomalies were found in 8 children. Two boys had underlying disease of acute lymphatic leukemia under chemotherapy. AFBN resolved on average 3-12 weeks after therapy. Ultrasound and enhanced CT were not necessary in cases of fever of unknown origin, even if pyuria nor urine culture is positive. Vesicoureteral reflux (VUR), malignancy and renal vascular malformation are potential risk factors of AFBN; careful radiological investigations should be performed. Key words: Acute focal bacterial nephritis, vesicoureteral reflux, children.
Published: 2013

38. Human TBK1: A Gatekeeper of Neuroinflammation

Author: Jean-Laurent Casanova, Vanessa Sancho-Shimizu, Shen-Ying Zhang, Liyana Ahmad, Medical Research Foundation, and Brunei Darussalam High Commission
Subjects: 0301 basic medicine, Central Nervous System, Pathology, medicine.medical_specialty, TBK1, Immunology, Gene Expression, Inflammation, Protein Serine-Threonine Kinases, medicine.disease_cause, Article, 03 medical and health sciences, TANK-binding kinase 1, medicine, Autophagy, Dementia, Humans, Low Tension Glaucoma, Amyotrophic lateral sclerosis, Molecular Biology, Neuroinflammation, Mutation, Medical And Health Sciences, business.industry, herpes simplex encephalitis, Amyotrophic Lateral Sclerosis, interferon, Biological Sciences, medicine.disease, 030104 developmental biology, glaucoma, Frontotemporal Dementia, Disease Progression, Molecular Medicine, Encephalitis, Herpes Simplex, Interferons, medicine.symptom, business, Frontotemporal dementia, dementia
Abstract: The importance of TANK binding kinase-1 (TBK1), a multimeric kinase that modulates inflammation and autophagy, in human health has been highlighted for the first time by the recent discoveries of mutations in TBK1 that underlie amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), normal tension glaucoma (NTG) or childhood herpes encephalitis (HSE). Gain-of-function mutations in TBK1 are associated with NTG, whereas loss-of-function mutations result in ALS/FTD or in HSE. In light of these new findings, we review the role of TBK1 in these seemingly unrelated, yet allelic diseases, and discuss the role of TBK1 in neurological diseases. This discovery has the potential to significantly increase our understanding of the molecular basis of these poorly understood neurological disorders.
Published: 2016

39. Mendelian Susceptibility to Infections with Viruses, Mycobacteria, Bacteria, and Candida

Author: Capucine Picard, Shen-Ying Zhang, Jacinta Bustamante, and Anne Puel
Subjects: Innate immune system, Microorganism, Biology, medicine.disease_cause, medicine.disease, biology.organism_classification, Microbiology, symbols.namesake, Herpes simplex virus, Immunology, medicine, Primary immunodeficiency, Mendelian inheritance, symbols, Pyogenic bacteria, Gene, Bacteria
Abstract: Classical primary immunodeficiencies confer a predisposition to multiple microorganisms or recurrent infectious diseases. However, over the last 30 years, a molecular explanation has been proposed for the severe idiopathic infections caused by viruses, mycobacteria, pyogenic bacteria, or fungi, such as Candida, in particular. Defects of several biologically related genes may confer a selective predisposition to infections with one of these specific groups of pathogens in otherwise healthy individuals. Such individuals present a new type of primary immunodeficiency, with severe and/or recurrent infections caused by a single family of microorganisms, as opposed to the broader defects in patients with ‘classical’ primary immunodeficiencies.
Published: 2016

40. Tissue Anchor Use in Arthroscopic Glenohumeral Surgery

Author: Marc Tompkins, John A Scanelli, Eric W. Carson, Shen-Ying Richard Ma, Matthew D. Milewski, and David R. Diduch
Subjects: medicine.medical_specialty, Rotator Cuff Injuries, Arthroscopy, Rotator Cuff, Suture Anchors, Absorbable Implants, Humans, Medicine, Orthopedics and Sports Medicine, Rotator cuff, Suture anchors, Labrum, Sutures, medicine.diagnostic_test, Shoulder Joint, business.industry, Rotator cuff injury, Equipment Design, medicine.disease, Surgery, medicine.anatomical_structure, Metals, Shoulder Injuries, business
Abstract: Arthroscopic surgery has become the mainstay of treatment of several common glenohumeral pathologies such as tears of the rotator cuff and labrum. Arthroscopic rotator cuff and labral repair provide outcomes comparable to those achieved with traditional open techniques, with the benefits of smaller incisions and less soft-tissue disruption. Development and improvement of tissue anchors and arthroscopic instrumentation has been integral to the increased popularity of arthroscopic glenohumeral repairs. Current anchors can be categorized by design and material composition. Awareness of the advantages and limitations of these implants may influence anchor selection.
Published: 2012

41. Granulocyte colony-stimulating factor enhances cellular proliferation and motor function recovery on rats subjected to traumatic brain injury

Author: Fu-Chou Cheng, Ming-Fu Wang, Hung-Chuan Pan, Shen-Ying Chen, Dar-Yu Yang, and Ying Ju Chen
Subjects: Male, medicine.medical_specialty, Doublecortin Protein, Traumatic brain injury, medicine.medical_treatment, Intraperitoneal injection, Granulocyte, Neuroprotection, Rats, Sprague-Dawley, Internal medicine, Granulocyte Colony-Stimulating Factor, Animals, Humans, Medicine, Cell Proliferation, Movement Disorders, business.industry, Recovery of Function, General Medicine, medicine.disease, Recombinant Proteins, Rats, Granulocyte colony-stimulating factor, Disease Models, Animal, Neuroprotective Agents, Endocrinology, medicine.anatomical_structure, Neurology, Brain Injuries, Anesthesia, Immunohistochemistry, Histopathology, Neurology (clinical), business, Motor cortex
Abstract: Traumatic brain injury (TBI) results in neurological dysfunction and death through primary or secondary mechanisms. Here, we evaluated the effect of osmotic pump delivery of granulocyte colony-stimulating factor (G-CSF) on the histopathology and motor function recovery of rats after experimental TBI.Sprague-Dawley rats were used as experimental model by fluid percussion device to cause brain injury on the motor cortex area. The rats were simultaneously subjected to TBI and were implanted of min-osmotic pump containing recombinant human G-CSF (300 μg/700 μl) via intraperitoneal injection. Motor function was assessed by rotarod test. 5-bromo-2'-deoxyuridine (BrdU) was used to label the proliferating cells and their differentiation was evaluated by histology and immunohistochemistry.The G-CSF group showed significantly better motor function recovery than the control group, and the effect lasted up to 14 days after TBI. Moreover, the G-CSF group exhibited a greater increase in the number of BrdU-positive cells compared with the control group. The G-CSF group also had a significantly higher number of DCX-positive cells in the ipsilateral subventricular zone (SVZ) than the control group.These data suggest that the beneficial effect of delivering G-CSF via an osmotic pump may improve the motor function and enhance neurogenesis in the SVZ of the injured brain.
Published: 2010

42. Primary immunodeficiencies of protective immunity to primary infections

Author: Shen-Ying Zhang, Jean-Laurent Casanova, Aziz Bousfiha, Jacinta Bustamante, Fatima Ailal, Stéphanie Boisson-Dupuis, Anne Puel, Capucine Picard, Laurent Abel, Jamila El-Baghdadi, and Emmanuelle Jouanguy
Subjects: Adult, Serotype, UNC93B1, Adolescent, Secondary infection, Immunology, Immunity, Immunologic Deficiency Syndromes, Disease, Biology, Infections, medicine.disease, medicine, Animals, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Disease Susceptibility, Early childhood, Child, Interleukin 12 receptor, beta 1 subunit, Encephalitis
Abstract: The vast majority of primary immunodeficiencies (PIDs) predispose affected individuals to recurrent or chronic infectious diseases, because they affect protective immunity to both primary and secondary or latent infections. We discuss here three recently described groups of PIDs that seem to impair immunity to primary infections without compromising immunity to secondary and latent infections. Patients with mutations in IL12B or IL12RB1 typically present mycobacterial disease in childhood with a favorable progression thereafter. Cross-protection between mycobacterial infections has even been observed. Patients with mutations in IRAK4 or MYD88 suffer from pyogenic bacterial diseases, including invasive pneumococcal diseases in particular. These diseases often recur, although not always with the same serotype, but the frequency of these recurrences tails off, with no further infections observed from adolescence onwards. Finally, mutations in UNC93B1 and TLR3 are associated with childhood herpes simplex encephalitis, which strikes only once in most patients, with almost no recorded cases of more than two bouts of this disease. Unlike infections in patients with other PIDs, the clinical course of which typically deteriorates with age even if appropriate treatment is given, the prognosis of patients with these three newly described PIDs tends to improve spontaneously with age, provided, of course, that the initial infection is properly managed. In other words, although life-threatening in early childhood, these new PIDs are associated with a favorable outcome in adulthood. They provide proof-of-principle that infectious diseases of childhood striking only once may result from single-gene inborn errors of immunity.
Published: 2010

43. Cerebral syphilis mimicking metastatic tumors: Report and review of the literature

Author: Shen Ying and Lao Li-Min
Subjects: medicine.medical_specialty, Neurology, business.industry, MEDLINE, Medicine, Syphilis, Neurology (clinical), business, medicine.disease, Dermatology
Published: 2018

44. A partial form of recessive STAT1 deficiency in humans

Author: Guillaume Vogt, Diana Averbuch, Jacinta Bustamante, Julien Lejeune, Dan Engelhard, Jean-Laurent Casanova, Xiao-Fei Kong, Ludovic de Beaucoudrey, Ariane Chapgier, Stéphanie Boisson-Dupuis, Shen-Ying Zhang, Laurent Abel, Jacqueline Feinberg, Eleonore Mayola, and Emmanuelle Jouanguy
Subjects: Male, Biology, medicine.disease_cause, medicine, Humans, Missense mutation, RNA, Messenger, Amino Acids, Allele, Alleles, Cells, Cultured, Messenger RNA, Mutation, Base Sequence, Siblings, Alternative splicing, General Medicine, medicine.disease, Molecular biology, Pedigree, Alternative Splicing, STAT1 Transcription Factor, Immunology, Primary immunodeficiency, Female, Interferons, Viral disease, Intracellular, Research Article
Abstract: Complete STAT1 deficiency is an autosomal recessive primary immunodeficiency caused by null mutations that abolish STAT1-dependent cellular responses to both IFN-alpha/beta and IFN-gamma. Affected children suffer from lethal intracellular bacterial and viral diseases. Here we report a recessive form of partial STAT1 deficiency, characterized by impaired but not abolished IFN-alpha/beta and IFN-gamma signaling. Two affected siblings suffered from severe but curable intracellular bacterial and viral diseases. Both were homozygous for a missense STAT1 mutation: g.C2086T (P696S). This STAT1 allele impaired the splicing of STAT1 mRNA, probably by disrupting an exonic splice enhancer. The misspliced forms were not translated into a mature protein. The allele was hypofunctional, because residual full-length mRNA production resulted in low but detectable levels of normally functional STAT1 proteins. The P696S amino acid substitution was not detrimental. The patients' cells, therefore, displayed impaired but not abolished responses to both IFN-alpha and IFN-gamma. We also show that recessive STAT1 deficiencies impaired the IL-27 and IFN-lambda1 signaling pathways, possibly contributing to the predisposition to bacterial and viral infections, respectively. Partial recessive STAT1 deficiency is what we believe to be a novel primary immunodeficiency, resulting in impairment of the response to at least 4 cytokines (IFN-alpha/beta, IFN-gamma, IFN-lambda1, and IL-27). It should be considered in patients with unexplained, severe, but curable intracellular bacterial and viral infections.
Published: 2009

45. Genetic susceptibility to herpes simplex virus 1 encephalitis in mice and humans

Author: Vanessa Sancho-Shimizu, Flore Rozenberg, Marc Tardieu, Laurent Abel, Jean-Laurent Casanova, Emmanuelle Jouanguy, and Shen-Ying Zhang
Subjects: viruses, Immunology, Herpesvirus 1, Human, medicine.disease_cause, Pathogenesis, Interferon-gamma, Mice, medicine, Genetic predisposition, Animals, Humans, Immunology and Allergy, Genetic Predisposition to Disease, business.industry, Membrane Transport Proteins, medicine.disease, Virology, I-kappa B Kinase, Toll-Like Receptor 3, Disease Models, Animal, STAT1 Transcription Factor, Herpes simplex virus, Healthy individuals, Interferon Type I, Encephalitis, Herpes Simplex, business, Encephalitis
Abstract: Herpes simplex encephalitis is a rare complication of herpes simplex virus 1 infection that strikes otherwise healthy individuals. Its pathogenesis has long remained elusive. We highlight the investigations dealing with the genetic basis of herpes simplex encephalitis in mice and humans.Mouse models have revealed the impact of various host genes on protective immunity to herpes simplex encephalitis through strain-dependent variability (forward genetics) and via targeted knockouts (reverse genetics). These studies established in particular the crucial role of IFNalpha/beta in immunity to herpes simplex virus 1, paving the way towards the elucidation of the genetic cause of human herpes simplex encephalitis. Two children with rare, specific STAT1 or NEMO mutations displayed a broad impairment of IFNalpha/beta and IFNlambda-mediated immunity and predisposition to several infectious diseases including herpes simplex encephalitis. In contrast, children with UNC93B1 and TLR3 mutations displayed a selective impairment of dsRNA-induced IFNalpha/beta and IFNlambda production and predisposition to isolated herpes simplex encephalitis.Herpes simplex encephalitis results from a series of monogenic primary immunodeficiencies that impair the TLR3 and UNC-93B-dependent production of IFNalpha/beta and IFNlambda in the central nervous system, at least in a fraction of children. This is not only crucial for the understanding of immunity to herpes simplex virus 1, but also for the diagnosis and treatment of herpes simplex encephalitis.
Published: 2007

46. Selective predisposition to bacterial infections in IRAK-4–deficient children: IRAK-4–dependent TLRs are otherwise redundant in protective immunity

Author: Sami Al-Hajjar, Carlos Rodríguez-Gallego, John I. Gallin, Toshiro Hara, Maya Chrabieh, Andrew C. Issekutz, Huey Hsuan Chang, Horst von Bernuth, Joanne Smart, Helen Chapel, Eric Vivier, László Maródi, David P. Speert, Mimi L.K. Tang, Jean-Laurent Casanova, Capucine Picard, Xiaoxia Li, Steven M. Holland, Shen-Ying Zhang, Franck J. Barrat, Stephan Ehl, Abdulaziz Al-Ghonaium, Ben Zion Garty, Chaim M. Roifman, Xavier Bossuyt, Douglas R. McDonald, Anne Puel, Hidetoshi Takada, Ofer Levy, Damien Sanlaville, Laurent Abel, Frederic Geissmann, Richard L. Miller, Cheng-Lung Ku, Kun Yang, Noorbibi K. Day-Good, Coleen K. Cunningham, Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Interactions cellulaires neuroendocriniennes ( ICN ), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and University of Groningen
Subjects: Male, Myeloid, Lipopolysaccharide, MESH : Cytokines, medicine.medical_treatment, MESH : Leukocytes, MESH : Child, Preschool, chemistry.chemical_compound, 0302 clinical medicine, MESH : Child, MESH: Child, Leukocytes, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Myeloid Cells, MESH : Female, Child, Cells, Cultured, MESH: Cytokines, 0303 health sciences, Toll-like receptor, MESH : Gene Expression Regulation, Interleukin, Cell Differentiation, PNEUMOCOCCAL MENINGITIS, MESH : Infant, Bacterial Infections, Articles, MYELOID DIFFERENTIATION FACTOR-88, MESH : Adult, MESH: Infant, MESH: Gene Expression Regulation, C-REACTIVE PROTEIN, Pedigree, 3. Good health, MESH : Bacterial Infections, Interleukin-1 Receptor-Associated Kinases, medicine.anatomical_structure, Cytokine, Child, Preschool, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Mutation, MESH : Cell Differentiation, IRAK4 KINASE-ACTIVITY, MESH: Toll-Like Receptors, MESH: Cells, Cultured, Adult, MESH: Cell Differentiation, MESH: Mutation, Adolescent, MESH : Myeloid Cells, MESH: Pedigree, MESH: Bacterial Infections, MESH : Male, Immunology, Biology, Article, MESH: Interleukin-1 Receptor-Associated Kinases, MESH: Leukocytes, IL-1 RECEPTOR, 03 medical and health sciences, Immunity, MESH : Adolescent, MESH : Cells, Cultured, medicine, Humans, 030304 developmental biology, TOLL-LIKE RECEPTORS, MESH: Adolescent, CUTTING EDGE, MESH: Humans, Innate immune system, MESH : Humans, MESH: Child, Preschool, HERPES-SIMPLEX-VIRUS, Infant, MESH: Adult, medicine.disease, MESH: Myeloid Cells, MESH: Male, Gene Expression Regulation, chemistry, MESH : Pedigree, MESH : Toll-Like Receptors, Mutation, PLASMACYTOID DENDRITIC CELLS, INNATE IMMUNITY, Primary immunodeficiency, MESH : Interleukin-1 Receptor-Associated Kinases, MESH: Female, 030215 immunology
Abstract: Human interleukin ( IL) 1 receptor - associated kinase 4 ( IRAK- 4) deficiency is a recently discovered primary immunodefi ciency that impairs Toll/ IL- 1R immunity, except for the Toll- like receptor ( TLR) 3 - and TLR4 - interferon ( IFN)-alpha/beta pathways. The clinical and immunological phenotype remains largely unknown. We diagnosed up to 28 patients with IRAK- 4 deficiency, tested blood TLR responses for individual leukocyte subsets, and TLR responses for multiple cytokines. The patients' peripheral blood mononuclear cells ( PBMCs) did not induce the 11 non- IFN cytokines tested upon activation with TLR agonists other than the nonspecific TLR3 agonist poly( I: C). The patients' individual cell subsets from both myeloid ( granulocytes, monocytes, monocyte- derived dendritic cells [ MDDCs], myeloid DCs [ MDCs], and plasmacytoid DCs) and lymphoid ( B, T, and NK cells) lineages did not respond to the TLR agonists that stimulated control cells, with the exception of residual responses to poly( I: C) and lipopolysaccharide in MDCs and MDDCs. Most patients ( 22 out of 28; 79%) suffered from invasive pneumococcal disease, which was often recurrent ( 13 out of 22; 59%). Other infections were rare, with the exception of severe staphylococcal disease ( 9 out of 28; 32%). Almost half of the patients died ( 12 out of 28; 43%). No death and no invasive infection occurred in patients older than 8 and 14 yr, respectively. The IRAK- 4 - dependent TLRs and IL- 1Rs are therefore vital for childhood immunity to pyogenic bacteria, particularly Streptococcus pneumoniae. Conversely, IRAK- 4 - dependent human TLRs appear to play a redundant role in protective immunity to most infections, at most limited to childhood immunity to some pyogenic bacteria.
Published: 2007

47. MxA Induction May Predict Sustained Virologic Responses of Chronic Hepatitis B Patients with IFN-α Treatment

Author: Xin-Xin Zhang, Xiao-Fei Kong, Dong-Hua Zhang, Zhi-Meng Lu, Lin Wang, Shen-Ying Zhang, Jie Xu, Qi-Ming Gong, Jian Gao, Gen-Di Jin, Yue Han, and Jie-Hong Jiang
Subjects: Adult, Male, Myxovirus Resistance Proteins, Hepatitis B virus, Genotype, Immunology, Stimulation, Interferon alpha-2, Antiviral Agents, Polymorphism, Single Nucleotide, Peripheral blood mononuclear cell, Polyethylene Glycols, law.invention, Mice, Hepatitis B, Chronic, GTP-Binding Proteins, law, Virology, Animals, Humans, Medicine, RNA, Messenger, Alleles, Messenger RNA, business.industry, Interferon-alpha, Cell Biology, Hepatitis B, medicine.disease, Protein kinase R, Recombinant Proteins, In vitro, Logistic Models, Recombinant DNA, business
Abstract: The objective of this study was to find potential biomarkers for predicting sustained virologic responses to interferon-alpha (IFN-alpha) treatment in chronic hepatitis B (CHB) patients. A total of 101 CHB patients were treated with pegylated IFN-alpha2a for 48 weeks and followed up for 24 weeks, including 34 IFN responders (IFN-Rs) and 67 IFN nonresponders (IFN-NRs). After peripheral blood mononuclear cells (PBMCs) and Epstein-Barr virus-transferred B (EBV-B) cell lines were treated with different concentrations of IFN-alpha in vitro, activated IFN-stimulated gene factor3 (ISGF3) and IFN-gamma-activation factor (GAF) were measured by EMSA, and MxA, OAS1, and PKR mRNA were measured by real-time PCR. Polymorphisms in the MxA promoter were genotyped to find the possible association. IFN-alpha-activated ISGF3 and GAF levels were similar between IFN-NRs and IFN-Rs. However, MxA mRNA induction in IFN-Rs was higher than that in IFN-NRs, and such discrepancy increased when highly concentrated IFN was used to stimulate. The OAS1 and PKR mRNA induction have a similar pattern between IFN-Rs and IFN-NRs. In addition, frequency of the MxA-88G/T genotype was significantly different between IFN-Rs and IFN-NRs, and this polymorphism was also functional because MxA mRNA induction in patients with GG genotype was lower than those with GT genotype. Regression analysis showed that MxA mRNA induction after 10,000 IU/mL IFN stimulation could serve as an independent factor for predicting IFN-alpha, with an area under curve (AUC) of 0.838, a positive predictive value of 68% for IFN-Rs, and a negative predictive value of 89% for IFN-NRs. MxA mRNA induced by IFN-alpha might predict sustained virologic responses to IFN-alpha treatment in CHB patients.
Published: 2007

48. Human primary immunodeficiencies of type I interferons

Author: Capucine Picard, Ariane Chapgier, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis, Anne Puel, Laurent Abel, Emmanuelle Jouanguy, and Shen-Ying Zhang
Subjects: Protective immunity, viruses, Herpesvirus 1, Human, Antiviral Agents, Models, Biological, Biochemistry, Pathogenesis, Immune system, Immunity, medicine, Animals, Humans, Genetic Predisposition to Disease, STAT1, Herpesviridae, TYK2 Kinase, biology, Immunologic Deficiency Syndromes, Membrane Transport Proteins, General Medicine, Prognosis, medicine.disease, Virology, Immunity, Innate, Human genetics, STAT1 Transcription Factor, Tyrosine kinase 2, Immune System, Immunology, biology.protein, Encephalitis
Abstract: Type I interferons (IFN-alpha/beta and related molecules) are essential for protective immunity to experimental infection by numerous viruses in the mouse model. In recent years, human primary immunodeficiencies affecting either the production of (UNC-93B deficiency) or the response to (STAT1 and TYK2 deficiencies) these IFNs have been reported. Affected patients are highly susceptible to certain viruses. Patients with STAT1 or TYK2 deficiency are susceptible to multiple viruses, including herpes simplex virus-1 (HSV-1), whereas UNC-93B-deficient patients present isolated HSV-1 encephalitis. However, these immunological defects are not limited to type I IFN-mediated immunity. Impaired type II IFN (IFN-gamma)-mediated immunity plays no more than a minor role in the pathogenesis of viral diseases in these patients, but the contribution of impaired type III IFN (IFN-lambda)-mediated immunity remains to be determined. These novel inherited disorders strongly suggest that type I IFN-mediated immunity is essential for protection against natural infections caused by several viruses in humans.
Published: 2007

49. Deciphering Human Cell-Autonomous Anti-HSV-1 Immunity in the Central Nervous System

Author: Fabien Gilbert Lafaille, Michael eCiancaneli, Jean-Laurent eCasanova, and Shen-Ying eZhang
Subjects: lcsh:Immunologic diseases. Allergy, Cell type, viruses, Immunology, Review, Biology, Virus, 03 medical and health sciences, 0302 clinical medicine, Immunity, HSE, disease modeling, medicine, Immunology and Allergy, TLR3, 030304 developmental biology, Neurons, Neurotropic virus, 0303 health sciences, hiPSCs, Microglia, Viral encephalitis, medicine.disease, HSV-1, Neural stem cell, 3. Good health, antiviral immunity, interferons, medicine.anatomical_structure, Astrocytes, Neuron, CNS, lcsh:RC581-607, 030217 neurology & neurosurgery
Abstract: Herpes simplex virus 1 (HSV-1) is a common virus that can rarely invade the human central nervous system (CNS), causing devastating encephalitis. The permissiveness to HSV-1 of the various relevant cell types of the CNS, neurons, astrocytes, oligodendrocytes, and microglia cells, as well as their response to viral infection, has been extensively studied in humans and other animals. Nevertheless, human CNS cell-based models of anti-HSV-1 immunity are of particular importance, as responses to any given neurotropic virus may differ between humans and other animals. Human CNS neuron cell lines as well as primary human CNS neurons, astrocytes, and microglia cells cultured/isolated from embryos or cadavers, have enabled the study of cell-autonomous anti-HSV-1 immunity in vitro. However, the paucity of biological samples and their lack of purity have hindered progress in the field, which furthermore suffers from the absence of testable primary human oligodendrocytes. Recently, the authors have established a human induced pluripotent stem cells (hiPSCs)-based model of anti-HSV-1 immunity in neurons, oligodendrocyte precursor cells, astrocytes, and neural stem cells, which has widened the scope of possible in vitro studies while permitting in-depth explorations. This mini-review summarizes the available data on human primary and iPSC-derived CNS cells for anti-HSV-1 immunity. The hiPSC-mediated study of anti-viral immunity in both healthy individuals and patients with viral encephalitis will be a powerful tool in dissecting the disease pathogenesis of CNS infections with HSV-1 and other neurotropic viruses.
Published: 2015

50. Inherited DOCK2 deficiency in patients with early-onset invasive infections

Author: Ergin Çiftçi, Kerry Dobbs, David Goldstein, Roberta E. Parrott, Samuli Rounioja, Cecilia Domínguez Conde, Ornella Patrizi, Kaan Boztug, Satoshi Okada, Janna Saarela, Emma Haapaniemi, Janet Chou, Yuval Itan, Mikael Knip, Talal A. Chatila, Berna Savaş, Luigi D. Notarangelo, Axel Schambach, Anne Marie Comeau, Michael Schuster, Sule Haskologlu, Merja Helminen, Michel J. Massaad, Alessandro Moretta, Pierre Lebon, Ivan Bilic, Flore Rozenberg, Silvia Parolini, Raif S. Geha, Sevgi Keles, Jean-Laurent Casanova, Rebecca H. Buckley, Giovanna Tabellini, Figen Dogu, Toshiro K. Ohsumi, Kerstin Felgentreff, Laurent Abel, Magali Audry, Christoph Bock, Aydan Ikinciogullari, Nina K. Serwas, Shen-Ying Zhang, Waleed Al-Herz, Bertrand Boisson, Adel M Alwahadneh, Vincent Pedergnana, Arzu Ensari, Kelly Capuder, Slavé Petrovski, Herrada, Anthony, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria] (CeMM ), Austrian Academy of Sciences (OeAW), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], 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 Brescia, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Necmettin Erbakan University [Konya, Turquie], Tampere University Hospital, Ankara University School of Medicine [Turkey], Massachusetts General Hospital [Boston, MA, USA], Università degli studi di Genova = University of Genoa (UniGe), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Children's Hospital, Folkhälsan Research Center, Faculty of Medecine [Helsinki], Columbia University [New York], Duke University [Durham], Hannover Medical School [Hannover] (MHH), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Kuwait University, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), Medizinische Universität Wien = Medical University of Vienna, Harvard Stem Cell Institute [Cambridge, USA] (HSCI), and Harvard University [Cambridge]
Subjects: Male, rac1 GTP-Binding Protein, MESH: Fatal Outcome, [SDV]Life Sciences [q-bio], Lymphocyte, medicine.medical_treatment, T-Lymphocytes, MESH: GTPase-Activating Proteins, Hematopoietic stem cell transplantation, Fatal Outcome, Interferon, MESH: Guanine Nucleotide Exchange Factors, Guanine Nucleotide Exchange Factors, Killer Cells, Child, B-Lymphocytes, Medicine (all), Hematopoietic Stem Cell Transplantation, General Medicine, MESH: Infant, 3. Good health, Pedigree, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Genetic Diseases, Natural, Female, Child, Preschool, Genes, Recessive, Genetic Diseases, Inborn, Humans, Immunologic Deficiency Syndromes, Infant, Killer Cells, Natural, Mutation, medicine.drug, MESH: Killer Cells, Natural, MESH: Genetic Diseases, Inborn, MESH: Mutation, MESH: Immunologic Deficiency Syndromes, MESH: Pedigree, Combined immunodeficiencies, Immunity, MESH: B-Lymphocytes, medicine, Recessive, Preschool, MESH: Genes, Recessive, MESH: Hematopoietic Stem Cell Transplantation, MESH: Humans, MESH: rac1 GTP-Binding Protein, business.industry, MESH: Child, Preschool, medicine.disease, MESH: Male, Transplantation, MESH: T-Lymphocytes, Inborn, Genes, Humoral immunity, Immunology, Primary immunodeficiency, business, MESH: Female
Abstract: International audience; Background Combined immunodeficiencies are marked by inborn errors of T-cell immunity in which the T cells that are present are quantitatively or functionally deficient. Impaired humoral immunity is also common. Patients have severe infections, autoimmunity, or both. The specific molecular, cellular, and clinical features of many types of combined immunodeficiencies remain unknown. Methods We performed genetic and cellular immunologic studies involving five unrelated children with early-onset invasive bacterial and viral infections, lymphopenia, and defective T-cell, B-cell, and natural killer (NK)-cell responses. Two patients died early in childhood; after allogeneic hematopoietic stem-cell transplantation, the other three had normalization of T-cell function and clinical improvement. Results We identified biallelic mutations in the dedicator of cytokinesis 2 gene (DOCK2) in these five patients. RAC1 activation was impaired in the T cells. Chemokine-induced migration and actin polymerization were defective in the T cells, B cells, and NK cells. NK-cell degranulation was also affected. Interferon-α and interferon-λ production by peripheral-blood mononuclear cells was diminished after viral infection. Moreover, in DOCK2-deficient fibroblasts, viral replication was increased and virus-induced cell death was enhanced; these conditions were normalized by treatment with interferon alfa-2b or after expression of wild-type DOCK2. Conclusions Autosomal recessive DOCK2 deficiency is a new mendelian disorder with pleiotropic defects of hematopoietic and nonhematopoietic immunity. Children with clinical features of combined immunodeficiencies, especially with early-onset, invasive infections, may have this condition. (Supported by the National Institutes of Health and others.).
Published: 2015

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