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1. Chronic mucocutaneous candidiasis and connective tissue disorder in humans with impaired JNK1-dependent responses to IL-17A/F and TGF-β

Author

Marco Ritelli, Harry C. Dietz, Danielle T. Avery, Bertrand Boisson, Soraya Boucherit, Lucie Grodecká, Stuart G. Tangye, Romain Lévy, Kathryn Payne, Tomáš Freiberger, Sophie Cypowyj, Juan Li, Valérie Cormier-Daire, Nicoletta Zoppi, Laurent Abel, Geetha Rao, Vivien Béziat, Andrea Guennoun, Benedetta Bigio, Maya Chrabieh, Salim Bougarn, Marina Colombi, Lei Shang, Emilie Corvilain, Yuval Itan, Anne Puel, Franck Rapaport, Nico Marr, Fransiska Malfait, Delfien Syx, Mélanie Migaud, Tanwir Habib, Sabri Boughorbel, Jean-Laurent Casanova, and Cindy S. Ma

Subjects
Male, 0301 basic medicine, Connective Tissue Disorder, MAPK8, Immunology, Mucocutaneous zone, Connective tissue, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, Transforming Growth Factor beta, medicine, Humans, Mitogen-Activated Protein Kinase 8, Chronic mucocutaneous candidiasis, Connective Tissue Diseases, Alleles, Cells, Cultured, business.industry, Candidiasis, Chronic Mucocutaneous, Interleukin-17, General Medicine, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, Signal transduction, Haploinsufficiency, business
Abstract

Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-β-dependent homeostasis of connective tissues. The signaling pathways involved are incompletely understood. We report a three-generation family with an autosomal dominant (AD) combination of CMC and a previously undescribed form of CTD that clinically overlaps with Ehlers-Danlos syndrome (EDS). The patients are heterozygous for a private splice-site variant of MAPK8, the gene encoding c-Jun N-terminal kinase 1 (JNK1), a component of the MAPK signaling pathway. This variant is loss-of-expression and loss-of-function in the patients' fibroblasts, which display AD JNK1 deficiency by haploinsufficiency. These cells have impaired, but not abolished, responses to IL-17A and IL-17F. Moreover, the development of the patients' TH17 cells was impaired ex vivo and in vitro, probably due to the involvement of JNK1 in the TGF-β-responsive pathway and further accounting for the patients' CMC. Consistently, the patients' fibroblasts displayed impaired JNK1- and c-Jun/ATF-2-dependent induction of key extracellular matrix (ECM) components and regulators, but not of EDS-causing gene products, in response to TGF-β. Furthermore, they displayed a transcriptional pattern in response to TGF-β different from that of fibroblasts from patients with Loeys-Dietz syndrome caused by mutations of TGFBR2 or SMAD3, further accounting for the patients' complex and unusual CTD phenotype. This experiment of nature indicates that the integrity of the human JNK1-dependent MAPK signaling pathway is essential for IL-17A- and IL-17F-dependent mucocutaneous immunity to Candida and for the TGF-β-dependent homeostasis of connective tissues.

Published
2019

2. Human IFN-γ immunity to mycobacteria is governed by both IL-12 and IL-23

Author

Cindy S. Ma, Jean-Laurent Casanova, Monika Schmidt, Federico Mele, Gaspard Kerner, James P. Di Santo, Cecilia S. Lindestam Arlehamn, Avneet Heer, Lluis Quintana-Murci, Alessandro Sette, Bernhard Fleckenstein, Tomi Lazarov, Sandra Jovic, Natalie Wong, Stéphanie Boisson-Dupuis, Daniela Latorre, Julia K. Joseph, Bertrand Boisson, Rubén Martínez-Barricarte, Caner Aytekin, Danielle T. Avery, Aydan Ikinciogullari, Figen Dogu, Jean-François Emile, Etienne Patin, Federica Sallusto, Yoann Seeleuthner, Yuval Itan, Laurent Abel, Franck Rapaport, Alejandro Nieto-Patlán, Frederic Geissmann, Satoshi Okada, Fabienne Jabot-Hanin, Stuart G. Tangye, Esther van de Vosse, Geetha Rao, Elissa K. Deenick, Jacinta Bustamante, Mélanie Migaud, Caroline Deswarte, Mohammed Reza Bloursaz, Laura Surace, Benedetta Bigio, Davood Mansouri, Anne Puel, Payam Tabarsi, Xiao-Fei Kong, Gönül Tanır, Vanessa L. Bryant, Noé Ramírez-Alejo, Seyed Alireza Mahdaviani, Janet Markle, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], University of New South Wales [Sydney] (UNSW), Università della Svizzera italiana = University of Italian Switzerland (USI), Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Sami Ulus Maternity and Children Training and Research Hospital, The Walter and Eliza Hall Institute of Medical Research (WEHI), University of Melbourne, The Royal Melbourne Hospital, 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), Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Génomique évolutive, modélisation et santé (GEMS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Hiroshima University, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Ankara University School of Medicine [Turkey], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], King‘s College London, La Jolla Institute for Immunology [La Jolla, CA, États-Unis], University of California [San Diego] (UC San Diego), University of California (UC), Hôpital Ambroise Paré [AP-HP], Leiden University Medical Center (LUMC), Universiteit Leiden, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), 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), The Laboratory of Human Genetics of Infectious Diseases was supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID) grant numbers 5R37AI095983, R01AI089970, and K99AI127932, the National Center for Research Resources and the National Center for Advancing Sciences (NCATS) of the NIH grant number UL1TR001866, the Rockefeller University, the St. Giles Foundation, the European Research Council (ERC-2010-AdG-268777 and grant no. 323183), Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), and the French National Research Agency (ANR) under the 'Investissement d’avenir' program (grant ANR-10-IAHU-01), ANR-TBPATHGEN (grant ANR-14-CE14-0007-01), ANR-IFNPHOX (grant ANR13-ISV3-0001-01), and ANR-GENMSMD (grant ANR16-CE17-0005-01). This work was supported by NIAID award no. U19AI118626 (to A.S. and F.S.). J.G.M. was funded by the Canadian Institutes of Health Research, the NIH Translational Science Award (CTSA) program (no. UL1 TR000043), the Swiss National Science Foundation (grant no. IZKOZ3_173586), the Charles H. Revson Foundation, and the NIAID (1K99AI127932-01A1). R.M.-B. was supported by the European Molecular Biology Organization (EMBO). N.R.-A. was supported by the National Council of Science and Technology of Mexico (CONACYT, 264011) and the Stony Wold-Herbert Fund Fellowship Grant. Y.I. was supported by the AXA Research Fund. S.G.T., E.K.D., and C.S.M. are supported by research grants and fellowships from the National Health and Medical Research Council of Australia (S.G.T., C.S.M., and E.K.D.) and the Office for Health and Medical Research of the State Government of NSW Australia (C.S.M.). A.S. is supported by NIH research grant HHSN272200900044C. J.B. is supported by SRC2017. The Institute for Research in Biomedicine and F.S. are supported by the Helmut Horten Foundation. S.O. was supported by the Aid for Scientific Research Grant from the Japanese Society for the Promotion of Science (16H05355) and the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-14-CE14-0007,TBPATHGEN,Dissection de la pathogenèse de la tuberculose par l'identification de défauts monogéniques de l'immunité dans les formes pédiatriques sévères de la maladie(2014), ANR-13-ISV3-0001,IFNGPHOX,L'immunité anti-tuberculeuse dépendante de l'IFN-gamma chez l'homme opère via la NADPH oxydase phagocytaire(2013), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), European Project: 268777,EC:FP7:ERC,ERC-2010-AdG_20100317,GENTB(2011), European Project: 323183,EC:FP7:ERC,ERC-2012-ADG_20120314,PREDICT(2013), Shahid Beheshti University, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique évolutive, modélisation et santé (CNRS-UMR2000), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of California, The Rockefeller University, St Giles laboratory of Human Genetics and Infectious Diseases, rockefeller university, Garvan Institute of Medical Research [Darlinghurst, Australia], Dis Training & Res Ctr, Shahid Beheshti University of Medical Sciences, Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Immunité Innée, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), Institut de Génomique d'Evry (IG), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Sami Ulus Children Hlth & Dis Training & Res Ctr, Ankara, Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Service d'anatomie pathologique [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Univ Erlangen Nurnberg, La Jolla Institute for Allergy and Immunology, Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Garvan Institute for Medical Research, and Institute for Research in Biomedicine

Subjects
MESH: Interleukin-12, 0301 basic medicine, MESH: Interferon-gamma, MESH: Pedigree, medicine.medical_treatment, Immunology, Population, Mycobacterium Infections, Nontuberculous, Biology, Interleukin-23, Article, Mycobacterium, Interferon-gamma, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, MESH: Mycobacterium, medicine, Humans, Interferon gamma, education, Interleukin 12 receptor, beta 1 subunit, MESH: Interleukin-23, education.field_of_study, MESH: Humans, General Medicine, MESH: Mycobacterium Infections, Nontuberculous, Natural killer T cell, Interleukin-12, Immunity, Innate, Pedigree, 3. Good health, 030104 developmental biology, Cytokine, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Interleukin 12, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Immunity, Innate, 030215 immunology, medicine.drug
Abstract

International audience; Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rβ1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rβ2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αβ T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4 + T cells, including, in particular , mycobacterium-specific TH1* cells (CD45RA− CCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rβ2 or IL-23R deficiency, relative to IL-12Rβ1 deficiency , is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R-and IL-12Rβ2-deficient than IL-12Rβ1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ dependent immunity to mycobacteria, both individually and much more so cooperatively.

Published
2018

3. A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity

Author

Warren J. Leonard, Nima Rezaei, Kathryn Payne, Isabelle Meyts, Laurent Abel, Cindy S. Ma, Marianne Leruez-Ville, Janet Chou, Alain Hovnanian, Jian-Xin Lin, Simon J. Pelham, Danielle T. Avery, Matthieu Bouaziz, Bethany Pillay, Tanwir Habib, Anne Puel, Sevgi Keles, Juan Li, Isabelle Pellier, Jamel El-Benna, Bernhard Fleckenstein, Ahmet Ozen, Vivien Béziat, Ingrid Müller-Fleckenstein, Damien Chaussabel, Samaneh Zoghi, Yi Wang, Paul Gray, Matthias Titeux, Yoann Zerbib, Talal A. Chatila, Marie-Alexandra Alyanakian, Capucine Picard, Orli Wargon, Ayper Somer, Marie-Olivia Chandesris, Thibaut Leclercq, Ibtihal Benhsaien, Aziz Belkadi, Jean-Laurent Casanova, Romain Lévy, Peng Li, Geetha Rao, Ai Ing Lim, James P. Di Santo, Nico Marr, Sylvie Fraitag, Frédégonde About, Elissa K. Deenick, Bertrand Boisson, Jacinta Bustamante, Mélanie Migaud, Bodo Grimbacher, Aziz Bousfiha, Fatima Ailal, Safa Baris, Antoine Guérin, Stuart G. Tangye, Romain Guery, Ning Du, Vimel Rattina, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Rockefeller University [New York], National Institutes of Health [Bethesda] (NIH), Garvan Institute of Medical Research [Darlinghurst, Australia], University of New South Wales [Sydney] (UNSW), CHU Ibn Rochd [Casablanca], Université Hassan II [Casablanca] (UH2MC), Service d'Immuno-Hémato-Oncologie Pédiatrique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University, Universal Scientific Education and Research Network (USERN), Marmara University [Kadıköy - İstanbul], Necmettin Erbakan University [Konya, Turquie], Immunité Innée, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Harvard Medical School [Boston] (HMS), Boston Children's Hospital, Centre d'infectiologie Necker-Pasteur [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Sidra Medicine, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Freiburg University Medical Center, Sydney children's hospital, Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Genetic skin diseases : from disease mechanism to therapies (Equipe Inserm U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pathologie [CHU Necker], Service d'immuno-hématologie pédiatrique [CHU Necker], Laboratoire de Virologie [CHU Necker], Université Paris Descartes - Paris 5 (UPD5), Centre d'étude des Déficits Immunitaires, University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Istanbul University, Research Center for Immunodeficiencies [Tehran, Iran], Tehran University of Medical Sciences (TUMS), University of New South Wales [Canberra Campus] (UNSW), Howard Hughes Medical Institute [New York], 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 supported by grants from INSERM, Paris Descartes University, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID), the Jeffrey Modell Foundation Translational Research Program, the French National Research Agency (ANR, grant nos. GENCMCD-ANR-11-BSV3–005-01, HGDIFD-ANR-14-CE15-0006-01, NKIR-ANR-13-PDOC-0025-01, and EURO-CMC-ANR-14-RARE-0005-02), and grants awarded under the 'Investissement d’avenir' program (grant no. ANR-10-IAHU-01), the National Institute of Allergy and Infectious Diseases of the NIH (grant nos. U01AI109697 and R01AI127564), the Rockefeller University, the Howard Hughes Medical Institute, the St. Giles Foundation, the Institut Pasteur, and FP7, under grant agreements 305578 (PathCO) and 317057 (HOMIN). We thank the Centre de Recherche Translationnelle (Institut Pasteur) for technical assistance. V.B. is supported by the ANR (grant no. NKIR-ANR-13-PDOC-0025-01). R.L. is supported by the INSERM Ph.D. program (Poste d’Accueil INSERM), a Fulbright grant (Franco-American commission), and a Philippe Foundation scholarship. Y.Z. received the 'médaille d’or du Centre Hospitalier Universitaire d’Amiens.' Y.W. is supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS, grant no. 13318). F. About holds a fellowship from Fondation pour la Recherche Médicale (FRM, grant no. FDM20140630671). A.G. is supported by an IFNGPHOX grant (no. ANR13-ISV3-0001-01) from ANR. B.G. was funded by BMBF (German Federal Ministry of Education and Research) grants 01E01303 and 01ZX1306F. I.M. is supported by a klinische onderzoeks-en opleidingsraad (clinical research council) grant from UZ Leuven, a klinisch onderzoeksfonds (clinical research fund) grant from KU Leuven, and an International Mobility Grant from Fonds voor Wetenschappelijk Onderzoek (fund for scientific research) Vlaanderen. C.S.M., E.K.D., and S.G.T. are supported by grants and fellowships from the National Health and Medical Research Council of Australia. C.S.M., P.G., E.K.D., and S.G.T. are members of CIRCA (Clinical Immunogenomics Research Consortia Australia), which is funded by the Office of Health and Medical Research of the NSW Government, the Jeffrey Modell Foundation, and the John Cook Brown Foundation. A.I.L. is a scholar of the Pasteur-Paris University International Ph.D. program and is supported by a Ph.D. International Training Network grant from the European Union’s Seventh Framework Program under grant agreement no. 317057 (HOMIN). T.A.C. was supported by a grant from the National Institute of Allergy and Infectious Diseases of the NIH (5R01AI065617). S.K. was supported by a grant from the Scientific and Technological Research Council of Turkey (1059B191300622). J.-X.L., P.L., N.D., and W.J.L. were supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH. A.P. was supported by an AP-HP interface contract., We thank the patients and their families for participating in this study. We thank J. E. Darnell and C. Mertens for advice and for providing reagents. We thank the members of the laboratory, especially F. Jabot-Hanin and V. Pedergnana, for their valuable input on linkage analysis, L. Amar, Y. Nemirovskaya, D. Papandrea, E. Anderson, M. Woollett, C. Desvallées, C. Patissier, and M. Corrias for administrative assistance, E. Jouanguy and Y. Itan for helpful discussions, S. Boucherit for clinical data collection, S. Jacques and the Cochin genomics platform for microarray experiments, and N. Goudin and R. Desveaux of the Necker Institute Imaging Facility., Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Garvan Institute of medical research, Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sidra Medicine [Doha, Qatar], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), Sydney Children's hospital, 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 Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Beziat, Vivien, Li, Juan, Lin, Jian-Xin, Ma, Cindy S., Li, Peng, Bousfiha, Aziz, Pellier, Isabelle, Zoghi, Samaneh, Baris, Safa, Keles, Sevgi, Gray, Paul, Du, Ning, Wang, Yi, Zerbib, Yoann, Levy, Romain, Leclercq, Thibaut, About, Fredegonde, Lim, Ai Ing, Rao, Geetha, Payne, Kathryn, Pelham, Simon J., Avery, Danielle T., Deenick, Elissa K., Pillay, Bethany, Chou, Janet, Guery, Romain, Belkadi, Aziz, Guerin, Antoine, Migaud, Melanie, Rattina, Vimel, Ailal, Fatima, Benhsaien, Ibtihal, Bouaziz, Matthieu, Habib, Tanwir, Chaussabel, Damien, Marr, Nico, El-Benna, Jamel, Grimbacher, Bodo, Wargon, Orli, Bustamante, Jacinta, Boisson, Bertrand, Mueller-Fleckenstein, Ingrid, Fleckenstein, Bernhard, Chandesris, Marie-Olivia, Titeux, Matthias, Fraitag, Sylvie, Alyanakian, Marie-Alexandra, Leruez-Ville, Marianne, Picard, Capucine, Meyts, Isabelle, Di Santo, James P., Hovnanian, Alain, Somer, Ayper, Ozen, Ahmet, Rezaei, Nima, Chatila, Talal A., Abel, Laurent, Leonard, Warren J., Tangye, Stuart G., Puel, Anne, and Casanova, Jean-Laurent

Subjects
0301 basic medicine, INBORN-ERRORS, Immunoglobulin E, MESH: STAT3 Transcription Factor/immunology, Loss of heterozygosity, PRECISION MEDICINE, Transcription (biology), OF-FUNCTION MUTATIONS, STAT3, MESH: Transcription Factors/metabolism, CELL-DIFFERENTIATION, MESH: Th2 Cells/metabolism, MESH: Immunoglobulin E/immunology, MESH: Middle Aged, MESH: Gene Expression Regulation/immunology, Cell Differentiation, General Medicine, MESH: RNA, Messenger/metabolism, MESH: Immunoglobulin E/blood, MESH: Zinc Fingers/genetics, READ ALIGNMENT, MESH: Transcription, Genetic/immunology, MESH: Cell Nucleus/metabolism, MESH: Young Adult, [SDV.IMM]Life Sciences [q-bio]/Immunology, SIGNAL TRANSDUCER, Job Syndrome, MESH: Homozygote, STAT3 Transcription Factor, Cell type, MESH: Lymphocyte Count, MESH: Pedigree, MESH: STAT3 Transcription Factor/genetics, Immunology, Biology, Article, MESH: Job Syndrome/immunology, MESH: Genes, Recessive/genetics, DIFFERENTIAL EXPRESSION, MESH: Genes, Recessive/immunology, MESH: Job Syndrome/blood, MESH: Transcription Factors/genetics, 03 medical and health sciences, MESH: Whole Exome Sequencing, MESH: Exons/genetics, Humans, Transcription factor, Gene, MESH: Adolescent, MESH: Consanguinity, MESH: Humans, CLINICAL-FEATURES, MESH: Th17 Cells/metabolism, MESH: Th17 Cells/immunology, MESH: Cytokines/immunology, MESH: Adult, MESH: Loss of Function Mutation, MESH: Job Syndrome/genetics, MESH: Cell Differentiation/genetics, Molecular biology, MESH: Male, MESH: Th2 Cells/immunology, IL-21 RECEPTOR, 030104 developmental biology, Gene Expression Regulation, MESH: STAT3 Transcription Factor/metabolism, MESH: Promoter Regions, Genetic/genetics, MESH: Cell Differentiation/immunology, T-CELLS, STAT protein, biology.protein, Th17 Cells, MESH: Transcription Factors/immunology, MESH: Cytokines/metabolism, MESH: Female
Abstract

Comment in :Who regulates whom: ZNF341 is an additional player in the STAT3/TH17 song. [Sci Immunol. 2018]; International audience; Heterozygosity for human signal transducer and activator of transcription 3 (STAT3) dominant-negative (DN) mutations underlies an autosomal dominant form of hyper-immunoglobulin E syndrome (HIES). We describe patients with an autosomal recessive form of HIES due to loss-of-function mutations of a previously uncharacterized gene, ZNF341 ZNF341 is a transcription factor that resides in the nucleus, where it binds a specific DNA motif present in various genes, including the STAT3 promoter. The patients' cells have low basal levels of STAT3 mRNA and protein. The autoinduction of STAT3 production, activation, and function by STAT3-activating cytokines is strongly impaired. Like patients with STAT3 DN mutations, ZNF341-deficient patients lack T helper 17 (TH17) cells, have an excess of TH2 cells, and have low memory B cells due to the tight dependence of STAT3 activity on ZNF341 in lymphocytes. Their milder extra-hematopoietic manifestations and stronger inflammatory responses reflect the lower ZNF341 dependence of STAT3 activity in other cell types. Human ZNF341 is essential for the STAT3 transcription-dependent autoinduction and sustained activity of STAT3.

Published
2018

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