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1. Case Report: Invasive Cryptococcosis in French Guiana: Immune and Genetic Investigation in Six Non-HIV Patients

Author

Jeanne Goupil de Bouillé, Loïc Epelboin, Fanny Henaff, Mélanie Migaud, Philippe Abboud, Denis Blanchet, Christine Aznar, Felix Djossou, Olivier Lortholary, Narcisse Elenga, Anne Puel, Fanny Lanternier, and Magalie Demar

Subjects
cryptococcosis, immunocompetent, STAT1 gene, autoantibodies against GM-CSF, antibodies against IFN-γ, fungal infection, Immunologic diseases. Allergy, RC581-607
Abstract

ObjectivesWe describe the clinical, mycological, immunological, and genetic characteristics of six HIV-negative patients presenting with invasive cryptococcosis.MethodsPatients with cryptococcosis without any of the classical risk factors, such as HIV infection, followed at Cayenne Hospital, were prospectively included. An immunologic and genetic assessment was performed.ResultsFive male patients and one female patient, 5 adults and one child, were investigated. All presented a neuromeningeal localization. Cryptococcus neoformans var. gattii and C. neoformans var. grubii were isolated in two and three patients, respectively, whereas one patient could not be investigated. Overall, we did not observe any global leukocyte defect. Two patients were found with high levels of circulating autoantibodies against Granulocyte macrophage-colony stimulating factor (GM-CSF), and none had detectable levels of autoantibodies against Interferon gamma (IFN-γ) Sequencing of STAT1 exons and flanking regions performed for four patients was wild type.ConclusionTo better understand cryptococcosis in patients with cryptococcosis but otherwise healthy, further explorations are needed with repeated immune checkups and strain virulence studies.

Published
2022
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2. Case Report: A New Gain-of-Function Mutation of STAT1 Identified in a Patient With Chronic Mucocutaneous Candidiasis and Rosacea-Like Demodicosis: An Emerging Association

Author

Martin Martinot, Anne Sophie Korganow, Mathieu Wald, Julie Second, Elodie Birckel, Antoine Mahé, Laurent Souply, Mahsa Mohseni-Zadeh, Laure Droy, Julien Tarabeux, Satoshi Okada, Mélanie Migaud, Anne Puel, and Aurelien Guffroy

Subjects
STAT1 GOF, mutation, IL-17, rosacea, Demodex, demodicosis, Immunologic diseases. Allergy, RC581-607
Abstract

PurposeHeterozygous missense STAT1 mutations leading to a gain of function (GOF) are the most frequent genetic cause of chronic mucocutaneous candidiasis (CMC). We describe the case of a patient presenting a new GOF mutation of STAT1 with the clinical symptoms of CMC, recurrent pneumonia, and persistent central erythema with papulopustules with ocular involvement related to rosacea-like demodicosis.MethodsGenetic analysis via targeted next-generation sequencing (NGS; NGS panel DIPAI v.1) exploring the 98 genes most frequently involved in primary immunodeficiencies, including STAT1, was performed to identify an underlying genetic defect.ResultsNGS identified a novel variant of STAT1, c.884C>A (exon 10), p.T295Y, not previously described. This variant was found to be gain of function using an in vitro luciferase reporter assay. Rosacea-like demodicosis was confirmed by substantial Demodex proliferation observed via the microscopic examination of a cutaneous sample. A review of literature retrieved 20 other cases of STAT1 GOF mutations associated with early-onset rosacea-like demodicosis, most with ocular involvement.ConclusionWe describe a new STAT1 GOF mutation associated with a phenotype of CMC and rosacea-like demodicosis. Rosacea-like demodicosis appears as a novel and important clinical phenotype among patients with STAT1 GOF mutation.

Published
2021
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3. Invasive Rhinosinusitis Caused by Alternaria infectoria in a Patient with Autosomal Recessive CARD9 Deficiency and a Review of the Literature

Author

Olivier Paccoud, Nicolas Vignier, Mohammed Boui, Mélanie Migaud, Pierre Vironneau, Romain Kania, Frédéric Méchaï, Sophie Brun, Alexandre Alanio, Arnault Tauziède-Espariat, Homa Adle-Biassette, Elise Ouedraogo, Jacinta Bustamante, Olivier Bouchaud, Jean-Laurent Casanova, Anne Puel, and Fanny Lanternier

Subjects
Alternaria infectoria, CARD9 deficiency, phaeohyphomycosis, invasive fungal sinusitis, Biology (General), QH301-705.5
Abstract

Phaeohyphomycoses comprise a heterogeneous group of fungal infections caused by dematiaceous fungi and have primarily been reported in patients with underlying acquired immunodeficiencies, such as hematological malignancies or solid-organ transplants. Over the past decade, a growing number of patients with phaeohyphomycosis but otherwise healthy were reported with autosomal recessive (AR) CARD9 deficiency. We report a 28-year-old woman who presented with invasive rhinosinusitis caused by Alternaria infectoria. Following a candidate gene sequencing approach, we identified a biallelic loss-of-function mutation of CARD9, thereby further broadening the spectrum of invasive fungal diseases found in patients with inherited CARD9 deficiency. In addition, we reviewed 17 other cases of phaeohyphomycosis associated with AR CARD9 deficiency. Physicians should maintain a high degree of suspicion for inborn errors of immunity, namely CARD9 deficiency, when caring for previously healthy patients with phaeohyphomycosis, regardless of age at first presentation.

Published
2022
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4. A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation

Author

Marieke De Bruyne, Levi Hoste, Delfien J. Bogaert, Lien Van den Bossche, Simon J. Tavernier, Eef Parthoens, Mélanie Migaud, Deborah Konopnicki, Jean Cyr Yombi, Bart N. Lambrecht, Sabine van Daele, Ana Karina Alves de Medeiros, Lieve Brochez, Rudi Beyaert, Elfride De Baere, Anne Puel, Jean-Laurent Casanova, Jean-Christophe Goffard, Savvas N. Savvides, Filomeen Haerynck, Jens Staal, and Melissa Dullaers

Subjects
CARD9 deficiency, founder mutation, BCL10, MALT1, CBM complex, NF-κB, Immunologic diseases. Allergy, RC581-607
Abstract

Background: Inherited CARD9 deficiency constitutes a primary immunodeficiency predisposing uniquely to chronic and invasive fungal infections. Certain mutations are shown to negatively impact CARD9 protein expression and/or NF-κB activation, but the underlying biochemical mechanism remains to be fully understood.Objectives: To investigate a possible founder origin of a known CARD9 R70W mutation in five families of Turkish origin. To explore the biochemical mechanism of immunodeficiency by R70W CARD9.Methods: We performed haplotype analysis using microsatellite markers and SNPs. We designed a model system exploiting a gain-of-function (GOF) CARD9 L213LI mutant that triggers constitutive NF-κB activation, analogous to an oncogenic CARD11 mutant, to study NF-κB signaling and signalosome formation. We performed reporter assays, immunoprecipitation and confocal imaging on HEK cells overexpressing different CARD9 variants.Results: We identified a common haplotype, thus providing evidence for a common Turkish founder. CARD9 R70W failed to activate NF-κB and abrogated NF-κB activation by WT CARD9 and by GOF CARD9. Notably, R70W CARD9 also exerted negative effects on NF-κB activation by CARD10, CARD11, and CARD14. Consistent with the NF-κB results, the R70W mutation prevented GOF CARD9 to pull down the signalosome partner proteins BCL10 and MALT1. This reflected into drastic reduction of BCL10 filamentous assemblies in a cellular context. Indeed, structural analysis revealed that position R70 in CARD9 maps at the putative interface between successive CARD domains in CARD9 filaments.Conclusions: The R70W mutation in CARD9 prevents NF-κB activation by inhibiting productive interactions with downstream BCL10 and MALT1, necessary for assembly of the filamentous CARD9-BCL10-MALT1 signalosome.

Published
2018
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5. Gain-of-Function Mutations in STAT1: A Recently Defined Cause for Chronic Mucocutaneous Candidiasis Disease Mimicking Combined Immunodeficiencies

Author

Sanem Eren Akarcan, Ezgi Ulusoy Severcan, Neslihan Edeer Karaca, Esra Isik, Guzide Aksu, Mélanie Migaud, Ferda Evin Gurkan, Elif Azarsiz, Anne Puel, Jean-Laurent Casanova, and Necil Kutukculer

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Chronic Mucocutaneous Candidiasis (CMC) is the chronic, recurrent, noninvasive Candida infections of the skin, mucous membranes, and nails. A 26-month-old girl was admitted with the complaints of recurrent oral Candidiasis, diarrhea, and respiratory infections. Candida albicans grew in oral mucosa swab. CMV and EBV DNA titers were elevated. She had hypergammaglobulinemia; IgE level, percentages of lymphocyte subgroups, and in vitro T-cell proliferation responses were normal. She had parenchymal nodules within the lungs and a calcific nodule in the liver. Chronic-recurrent infections with different pathogens leading to significant morbidity suggested combined immunodeficiency, CMC, or Mendelian susceptibility to mycobacterial diseases. Genetic analysis revealed a predefined heterozygous gain-of-function mutation (GOF) (c.1154 C>T, p.Thr385Met) in the gene coding STAT1 molecule. Hematopoietic stem cell transplantation (HSCT) was planned because of severe recurring infections. Patients with STAT1 GOF mutations may exhibit diverse phenotypes including infectious and noninfectious findings. HSCT should be considered as an early treatment option before permanent organ damage leading to morbidity and mortality develops. This case is presented to prompt clinicians to consider STAT1 GOF mutations in the differential diagnosis of patients with chronic Candidiasis and recurrent infections with multiple organisms, since these mutations are responsible for nearly half of CMC cases reported.

Published
2017
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6. Human IL-23 is essential for IFN-γ–dependent immunity to mycobacteria

Author

Quentin Philippot, Masato Ogishi, Jonathan Bohlen, Julia Puchan, Andrés Augusto Arias, Tina Nguyen, Marta Martin-Fernandez, Clement Conil, Darawan Rinchai, Mana Momenilandi, Seyed Alireza Mahdaviani, Mohammad Keramatipour, Jérémie Rosain, Rui Yang, Taushif Khan, Anna-Lena Neehus, Marie Materna, Ji Eun Han, Jessica Peel, Federico Mele, Marc Weisshaar, Sandra Jovic, Paul Bastard, Romain Lévy, Tom Le Voyer, Peng Zhang, Majistor Raj Luxman Maglorius Renkilaraj, Carlos A. Arango-Franco, Simon Pelham, Yoann Seeleuthner, Mathieu Pochon, Manar Mahmoud Ahmad Ata, Fatima Al Ali, Mélanie Migaud, Camille Soudée, Tatiana Kochetkov, Anne Molitor, Raphael Carapito, Seiamak Bahram, Bertrand Boisson, Claire Fieschi, Davood Mansouri, Nico Marr, Satoshi Okada, Mohammad Shahrooei, Nima Parvaneh, Zahra Chavoshzadeh, Aurélie Cobat, Dusan Bogunovic, Laurent Abel, Stuart G. Tangye, Cindy S. Ma, Vivien Béziat, Federica Sallusto, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Jean-Laurent Casanova, and Anne Puel

Subjects
Immunology, General Medicine
Abstract

Patients with autosomal recessive (AR) IL-12p40 or IL-12Rβ1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium -inducible IFN-γ immunity in both Vδ2 + γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F–dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ–dependent immunity to Mycobacterium in at least two lymphocyte subsets.

Published
2023

7. Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Author

Jérémie Rosain, Anna-Lena Neehus, Jérémy Manry, Rui Yang, Jérémie Le Pen, Wassim Daher, Zhiyong Liu, Yi-Hao Chan, Natalia Tahuil, Özden Türel, Mathieu Bourgey, Masato Ogishi, Jean-Marc Doisne, Helena M. Izquierdo, Takayoshi Shirasaki, Tom Le Voyer, Antoine Guérin, Paul Bastard, Marcela Moncada-Vélez, Ji Eun Han, Taushif Khan, Franck Rapaport, Seon-Hui Hong, Andrew Cheung, Kathrin Haake, Barbara C. Mindt, Laura Pérez, Quentin Philippot, Danyel Lee, Peng Zhang, Darawan Rinchai, Fatima Al Ali, Manar Mahmoud Ahmad Ata, Mahbuba Rahman, Jessica N. Peel, Søren Heissel, Henrik Molina, Yasemin Kendir-Demirkol, Rasheed Bailey, Shuxiang Zhao, Jonathan Bohlen, Mathieu Mancini, Yoann Seeleuthner, Marie Roelens, Lazaro Lorenzo, Camille Soudée, María Elvira Josefina Paz, María Laura González, Mohamed Jeljeli, Jean Soulier, Serge Romana, Anne-Sophie L’Honneur, Marie Materna, Rubén Martínez-Barricarte, Mathieu Pochon, Carmen Oleaga-Quintas, Alexandre Michev, Mélanie Migaud, Romain Lévy, Marie-Alexandra Alyanakian, Flore Rozenberg, Carys A. Croft, Guillaume Vogt, Jean-François Emile, Laurent Kremer, Cindy S. Ma, Jörg H. Fritz, Stanley M. Lemon, András N. Spaan, Nicolas Manel, Laurent Abel, Margaret R. MacDonald, Stéphanie Boisson-Dupuis, Nico Marr, Stuart G. Tangye, James P. Di Santo, Qian Zhang, Shen-Ying Zhang, Charles M. Rice, Vivien Béziat, Nico Lachmann, David Langlais, Jean-Laurent Casanova, Philippe Gros, Jacinta Bustamante, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hannover Medical School [Hannover] (MHH), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Yong Loo Lin School of Medicine [Singapore], Hospital del Niño Jesus, San Miguel de Tucumán, Bezmiâlem Vakıf Üniversitesi, McGill University = Université McGill [Montréal, Canada], Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris], University of North Carolina System (UNC), Garvan Institute of medical research, The University of Sydney, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], East China Normal University [Shangaï] (ECNU), Sidra Medicine [Doha, Qatar], 'Juan Pedro Garrahan' National Hospital of Pediatrics, Buenos Aires, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Cochin [AP-HP], Hopital Saint-Louis [AP-HP] (AP-HP), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Hôpital Ambroise Paré [AP-HP], Université de Montpellier (UM), Howard Hughes Medical Institute (HHMI), The Laboratory of Human Genetics of Infectious Diseases is supported in part by grants from Inserm, Paris Cité University, the St. Giles Foundation, The Rockefeller University, the Center for Clinical and Translational Science (UL1TR001866), the National Center for Research Resources and the National Center for Advancing Sciences, the National Institutes of Health (NIH), (R01AI095983, R01AI088364, R01AI163029, and U19AI162568), the National Institute of Allergy and Infectious Diseases, 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 ANRS Nord-Sud (ANRS-COV05), ANRS (ECTZ170784-ANRS0073), GENVIR (ANR-20-CE93-003), GENMSMD (ANR-16-CE17-0005-01), AABIFNCOV (ANR-20-CO11-0001), GenMIS-C (ANR-21-COVR-0039), SUNLIVE (ANR-19-CE15-0012-01), MAFMACRO (ANR-22-CE92-0008) grants, Ecos-NORD (ECOS N°C19S01), the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JPB Foundation, the European Union’s Horizon 2020 research and innovation program (824110, EASI-Genomics), the Square Foundation, Grandir–Fonds de solidarité pour l’Enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), and REACTing-INSERM. The Laboratory of Virology and Infectious Disease was supported in part by the NIH (R01AI091707-10 to C.M.R.). J.L.P. was supported by the Francois Wallace Monahan Postdoctoral Fellowship at The Rockefeller University and the European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018). N. Marr was supported by Sidra Medicine and the Qatar National Research Fund (NPRP9-251-3-045). The Yale Center for Mendelian Genomics (UM1HG006504) was funded by the National Human Genome Research Institute, the Yale GSP Coordinating Center (U24 HG008956), and the Yale High-Performance Computing Center (S10OD018521). This research was partly supported by Calcul Québec, Compute Canada Canadian Institutes of Health Research (CIHR) Project Grant to D. Langlais. (#168959) and a CIHR Foundation Grant (to P.G.). D. Langlais was also supported by an FRQS Chercheur-Boursier Junior 1 Award and the Calgary Foundation for Innovation John R. Evans Leaders Fund. P.G. is supported by a Distinguished James McGill Professorship award from McGill University. S.M.L is supported by the NIH: R01-AI103083 and R01-AI150095. J.R. was supported by poste d’accueil Inserm'. J.R., P.B., and T.L.V were supported by the MD-PhD program of the Imagine Institute by the Bettencourt Schueller Foundation. N.L received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (852178 grant), German Research Foundation,(DFG) under Germany’s Excellence Strategy—EXC 2155—project number 390874280 and REBIRTH 'Förderung aus Mitteln des Niedersächsischen Vorab'. A.-L.N. was supported by the international PhD program of the Imagine Institute, by the Bettencourt Schueller Foundation and the fin de thèse FRM program (FDT202204015102). R.Y. was supported by the Sackler Center for Biomedicine and Nutrition, the Shapiro-Silverberg Fund for the Advancement of Translational Research at the Center for Clinical and Translational Science of the Rockefeller University, and the Research Grant Program from the Immune Deficiency Foundation. D. Lee. was supported by FRMfellowship (FDM202006011282). C.S.M was supported by an Early-Mid Career Research Fellowship from the Department of Health of the New South Wales Government of Australia. S.G.T was supported by an NHMRC Leadership 3 Investigator Grant (1176665) and NHMRC grant (1113904). M.O. was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology, the Honjo International Scholarship Foundation, and the New York Hideyo Noguchi Memorial Society. This work was supported by grants from ANRS (ECTZ118797), Sidaction (20-2-AEQ-12822-2), and FRM (EQU202103012774) to N. Manel, and H.I. was supported by fellowships from Institut Curie, Seneca Foundation (20941/PD/18), and ANRS (ECTZ171453). A.N.S. was supported in part by the European Union’s Horizon 2020 research and innovation program (789645 Marie Sklodowska-Curie grant). Y.-H.C. is supported by an A∗STAR International Fellowship. J. Bohlen is an EMBO postdoctoral fellow. We thank the NIH Tetramer Core Facility (NTCF) for providing the 5-OP-RU-loaded MR1 tetramer, which was developed jointly with Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), 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), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), ANR-19-CE15-0012,SUNLIVE,Variabilité structurale et fonctionnelle des lipides complexes chez les mycobactéries : de l'assemblage de la paroi à la physiopathologie et virulence(2019), ANR-22-CE92-0008,MAFMACRO,Genetic predisposition and the role of myeloid cells in the susceptibility to mycobacterial infection(2022), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), and TÜREL, ÖZDEN

Subjects
inborn errors of immunity, Temel Bilimler, [SDV]Life Sciences [q-bio], interferon-stimulated gene, Life Sciences, Molecular Biology and Genetics, Genel Biyokimya, Genetik ve Moleküler Biyoloji, IRF1, General Biochemistry, Genetics and Molecular Biology, Mycobacterium, macrophages, interferon-γ, Yaşam Bilimleri, viruses, Cytogenetic, Natural Sciences, Moleküler Biyoloji ve Genetik, Sitogenetik
Abstract

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity.

Published
2023

8. Impaired thymic AIRE expression underlies autoantibodies against type I IFNs in humans with inborn errors of the alternative NF-kB pathway

Author

Tom Le Voyer, Adrian Gervais, Jérémie Rosain, Audrey Parent, Axel Cederholm, Darawan Rinchai, Lucy Bizien, Gonca Hancioglu, Quentin Philippot, Mame Sokhna Gueye, Majistor Raj Luxman, Maglorius Renkilaraj, Masato Ogishi, Camille Soudée, Mélanie Migaud, Flore Rozenberg, Mana Momenilandi, Quentin Riller, Luisa Imberti, Ottavia Delmonte, Gabriele Müller, Bärbel Keller, Julio Orrego, William Alexander Gallego, Tamar Rubin, Melike Emiroglu, Nima Parvaneh, Daniel Eriksson, Maribel Aranda-Guillen, David I Berrios, Linda Vong, Connie H Katelaris, Peter Mustillo, Johannes Rädler, Jonathan Bohlen, Jale Bengi Celik, Camila Astudillo, Sarah Winter, Audrey Guichard, Vivien Béziat, Jacinta Bustamante, Qiang Pan-Hammarström, Yu Zhang, Lindsey B Rosen, Steve M Holland, Heather Kenney, Kaan Boztuğ, Nizar Mahlaoui, Sylvain Latour, Roshini Abraham, Vassilios Lougaris, Fabian Hauck, Anna Sediva, Faranaz Atschekzei, M Cecilia Poli, Mary A Slatter, Boaz Palterer, Michael D Keller, Alberto Pinzon-Charry, Anna Sullivan, Luke Droney, Daniel Suan, Nathalie Aladjidi, Miguel Hie, Estibaliz Lazaro, Jose Franco, Sevgi Keles, Marion Malphette, Marlene Pasquet, Maria Elena Maccari, Andrea Meinhardt, Aydan Ikinciogullari, Mohammad Shahrooei, Fatih Celmeli, Patrick Frosk, Christopher C Goodnow, Paul E Gray, Alexandre Belot, Hye Sun Kuehn, Sergio D Rosenzweig, Francesco Licciardi, Amélie Servettaz, Vincent Barlogis, Guillaume Le Guenno, Vera-Maria Herrmann, Taco Kuijpers, Grégoire Ducoux, Françoise Sarrot-Reynauld, Catharina Schuetz, Charlotte Cunningham-Rundles, Frédéric Rieux-Laucat, Stuart G Tangye, Cristina Sobacchi, Rainer Doffinger, Klaus Warnatz, Bodo Grimbacher, Claire Fieschi, Laureline Berteloot, Vanessa Bryant, Sophie Trouillet Assant, Luigi D Notarangelo, Helen Su, Benedicte Neven, Laurent Abel, Qian Zhang, Bertrand Boisson, Aurélie Cobat, Emmanuelle Jouanguy, Olle Kampe, Paul Bastard, Chaim Roifman, Nils Landegren, Mark S Anderson, Jean-Laurent Casanova, and Anne Puel

Abstract

Patients with inborn errors of the alternative NF-κB pathway have low thymic AIRE expression, leading to the development of auto-Abs neutralizing type I IFNs, and severe viral diseases.

Published
2023

9. CARD9 Expression Pattern, Gene Dosage, and Immunodeficiency Phenotype Revisited

Author

Vasileios Oikonomou, Sophia Samir, Jennifer Stoddard, Daisuke Yamanaka, Anne Puel, Julie E. Niemela, Michail S. Lionakis, Mary Garofalo, Mélanie Migaud, Shubham Goel, Hye Sun Kuehn, Thomas A. Fleisher, Javier Chinen, and Sergio D. Rosenzweig

Subjects
Immunology, Gene Dosage, T cells, MAPK signaling, Biology, Gene dosage, Article, BCL10, Mice, Exon, inflammatory bowel disease, CBM complex, medicine, Animals, Humans, Th, Immunology and Allergy, Allele, Gene, Alleles, Immunodeficiency, Candida, human immunology, B cells, fungal infection, MALT1, Candidiasis, Chronic Mucocutaneous, Homozygote, medicine.disease, Molecular biology, Null allele, B cells, Th, CARD Signaling Adaptor Proteins, Phenotype, TRIM62, Primary immunodeficiency, mouse immunology, Haploinsufficiency, CARD9
Abstract

BACKGROUND: CARD9 deficiency is an autosomal recessive primary immunodeficiency underlying increased susceptibility to fungal infection primarily presenting as invasive CNS Candida and/or cutaneous/invasive dermatophyte infections. More recently, a rare heterozygous dominant negative CARD9 variant c.1434 + 1G > C was reported to be protective from inflammatory bowel disease. OBJECTIVE: We studied two siblings carrying homozygous CARD9 variants (c.1434 + 1G > C) and born to heterozygous asymptomatic parents. One sibling was asymptomatic and the other presented with candida esophagitis, upper respiratory infections, hypogammaglobulinemia, and low class-switched memory B cells. METHODS AND RESULTS: The CARD9 c.1434 + 1G > C variant generated two mutant transcripts confirmed by mRNA and protein expression: an out-of-frame c.1358–1434 deletion/ ~ 55 kDa protein (CARD9Δex.11) and an in-frame c.1417–1434 deletion/ ~ 61 kDa protein (CARD9Δ18 nt.). Neither transcript was able to form a complete/functional CBM complex, which includes TRIM62. Based on the index patient’s CVID-like phenotype, CARD9 expression was tested and detected in lymphocytes and monocytes from humans and mice. The functional impact of different CARD9 mutations and gene dosage conditions was evaluated in heterozygous and homozygous c.1434 + 1 G > C members of the index family, and in WT (two WT alleles), haploinsufficiency (one WT, one null allele), and null (two null alleles) individuals. CARD9 gene dosage impacted lymphocyte and monocyte functions including cytokine generation, MAPK activation, T-helper commitment, transcription, plasmablast differentiation, and immunoglobulin production in a differential manner. CONCLUSIONS: CARD9 exon 11 integrity is critical to CBM complex function. CARD9 is expressed and affects particular T and B cell functions in a gene dosage-dependent manner, which in turn may contribute to the phenotype of CARD9 deficiency.

Published
2021

10. Inherited human ZNF341 deficiency

Author

Vivien Béziat, Claire Fieschi, Mana Momenilandi, Mélanie Migaud, Brahim Belaid, Reda Djidjik, and Anne Puel

Subjects
Immunology, Immunology and Allergy
Published
2023

11. Anti-GM-CSF neutralizing autoantibodies in Colombian patients with disseminated cryptococcosis

Author

Carlos A. Arango-Franco, Mélanie Migaud, Isabel Cristina Ramírez-Sánchez, Karen Arango, Marcela Moncada-Vélez, Julián Rojas, Adrian Gervais, Santiago Patiño Giraldo, Lizeth J Perez-Zapata, Jesús A. Álvarez Álvarez, Julio César Orrego, Gustavo Roncancio Villamil, Stéphanie Boisson-Dupuis, Emmanuelle Jouanguy, Laurent Abel, Jean-Laurent Casanova, Jacinta Bustamante, Andrés A. Arias, José Luis Franco, and Anne Puel

Subjects
Immunology, Immunology and Allergy
Abstract

Abstract Background Cryptococcosis is a potentially life-threatening fungal disease caused by encapsulated yeasts of the genus Cryptococcus, mostly C. neoformans or C. gattii. Cryptococcal meningitis is the most frequent clinical manifestation in humans. Neutralizing autoantibodies (auto-Abs) against granulocyte–macrophage colony-stimulating factor (GM-CSF) have recently been discovered in otherwise healthy adult patients with cryptococcal meningitis, mostly caused by C. gattii. We hypothesized that three Colombian patients with cryptococcal meningitis caused by C. neoformans in two of them would carry high plasma levels of neutralizing auto-Abs against GM-CSF. Methods We reviewed medical and laboratory records, performed immunological evaluations, and tested for anti-cytokine auto-Abs three previously healthy HIV-negative adults with disseminated cryptococcosis. Results Peripheral blood leukocyte subset levels and serum immunoglobulin concentrations were within the normal ranges. We detected high levels of neutralizing auto-Abs against GM-CSF in the plasma of all three patients. Conclusions We report three Colombian patients with disseminated cryptococcosis associated with neutralizing auto-Abs against GM-CSF. Further studies should evaluate the genetic contribution to anti-GM-CSF autoantibody production and the role of the GM-CSF signaling pathway in the immune response to Cryptococcus spp.

Published
2022

12. Autoimmune polyendocrine syndrome type 1 (APECED) in the Indian population: case report and review of a series of 45 patients

Author

R Gulati, N Gallo, Alessandra Fierabracci, M Kumar, A Arena, Anne Puel, Corrado Betterle, Mélanie Migaud, Vir Singh Negi, F Toto, and K G Chengappa

Subjects
medicine.medical_specialty, animal structures, biology, business.industry, Endocrinology, Diabetes and Metabolism, Autoantibody, 030209 endocrinology & metabolism, Retrospective cohort study, Disease, Autoimmune regulator, medicine.disease, Dermatology, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Autoimmune polyendocrine syndrome type 1, Hypoparathyroidism, 030220 oncology & carcinogenesis, biology.protein, Medicine, Antibody, Chronic mucocutaneous candidiasis, business
Abstract

Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) or autoimmune polyglandular syndrome type 1 (APS-1) is a rare autosomal recessive genetic disease due to mutations in the AIRE (AutoImmune REgulator) gene. The clinical diagnosis is classically based on the presence of at least two of the three main components: chronic mucocutaneous candidiasis, hypoparathyroidism and primary adrenal insufficiency. Patients often suffer from other endocrine or non-endocrine autoimmune conditions throughout life. APECED etiopathogenesis is mediated by T lymphocytes. Autoantibodies against proteins of the affected organs are found in the serum of APECED patients as well as neutralizing antibodies against cytokines. We report here the clinical and genetic characteristics of 45 Indian APECED patients in comparison to Finnish, Sardinian, Turkish and North/South American cohorts from their published results. We also report a new case of APECED of Indian origin, a 2-year old child suffering from chronic mucocutaneous candidiasis since the age of 8 months, with confirmatory AIRE homozygous mutation c.274C > T (p.R92W). With the inherent limitations of a retrospective study, analysis of Indian APECED patients suggested that compared to classic criteria, application of Ferre/Lionakis criteria validated in North/South American patients could help in earlier diagnosis in 3 of 8 (37.5%) patients for whom adequate information for evaluation was available.

Published
2020

13. Three Copies of Four Interferon Receptor Genes Underlie a Mild Type I Interferonopathy in Down Syndrome

Author

Anne Sophie Rebillat, Marie Goulet, Darawan Rinchai, Tanwir Habib, Vincent Bondet, Martine Conte, Anne Puel, Clotilde Mircher, Xiao-Fei Kong, Luyan Liu, Puthen V. Jithesh, Arnold Munnich, Laurent Abel, Damien Chaussabel, Stanislas Lyonnet, Jean-Laurent Casanova, Mohammed Elanbari, Emilie Nonnotte, Jacinta Bustamante, Mélanie Migaud, Nicolas Gürtler, Lisa Worley, Stuart G. Tangye, Aimé Ravel, Cindy S. Ma, Darragh Duffy, Stéphanie Boisson-Dupuis, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Columbia University Irving Medical Center (CUIMC), Garvan Institute of Medical Research [Darlinghurst, Australia], St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW), Sidra Medical and Research Center [Doha, Qatar], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Jérôme Lejeune, University Hospital Basel [Basel], 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 de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Embryology and genetics of human malformation (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Fédération de Génétique, 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), Service d'immuno-hématologie pédiatrique [CHU Necker], X-F.K was supported by the Jerome Lejeune Foundation and Alexander’s Angels Inc. X-F.K is currently a gastroenterology fellow in CUIMC supported by NIH grant T32 DK083256. The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the St. Giles Foundation, the Jeffrey Modell Foundation, The Rockefeller University Center for Clinical and Translational Science grant number UL1TR001866 from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (grants 5R01AI127564 and 5R37AI095983), 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), ANR-IFNGPHOX (ANR-13-ISV3-0001-01) and ANR-GENMSMD (ANR-16-CE17-0005-01), LTh-MSMD-CMCD (ANR-18-CE93-0008-01), HGDIFD (ANR-14-CE15-0006-01), Institut National de la Santé et de la Recherche Médicale (INSERM), University of Paris, and The Rockefeller University and the Helmut Horten Foundation., We thank Yanick Crow, Barry Coller, Charlie Rice, James Krueger, and Timothy Wang for helpful discussions and critical reading. We thank Y. Nemirovskaya, T. Kochetkov, M. Romanick, L. Amar, C. Patissier, C. Desvallées, M. Woollett, A. Gall, and J. Gonzalez for technical and secretarial assistance and all members of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), 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), ANR-18-CE93-0008,LTh-MSMD-CMCD,Différenciation des lymphocytes T-helper (Th) dans les défauts génétiques de l'immunité contre Mycobacterium et/ou Candida species.(2018), ANR-14-CE15-0006,HGDIFD,Déterminisme génétique des infections fongiques invasives chez l'homme(2014), Garvan Institute of medical research, Institut Pasteur [Paris] (IP)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Embryology and genetics of human malformation, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)

Subjects
Male, 0301 basic medicine, Down syndrome, Gene Dosage, Monocytes, JAK-STAT, 0302 clinical medicine, T-Lymphocyte Subsets, Interferon, Immunology and Allergy, Medicine, STAT1, Child, Receptors, Interferon, B-Lymphocytes, biology, interferonopathy, Chromosome Mapping, JAK-STAT signaling pathway, Middle Aged, Penetrance, interferon receptors, 3. Good health, STAT1 Transcription Factor, Child, Preschool, Interferon Type I, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Disease Susceptibility, medicine.drug, Adult, Adolescent, Immunology, Article, Young Adult, 03 medical and health sciences, Downregulation and upregulation, Humans, Genetic Predisposition to Disease, business.industry, Gene Expression Profiling, medicine.disease, 030104 developmental biology, Genetic Loci, biology.protein, Transcriptome, business, Chromosome 21, CD8, 030215 immunology
Abstract

International audience; Down syndrome (DS) is characterized by the occurrence of three copies of human chromosome 21 (HSA21). HSA21 contains a cluster of four interferon receptor (IFN-R) genes: IFNAR1, IFNAR2, IFNGR2, and IL10RB. DS patients often develop mucocutaneous infections and autoimmune diseases, mimicking patients with heterozygous gain-of-function (GOF) STAT1 mutations, which enhance cellular responses to three types of interferon (IFN). A gene dosage effect at these four loci may contribute to the infectious and autoimmune manifestations observed in individuals with DS. We report high levels of IFN-αR1, IFN-αR2, and IFN-γR2 expression on the surface of monocytes and EBV-transformed-B (EBV-B) cells from studying 45 DS patients. Total and phosphorylated STAT1 (STAT1 and pSTAT1) levels were constitutively high in unstimulated and IFN-α- and IFN-γ-stimulated monocytes from DS patients but lower than those in patients with GOF STAT1 mutations. Following stimulation with IFN-α or -γ, but not with IL-6 or IL-21, pSTAT1 and IFN-γ activation factor (GAF) DNA-binding activities were significantly higher in the EBV-B cells of DS patients than in controls. These responses resemble the dysregulated responses observed in patients with STAT1 GOF mutations. Concentrations of plasma type I IFNs were high in 12% of the DS patients tested (1.8% in the healthy controls). Levels of type I IFNs, IFN-Rs, and STAT1 were similar in DS patients with and without recurrent skin infections. We performed a genome-wide transcriptomic analysis based on principal component analysis and interferon modules on circulating monocytes. We found that DS monocytes had levels of both IFN-α- and IFN-γ-inducible ISGs intermediate to those of monocytes from healthy controls and from patients with GOF STAT1 mutations. Unlike patients with GOF STAT1 mutations, patients with DS had normal circulating Th17 counts and a high proportion of terminally differentiated CD8+ T cells with low levels of STAT1 expression. We conclude a mild interferonopathy in Down syndrome leads to an incomplete penetrance at both cellular and clinical level, which is not correlate with recurrent skin bacterial or fungal infections. The constitutive upregulation of type I and type II IFN-R, at least in monocytes of DS patients, may contribute to the autoimmune diseases observed in these individuals.

Published
2020

14. Inherited CARD9 Deficiency in a Patient with Both Exophiala spinifera and Aspergillus nomius Severe Infections

Author

Laura Perez, Fernando Messina, Matías Oleastro, Jean-Laurent Casanova, Alicia Arechavala, Ricardo Negroni, Jacinta Bustamante, Mélanie Migaud, Gabriela Santiso, and Anne Puel

Subjects
0301 basic medicine, medicine.medical_specialty, Posaconazole, Immunology, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Medical microbiology, Immunity, Exophiala, Humans, Immunology and Allergy, Medicine, Pneumonectomy, Cells, Cultured, Whole blood, Aspergillus, biology, Interleukin-6, business.industry, Candidiasis, Chronic Mucocutaneous, Interleukin, Middle Aged, biology.organism_classification, medicine.disease, Pedigree, CARD Signaling Adaptor Proteins, Phaeohyphomycosis, 030104 developmental biology, chemistry, Mutation, Female, Pulmonary Aspergillosis, Caspofungin, business, 030215 immunology, medicine.drug
Abstract

PURPOSE. Caspase-associated recruitment domain-9 (CARD9) deficiency is an inborn error of immunity that typically predisposes otherwise healthy patients to single fungal infections and the occurrence of multiple invasive fungal infections is rare. It has been described as the first known condition that predisposes to extrapulmonary Aspergillus infection with preserved lungs. We present a patient that expands the clinical variability of CARD9 deficiency. MATERIALS AND METHODS. Genetic analysis was performed by Sanger sequencing. Neutrophils and mononuclear phagocyte response to fungal stimulation were evaluated through luminol-enhanced chemiluminescence and whole blood production of the proinflammatory mediator IL-6 respectively. RESULTS. We report a 56-year-old Argentinean woman, whose invasive Exophiala spinifera infection at the age of 32 years was unexplained and reported in year 2004. At the age of 49 years, she presented with chronic pulmonary disease due to Aspergillus nomius. After partial improvement following treatment with caspofungin and posaconazole, right pulmonary bilobectomy was performed. Despite administration of multiple courses of antifungals, sustained clinical remission could not be achieved. We recently found that the patient’s blood showed an impaired production of interleukin (IL)-6 when stimulated with zymosan. We also found that she is homozygous for a previously reported CARD9 loss-of-function mutation (Q289*). CONCLUSIONS. This is the first report of a patient with inherited CARD9 deficiency and chronic invasive pulmonary aspergillosis (IPA) due to A. nomius. Inherited CARD9 deficiency should be considered in otherwise healthy children and adults with one or more invasive fungal diseases.

Published
2020

15. Candidose cutanéo-muqueuse chronique avec mutation gain-de-fonction du gène STAT1 associée à des infections herpétiques et à mycobactérie

Author

Anne Puel, Aziz Bousfiha, Fatima Ailal, Ibtihal Benhsaien, F.Z. El Fatoiki, Mélanie Migaud, Bouchra Baghad, and Soumiya Chiheb

Subjects
Gynecology, medicine.medical_specialty, biology, business.industry, Dermatology, medicine.disease, Immunologic Deficiency Syndromes, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Herpes virus, medicine, biology.protein, Gain of function mutation, STAT1, Chronic mucocutaneous candidiasis, business
Abstract

Resume Introduction La candidose cutaneo-muqueuse chronique (CCMC) est caracterisee par une susceptibilite a developper une infection chronique ou recidivante a des levures du genre Candida spp., atteignant la peau, les ongles et les muqueuses. Nous decrivons un patient presentant une CCMC et porteur d’une mutation heterozygote gain-de-fonction du STAT1. Observation Un garcon de 5 ans sans notion de consanguinite presentait depuis l’âge de 8 mois des episodes recurrents de muguet buccal, de candidose ungueale chronique et de ginvivo-stomatite herpetique. Il presentait egalement une adenite a mycobacterie, secondaire a la vaccination par le BCG et une rosacee atypique. L’etude genetique objectivait la mutation gain-de-fonction du gene STAT1. Discussion Le diagnostic de CCMC a ete retenu malgre un tableau clinique peu specifique, en raison de la presence d’une mutation gain-de-fonction du gene STAT1. Cette mutation affecte la production d’IL-17, cytokine cle dans la defense muco-cutanee contre les candidoses. L’association a une adenite a mycobacterie reste rare et mal elucidee. La presence de la rosacee atypique dans ce contexte est evocatrice de cette entite. Le traitement antifongique et la prevention des complications sont les elements cles pour reduire la morbidite et la mortalite liees a cette affection. Conclusion La CCMC due a la mutation gain-de-fonction du STAT1 se caracterise par un large spectre clinique et doit etre suspectee devant toute infection fongique chronique ou recidivante associee ou non a d’autres infections.

Published
2020

16. Impaired respiratory burst contributes to infections in PKC-deficient patients

Author

Paul A. Brogan, Alexandre Belot, Tom Le Voyer, Jacinta Bustamante, Mélanie Migaud, Marion Roderick, Gulbu Uzel, Figen Dogu, Jean-Laurent Casanova, Anna Lena Neehus, Jamel El-Benna, Ahmet Ozen, Laurent Abel, Erdal Ince, Mohammad Shahrooei, Engin Altundag, Elif Karakoc-Aydiner, Gonca Hancioglu, Anne Puel, Aydan Ikinciogullari, Manon Roynard, Kunihiko Moriya, Kaan Boztug, Karim Dorgham, Romain Lévy, Kathrin Haake, Alisan Yildiran, Sule Haskologlu, Nico Lachmann, Safa Baris, Guy Gorochov, Nima Parvaneh, Alejandro Nieto-Patlán, Hassan Abolhassani, Ayca Kiykim, Neehus, Anna-Lena, Moriya, Kunihiko, Nieto-Patlan, Alejandro, Le Voyer, Tom, Levy, Romain, Ozen, Ahmet, Karakoc-Aydiner, Elif, Baris, Safa, Yildiran, Alisan, Altundag, Engin, Roynard, Manon, Haake, Kathrin, Migaud, Melanie, Dorgham, Karim, Gorochov, Guy, Abel, Laurent, Lachmann, Nico, Dogu, Figen, Haskologlu, Sule, Ince, Erdal, El-Benna, Jamel, Uzel, Gulbu, Kiykim, Ayca, Boztug, Kaan, Roderick, Marion R., Shahrooei, Mohammad, Brogan, Paul A., Abolhassani, Hassan, Hancioglu, Gonca, Parvaneh, Nima, Belot, Alexandre, Ikinciogullari, Aydan, Casanova, Jean-Laurent, Puel, Anne, Bustamante, Jacinta, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)

Subjects
Male, 0301 basic medicine, Nadph Oxidase, Phagocyte, CELL-SURVIVAL, P47(Phox) Phosphorylation, medicine.disease_cause, Autoimmunity, 0302 clinical medicine, Chronic granulomatous disease, NADPH oxidase complex, Lymphoproliferative Syndrome, NADPH OXIDASE, Protein Isoforms, Immunology and Allergy, CRYSTAL-STRUCTURE, Phosphorylation, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Respiratory Burst, chemistry.chemical_classification, B-Lymphocytes, TYROSINE PHOSPHORYLATION, NADPH oxidase, Chronic Granulomatous-Disease, biology, Pedigree, 3. Good health, Respiratory burst, Cell-Survival, Protein Kinase C-delta, CHRONIC GRANULOMATOUS-DISEASE, medicine.anatomical_structure, LYMPHOPROLIFERATIVE SYNDROME, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Tyrosine Phosphorylation, Immunology, Infections, 03 medical and health sciences, Phagocytosis, P47(PHOX) PHOSPHORYLATION, medicine, THREONINE 154, Humans, PROTEIN-KINASE-C, Protein-Kinase-C, Crystal-Structure, Reactive oxygen species, business.industry, Infant, NADPH Oxidases, Threonine 154, Neutrophil extracellular traps, medicine.disease, Systemic-Lupus-Erythematosus, 030104 developmental biology, chemistry, biology.protein, business, 030215 immunology
Abstract

Patients with autosomal recessive protein kinase C delta (PKC delta) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKC delta-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40(phox) normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKC delta in activation of the NADPH oxidase complex. Our findings thus show that patients with PKC delta deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype. Yale Center for Mendelian Genomics - National Human Genome Research Institute [UM1HG006504]; National Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [5R01AI089970, 5R37AI095983, R01AI127564-01]; National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR); National Center for Advancing Translational Sciences of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Advancing Translational Sciences (NCATS) [8UL1TR001866]; Rockefeller University; St. Giles Foundation; INSERMInstitut National de la Sante et de la Recherche Medicale (Inserm)European Commission; University of Paris; French Foundation for Medical ResearchFondation pour la Recherche Medicale [EQU201903007798]; Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]; SCOR Corporate Foundation for Science; French National Research Agency (ANR) under the Investments for the future programFrench National Research Agency (ANR) [ANR-10-IAHU-01]; ANR-IFNPHOX [ANR-13-ISV3-0001-01]; ANR-GENMSMDFrench National Research Agency (ANR) [ANR-16-CE17-0005-01]; ANR-GENCMCD [ANR-11-BSV3-005-01]; ANR-HGDIFDFrench National Research Agency (ANR) [ANR-14-CE15-0006-01]; Bettencourt Schueller Foundation; International PhD program of the Imagine Institute; Japanese Foundation; EURO-CMC project [ANR-14-RARE-0005-02]; Societe Nationale Francaise de Medecine Interne (Bourse Marcel Simon); INSERM PhD program for medical doctors (poste d'accueil INSERM); Fulbright grant (Franco-American commission); MD-PhD program of Imagine Institute; Consejo Nacional de Ciencia y Tecnologa National PhD Fellowship Program; National Institute for Health Research Biomedical Research CentreNational Institute for Health Research (NIHR); Great Ormond Street Hospital Charity; Deutsche Forschungsgemeinschaft under Germany's Excellence StrategyGerman Research Foundation (DFG) [EXC 2155, 390874280]; REBIRTH Center for Translational Regenerative Medicine through the State of Lower Saxony [MWK: ZN3440] This paper is dedicated to the memory of Prof. Asghar Agha-mohammadi, who passed away in November 2020, and made immense contributions to the understanding and treatment of primary immunodeficiencies. We thank all patients, their relatives, and the treatment teams for their cooperation in this study. We thank all the members of the Laboratory of Human Genetics of Infectious Diseases for helpful discussions. We also thank Christine Rivalain, Cecile Pa-tissier, Lazaro Lorenzo-Diaz, Dominick Papandrea, Dana Liu, and Yelena Nemirovskaya for administrative assistance and Gaspard Kerner for statistical advice. We thank the Necker Institute Imaging Facility for technical advice. The graphical abstract was created with BioRender.com under subscription. This research was supported by the Yale Center for Mendelian Genomics funded by the National Human Genome Research Insti-tute (UM1HG006504) . The Howard Hughes Medical Institute lab-oratory was funded in part by the National Institute of Allergy and Infectious Diseases (grants 5R01AI089970, 5R37AI095983, and R01AI127564-01) , the National Center for Research Resources, and the National Center for Advancing Translational Sciences of the National Institutes of Health (grant 8UL1TR001866 for J-L. Casa-nova) , the Rockefeller University, the St. Giles Foundation, INSERM, the University of Paris, the French Foundation for MedicalResearch (EQU201903007798) , the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) , the SCOR Corporate Foundation for Science, and the French National Research Agency (ANR) under the Investments for the future program (grant ANR-10-IAHU-01) , ANR-IFNPHOX (grant ANR-13-ISV3-0001-01 for J. Bustamante) , ANR-GENMSMD (grant ANR-16-CE17-0005-01 for J. Bustamante) , ANR-GENCMCD (grant ANR-11-BSV3-005-01 for A. Puel) , and ANR-HGDIFD (grant ANR-14-CE15-0006-01 for J. Bustamante) . A-L. Neehus was sup-ported by the Bettencourt Schueller Foundation and the Interna-tional PhD program of the Imagine Institute, K. Moriya by a Japanese Foundation for Pediatric Research fellowship grant and EURO-CMC project (grant ANR-14-RARE-0005-02 for J. Bustamante) , R. Levy by the Societe Nationale Francaise de Medecine Interne (Bourse Marcel Simon) , the INSERM PhD program for medical doctors (poste d'accueil INSERM) , and the Fulbright grant (Franco-American commission) , T. Le Voyer by the Bettencourt Schueller Foundation and the MD-PhD program of Imagine Institute, and A. Nieto-Patlan by the Consejo Nacional de Ciencia y Tecnologa Na-tional PhD Fellowship Program. All research at the Great Ormond Street Hospital National Health Service Foundation Trust is sup-ported by the National Institute for Health Research Biomedical Research Centre. P.A. Brogan also acknowledges support from the Great Ormond Street Hospital Charity. N. Lachmann acknowledges support from the Deutsche Forschungsgemeinschaft under Ger-many's Excellence Strategy-EXC 2155-project number 390874280 and the REBIRTH Center for Translational Regenerative Medicine funded through the State of Lower Saxony (MWK: ZN3440) . Author contributions: A-L. Neehus, J-L. Casanova, A. Puel, and J. Bustamante conceived and designed the study. A-L. Neehus, K. Moriya, T. Le Voyer, A. Nieto-Patlan, R. Levy, M. Roynard, K. Haake, M. Migaud, and K. Dorgham performed the experiments. A. ozen, E. Karakoc-Aydiner, S. Baris, A. Yildiran, E. Altundag, F. Dogu, S. Has-kologlu, E. Ince, G. Uzel, A. Kiykim, K. Boztug, M.R. Roderick, M. Shahrooei, P.A. Brogan, H. Abolhassani, G. Hancioglu, N. Parvaneh, A.; Belot, and A. Ikinciogullari were the treating physicians respon-sible for clinical diagnosis, deep phenotyping, sample collection, and patient follow-up. G. Gorochov, L. Abel, N. Lachmann, J. El-Benna, and A. Belot provided conceptual advice. A-L. Neehus, J-L. Casanova, A. Puel, and J. Bustamante analyzed the results and wrote the man-uscript. All authors revised the manuscript and approved the final manuscript as submitted. Disclosures: P.A. Brogan reported personal fees from Sobi, No-vartis, Roche, and GSK, and grants from Sobi outside the sub-mitted work. No other disclosures were reported.

Published
2021

17. 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

18. Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents

Author

Rui Yang, Rubén Martínez-Barricarte, Janet Markle, Franck Rapaport, Stuart G. Tangye, Mathieu Bourgey, David Langlais, Anne Puel, Aziz Belkadi, Masato Ogishi, Simon J. Pelham, Jean-Laurent Casanova, Bertrand Boisson, Cindy S. Ma, Vivien Béziat, Eman Abou Moussa, Jérémie Rosain, Laurent Abel, Tomi Lazarov, Serkan Belkaya, Fatima Ailal, Ibtihal Benhsaien, Coralie Briand, Alessandro Plebani, Romain Lévy, Frederic Geissmann, Caroline Deswarte, Andrea Guennoun, Luis R. Saraiva, Tanwir Habib, Mehdi Emam, Vassilios Lougaris, Philippe Gros, Yu Jerry Zhou, Ahmed Aziz Bousfiha, Geetha Rao, Kathryn Payne, Sylvain Breton, Ai Ing Lim, Kang Liu, Kunihiko Moriya, Danielle T. Avery, Bénédicte Neven, Nico Marr, Jacinta Bustamante, Mélanie Migaud, and James P. Di Santo

Subjects
Myeloid, Primary Immunodeficiency Diseases, Naive B cell, Adaptive Immunity, Biology, Lymphocyte Activation, Consanguinity, Immunity, medicine, Humans, Protein Isoforms, Myeloid Cells, Lymphocytes, Child, B cell, CD86, Host Microbial Interactions, Homozygote, Hematopoietic Stem Cell Transplantation, General Medicine, Acquired immune system, Immunity, Innate, Proto-Oncogene Proteins c-rel, medicine.anatomical_structure, Mutation, Immunology, Female, Genes, rel, REL, CD8, Research Article
Abstract

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8(+) T cells, memory CD4(+) T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4(+) T cells. In naive CD4(+) T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient’s naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.

Published
2021

19. Pediatric Demodicosis Associated with Gain-of-Function Variant in STAT1 Presenting as Rosacea-Type Rash

Author

Ibtihal Benhsaien, Fatima Ailal, Bouchra Baghad, Ahmed Aziz Bousfiha, Fatima Zahra El Fatoiki, Mélanie Migaud, Soumiya Chiheb, and Anne Puel

Subjects
medicine.medical_specialty, business.industry, Immunology, MEDLINE, medicine.disease, Rash, Dermatology, Medical microbiology, Gain of function, Rosacea, medicine, Demodicosis, Immunology and Allergy, medicine.symptom, business
Published
2021

20. Autoantibodies neutralizing type I IFNs are present in

Author

Paul, Bastard, Adrian, Gervais, Tom, Le Voyer, Jérémie, Rosain, Quentin, Philippot, Jérémy, Manry, Eleftherios, Michailidis, Hans-Heinrich, Hoffmann, Shohei, Eto, Marina, Garcia-Prat, Lucy, Bizien, Alba, Parra-Martínez, Rui, Yang, Liis, Haljasmägi, Mélanie, Migaud, Karita, Särekannu, Julia, Maslovskaja, Nicolas, de Prost, Yacine, Tandjaoui-Lambiotte, Charles-Edouard, Luyt, Blanca, Amador-Borrero, Alexandre, Gaudet, Julien, Poissy, Pascal, Morel, Pascale, Richard, Fabrice, Cognasse, Jesus, Troya, Sophie, Trouillet-Assant, Alexandre, Belot, Kahina, Saker, Pierre, Garçon, Jacques G, Rivière, Jean-Christophe, Lagier, Stéphanie, Gentile, Lindsey B, Rosen, Elana, Shaw, Tomohiro, Morio, Junko, Tanaka, David, Dalmau, Pierre-Louis, Tharaux, Damien, Sene, Alain, Stepanian, Bruno, Megarbane, Vasiliki, Triantafyllia, Arnaud, Fekkar, James R, Heath, José Luis, Franco, Juan-Manuel, Anaya, Jordi, Solé-Violán, Luisa, Imberti, Andrea, Biondi, Paolo, Bonfanti, Riccardo, Castagnoli, Ottavia M, Delmonte, Yu, Zhang, Andrew L, Snow, Steven M, Holland, Catherine, Biggs, Marcela, Moncada-Vélez, Andrés Augusto, Arias, Lazaro, Lorenzo, Soraya, Boucherit, Boubacar, Coulibaly, Dany, Anglicheau, Anna M, Planas, Filomeen, Haerynck, Sotirija, Duvlis, Robert L, Nussbaum, Tayfun, Ozcelik, Sevgi, Keles, Ahmed A, Bousfiha, Jalila, El Bakkouri, Carolina, Ramirez-Santana, Stéphane, Paul, Qiang, Pan-Hammarström, Lennart, Hammarström, Annabelle, Dupont, Alina, Kurolap, Christine N, Metz, Alessandro, Aiuti, Giorgio, Casari, Vito, Lampasona, Fabio, Ciceri, Lucila A, Barreiros, Elena, Dominguez-Garrido, Mateus, Vidigal, Mayana, Zatz, Diederik, van de Beek, Sabina, Sahanic, Ivan, Tancevski, Yurii, Stepanovskyy, Oksana, Boyarchuk, Yoko, Nukui, Miyuki, Tsumura, Loreto, Vidaur, Stuart G, Tangye, Sonia, Burrel, Darragh, Duffy, Lluis, Quintana-Murci, Adam, Klocperk, Nelli Y, Kann, Anna, Shcherbina, Yu-Lung, Lau, Daniel, Leung, Matthieu, Coulongeat, Julien, Marlet, Rutger, Koning, Luis Felipe, Reyes, Angélique, Chauvineau-Grenier, Fabienne, Venet, Guillaume, Monneret, Michel C, Nussenzweig, Romain, Arrestier, Idris, Boudhabhay, Hagit, Baris-Feldman, David, Hagin, Joost, Wauters, Isabelle, Meyts, Adam H, Dyer, Sean P, Kennelly, Nollaig M, Bourke, Rabih, Halwani, Narjes Saheb, Sharif-Askari, Karim, Dorgham, Jérome, Sallette, Souad Mehlal, Sedkaoui, Suzan, AlKhater, Raúl, Rigo-Bonnin, Francisco, Morandeira, Lucie, Roussel, Donald C, Vinh, Sisse Rye, Ostrowski, Antonio, Condino-Neto, Carolina, Prando, Anastasiia, Bonradenko, András N, Spaan, Laurent, Gilardin, Jacques, Fellay, Stanislas, Lyonnet, Kaya, Bilguvar, Richard P, Lifton, Shrikant, Mane, Mark S, Anderson, Bertrand, Boisson, Vivien, Béziat, Shen-Ying, Zhang, Evangelos, Vandreakos, Olivier, Hermine, Aurora, Pujol, Pärt, Peterson, Trine H, Mogensen, Lee, Rowen, James, Mond, Stéphanie, Debette, Xavier, de Lamballerie, Xavier, Duval, France, Mentré, Marie, Zins, Pere, Soler-Palacin, Roger, Colobran, Guy, Gorochov, Xavier, Solanich, Sophie, Susen, Javier, Martinez-Picado, Didier, Raoult, Marc, Vasse, Peter K, Gregersen, Lorenzo, Piemonti, Carlos, Rodríguez-Gallego, Luigi D, Notarangelo, Helen C, Su, Kai, Kisand, Satoshi, Okada, Anne, Puel, Emmanuelle, Jouanguy, Charles M, Rice, Pierre, Tiberghien, Qian, Zhang, Aurélie, Cobat, Laurent, Abel, and Hind, Hamzeh-Cognasse

Subjects
Adult, Aged, 80 and over, Adolescent, Critical Illness, Infant, Newborn, COVID-19, Infant, Interferon-alpha, Middle Aged, Antibodies, Neutralizing, Young Adult, Case-Control Studies, Child, Preschool, Immunoglobulin G, Interferon Type I, Humans, Child, Aged, Autoantibodies
Abstract

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4%80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals70 years, 2.3% between 70 and 80 years, and 6.3%80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases.

Published
2021

21. Deficiency of Interleukin-1 Receptor Antagonist: A Case with Late Onset Severe Inflammatory Arthritis, Nail Psoriasis with Onychomycosis and Well Responsive to Adalimumab Therapy

Author

Sanem Eren Akarcan, Jean-Laurent Casanova, Guzide Aksu, Neslihan Edeer Karaca, Anne Puel, Kunihiko Moriya, Necil Kutukculer, Mélanie Migaud, and Ege Üniversitesi

Subjects
lcsh:Immunologic diseases. Allergy, 0301 basic medicine, medicine.medical_specialty, Inflammatory arthritis, Immunology, Case Report, Systemic inflammation, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Adalimumab, medicine, Immunology and Allergy, Respiratory distress, business.industry, Osteomyelitis, medicine.disease, Periostitis, Dermatology, Canakinumab, 030104 developmental biology, Interleukin 1 receptor antagonist, medicine.symptom, lcsh:RC581-607, business, medicine.drug
Abstract

WOS: 000481922900001, PubMed ID: 31467740, DIRA (deficiency of the IL-1Ra) is a rare condition that usually presents in the neonatal period. Patients with DIRA present with systemic inflammation, respiratory distress, joint swelling, pustular rash, multifocal osteomyelitis, and periostitis. Previously, we reported a patient with a novel mutation in IL1RN with a healthy neonatal period, a late-onset of pustular dermatosis, inflammatory arthritis, and excellent response to canakinumab treatment. Herein, we are presenting a new case of late-onset DIRA syndrome, carrying a different mutation and showing different clinical findings. This patient is the first one in the literature with the inflammatory arthritis, nail psoriasis, and onychomycosis and with her remarkable response to monoclonal antibodies. The case responded well and fully recovered after treatment with adalimumab, but not with canakinumab. The DIRA disease can lead to death from multiple organ failures and if recognized early, the treatment with replacement of the deficient protein with biologic agents induces rapid and complete remission. Therefore, clinical symptoms should be learned exactly by the pediatricians, pediatric rheumatologists, and immunologists; and molecular analysis targeting this defect must be performed as early as possible.

Published
2019

22. Detection of homozygous and hemizygous complete or partial exon deletions by whole-exome sequencing

Author

Jacinta Bustamante, Mélanie Migaud, Carla Nasca, Jérémie Rosain, Jean-Laurent Casanova, Laurent Abel, Gaspard Kerner, Aurélie Cobat, Bertrand Boisson, Yoann Seeleuthner, Benedetta Bigio, and Anne Puel

Subjects
AcademicSubjects/SCI01140, 0303 health sciences, AcademicSubjects/SCI01060, Computer science, AcademicSubjects/SCI00030, Computational biology, AcademicSubjects/SCI01180, 3. Good health, Euclidean distance, 03 medical and health sciences, Exon, 0302 clinical medicine, Simulated data, Sliding window protocol, Methods Article, Control set, AcademicSubjects/SCI00980, Copy-number variation, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract

The detection of copy number variations (CNVs) in whole-exome sequencing (WES) data is important, as CNVs may underlie a number of human genetic disorders. The recently developed HMZDelFinder algorithm can detect rare homozygous and hemizygous (HMZ) deletions in WES data more effectively than other widely used tools. Here, we present HMZDelFinder_opt, an approach that outperforms HMZDelFinder for the detection of HMZ deletions, including partial exon deletions in particular, in WES data from laboratory patient collections that were generated over time in different experimental conditions. We show that using an optimized reference control set of WES data, based on a PCA-derived Euclidean distance for coverage, strongly improves the detection of HMZ complete exon deletions both in real patients carrying validated disease-causing deletions and in simulated data. Furthermore, we develop a sliding window approach enabling HMZDelFinder_opt to identify HMZ partial deletions of exons that are undiscovered by HMZDelFinder. HMZDelFinder_opt is a timely and powerful approach for detecting HMZ deletions, particularly partial exon deletions, in WES data from inherently heterogeneous laboratory patient collections.

Published
2021

23. 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

24. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Author

Vivien, Béziat, Simon J, Tavernier, Yin-Huai, Chen, Cindy S, Ma, Marie, Materna, Arian, Laurence, Jens, Staal, Dominik, Aschenbrenner, Lisa, Roels, Lisa, Worley, Kathleen, Claes, Lisa, Gartner, Lisa A, Kohn, Marieke, De Bruyne, Klaus, Schmitz-Abe, Louis-Marie, Charbonnier, Sevgi, Keles, Justine, Nammour, Natasha, Vladikine, Majistor Raj Luxman, Maglorius Renkilaraj, Yoann, Seeleuthner, Mélanie, Migaud, Jérémie, Rosain, Mohamed, Jeljeli, Bertrand, Boisson, Eva, Van Braeckel, Jill A, Rosenfeld, Hongzheng, Dai, Lindsay C, Burrage, David R, Murdock, Bart N, Lambrecht, Véronique, Avettand-Fenoel, Tiphanie P, Vogel, Charles R, Esther, Sule, Haskologlu, Figen, Dogu, Peter, Ciznar, David, Boutboul, Marie, Ouachée-Chardin, Jean, Amourette, Marie-Noëlle, Lebras, Clément, Gauvain, Colas, Tcherakian, Aydan, Ikinciogullari, Rudi, Beyaert, Laurent, Abel, Joshua D, Milner, Bodo, Grimbacher, Louis-Jean, Couderc, Manish J, Butte, Alexandra F, Freeman, Émilie, Catherinot, Claire, Fieschi, Talal A, Chatila, Stuart G, Tangye, Holm H, Uhlig, Filomeen, Haerynck, Jean-Laurent, Casanova, Anne, Puel, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Laboratory of 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), Ghent University Hospital, VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Center for Medical Genetics [Ghent], John Radcliffe Hospital [Oxford University Hospital], University of Oxford [Oxford], Garvan Institute of Medical Research [Darlinghurst, Australia], St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales [Sydney] (UNSW), University of California, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Necmettin Erbakan University [Konya, Turquie], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Baylor College of Medicine (BCM), Baylor University, Laboratoire de Virologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Ankara University School of Medicine [Turkey], Comenius University in Bratislava, Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Groupe Hospitalier Artois-Ternois Centre Hospitalier d’Arras, Service de pneumologie [Hôpital Foch], Hôpital Foch [Suresnes], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Columbia University Irving Medical Center (CUIMC), Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Centre for Integrative Biological Signaling Studies [Freiburg, Germany], University of Freiburg [Freiburg], Hanover Medical School, Laboratoire de recherche sur les mécanismes moléculaires et pharmacologiques de l’obstruction bronchique (LOBIP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], and University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW)

Subjects
Male, Adolescent, Models, Biological, Young Adult, Th2 Cells, Loss of Function Mutation, Cytokine Receptor gp130, Humans, Immunodeficiency, Child, Alleles, Cells, Cultured, Genes, Dominant, Human disease genetics, Cell Membrane, Correction, Fibroblasts, Middle Aged, Pedigree, Up-Regulation, Kinetics, C-Reactive Protein, Genetics, Population, HEK293 Cells, Phenotype, Mutation, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Job Syndrome
Abstract

International audience; Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

Published
2020

25. Rosacea as a striking feature in family members with a <scp>STAT</scp> 1 gain‐of‐function mutation

Author

N.H. Segura‐Mendez, Lizbeth Blancas-Galicia, Luz Orozco-Covarrubias, Mélanie Migaud, M.A. Suárez-Gutiérrez, Sara Elva Espinosa-Padilla, Jean-Laurent Casanova, P. O′Farrill‐Romanillos, Marimar Sáez-de-Ocariz, and Anne Puel

Subjects
Genetics, Infectious Diseases, Feature (computer vision), business.industry, Rosacea, Mutation (genetic algorithm), Gain of function mutation, Medicine, Dermatology, business, medicine.disease
Published
2020

27. A novel AIRE gene mutation in a patient with autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy revealed by alopecia areata

Author

Aycha Arousse, Mohamed Denguezli, Amina Aounallah, Najet Ghariani, Rafiaa Nouira, Anne Puel, Dorra H'mida-Ben Brahim, Lobna Boussofara, Mélanie Migaud, and Jean-Laurent Casanova

Subjects
0301 basic medicine, autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy, AA, alopecia areata, Case Report, Dermatology, Gene mutation, polyendocriopathy, CMC, chronic mucocutaneous candidiasis, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Interferon, APECED, autoimmune polyendocrinopathy candidiasis and ectodermal dystrophy, medicine, genetics, IFN, interferon, alopecia areata, Chronic mucocutaneous candidiasis, Auto-Abs, auto-antibodies, business.industry, Autoantibody, Interleukin, T helper cell, Autoimmune polyendocrinopathy, Alopecia areata, medicine.disease, IL, interleukin, 030104 developmental biology, medicine.anatomical_structure, Th, T helper cell, Immunology, business, medicine.drug
Published
2018

28. A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency

Author

Yuriy Stepanovskiy, Liudmyla Chernyshova, Elfride De Baere, Davood Mansouri, Nima Parvaneh, Mahboubeh Mansouri, María Teresa Herrera, S. Alireza Mahdaviani, Fabienne Jabot-Hanin, Jacinta Bustamante, Mélanie Migaud, Laurent Abel, Anne Puel, Jérémie Rosain, Alejandro Nieto-Patlán, Frédéric Tores, Mehrnaz Mesdaghi, Emilie Corvilain, Gaspard Kerner, Virginie Grandin, Edna Venegas-Montoya, Capucine Picard, Stéphanie Boisson-Dupuis, Patrick Nitschke, Sigifredo Pedraza-Sánchez, Carmen Oleaga-Quintas, Stéphane Marot, Caroline Deswarte, Jean-Laurent Casanova, Christine Bole-Feysot, Hannah Verdin, Anastasia Bondarenko, Garyfallia Syridou, Maria Tsolia, Sara Elva Espinosa-Padilla, Nathalie Lambert, Corinne Jacques, Lizbeth Blancas-Galicia, and Marco Antonio Yamazaki-Nakashimada

Subjects
Male, 0301 basic medicine, DNA Copy Number Variations, Immunology, Gene Expression, Alu element, Locus (genetics), Biology, Genome, Article, Interferon-gamma, 03 medical and health sciences, symbols.namesake, Alu Elements, Gene duplication, Interleukin-12 Receptor beta 1 Subunit, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Copy-number variation, Indel, Interleukin 12 receptor, beta 1 subunit, Alleles, Genetic Association Studies, Genetics, Mycobacterium Infections, Base Sequence, Chromosome Mapping, Pedigree, Phenotype, 030104 developmental biology, Mutation, Mendelian inheritance, symbols, Female
Abstract

PURPOSE: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rβ1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rβ1 deficiency due to CNVs. METHODS: We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variation by IL12RB1-targeted next-generation sequencing (NGS). RESULTS: We identified six new IL-12Rβ1-deficient patients with a complete loss of IL-12Rβ1 expression on PHA-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, in either the homozygous state (n=1) or in trans (n=4) with a single nucleotide variation (n=3) or a small indel (n=1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%). CONCLUSION: The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rβ1 deficiency.

Published
2018

29. 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

30. Delay in the Diagnosis of APECED: A Case Report and Review of Literature from Iran

Author

Mahnaz Jamee, Davood Mansouri, Gholamreza Azizi, Nematollah Joneidi, Mehdi Ghaini, Shabnam Eskandarzade, Ali Akbar Velayati, Majid Marjani, Mélanie Migaud, Jl Casanova, Anne Puel, Afshin Moniri, Seyed Alireza Mahdaviani, and Hosseinali Ghaffaripour

Subjects
0301 basic medicine, Adult, Male, Asplenia, medicine.medical_specialty, animal structures, Immunology, 03 medical and health sciences, 0302 clinical medicine, medicine, Adrenal insufficiency, Humans, Chronic mucocutaneous candidiasis, Polyendocrinopathies, Autoimmune, Autoantibodies, business.industry, Alopecia totalis, Homozygote, General Medicine, Autoimmune polyendocrinopathy, medicine.disease, Autoimmune regulator, Dermatology, humanities, Pedigree, 030104 developmental biology, Autoimmune polyendocrine syndrome type 1, Hypoparathyroidism, 030220 oncology & carcinogenesis, Mutation, Cytokines, business, Transcription Factors
Abstract

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) syndrome is a rare monogenic autosomal recessive disorder caused by biallelic mutations in the AIRE (autoimmune regulator) gene. Patients with APECED present with heterogeneous endocrine and non-endocrine manifestations. In this study, we report an Iranian patient who presented with Addison disease, chronic mucocutaneous candidiasis, alopecia totalis, keratopathy and asplenia treated as an isolated endocrinopathy for 25 years. In the adulthood, the diagnosis of APECED was made by genetic analysis which demonstrated homozygous nonsense p.R257* (c.769C>T) mutation of AIRE. APECED has been shown to be frequent in some ethnicities including Iranian Jews. Therefore, we reviewed 39 Iranian APECED patients published in the literature. We found that most of the Iranian patients were of Jewish ethnic background and presented hypoparathyroidism, adrenal insufficiency, and candidiasis as the main clinical manifestation.

Published
2019

31. Functional analysis of two STAT1 gain-of-function mutations in two Iranian families with autosomal dominant chronic mucocutaneous candidiasis

Author

Anne Puel, Nioosha Nekooie-Marnany, Jean-Laurent Casanova, Mélanie Migaud, Seyed-Mehran Modaressadeghi, Mazdak Ganjalikhani-Hakemi, Vajiheh Ostadi, and Roya Sherkat

Subjects
Male, Adolescent, T cell, Gene Expression, Iran, Mucocutaneous Candidiasis, medicine.disease_cause, Peripheral blood mononuclear cell, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Antigen, Interferon, medicine, Humans, Family, Chronic mucocutaneous candidiasis, Phosphorylation, Candida albicans, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Mutation, biology, business.industry, Candidiasis, Chronic Mucocutaneous, Interleukin-17, General Medicine, medicine.disease, biology.organism_classification, Flow Cytometry, Infectious Diseases, medicine.anatomical_structure, STAT1 Transcription Factor, Child, Preschool, Gain of Function Mutation, Immunology, Th17 Cells, Female, business, 030215 immunology, medicine.drug
Abstract

Candidiasis is characterized by susceptibility to recurrent or persistent infections caused by Candida spp., typically Candida albicans, of cutaneous and mucosal surfaces. In this report, function and frequency of Th17 cells as well as genetics of patients susceptible to mucocutaneous candidiasis were studied. For patients, T-cell proliferation tests in response to Candida antigen, Th17 cell proportions, and STAT1 phosphorylation were evaluated through flow cytometry. Expression of IL17A, IL17F and IL22 genes were measured by real-time quantitative PCR. At the same time, whole exome sequencing was performed for all patients. We identified two heterozygous substitutions, one: c.821G > A (p. R274Q) was found in a multiplex family with three individuals affected, the second one: c.812A > C (p. Q271P) was found in a sporadic case. Both mutations are located in the coiled-coil domain (CCD) of STAT1. The frequency of Th17 cells, IL17A, IL17F, and IL22 gene expression in patients’ peripheral blood mononuclear cells (PBMCs), and T-cell proliferation to Candida antigens were significantly reduced in the patients as compared to healthy controls. An increased STAT1 phosphorylation was observed in patients’ PBMCs upon interferon (IFN)-γ stimulation as compared to healthy controls. We report two different but neighboring heterozygous mutations, located in exon 10 of the STAT1 gene, in four Iranian patients with CMC, one of whom also had hypothyroidism. These mutations were associated with impaired T cell proliferation to Candida antigen, low Th17 cell proportions, and increased STAT1 phosphorylation upon IFN-γ. We suggest that interfering with STAT1 phosphorylation might be a promising way for potential therapeutic measurements for such patients.

Published
2019

32. 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

33. Human gut mycobiota tune immunity via CARD9-dependent induction of anti-fungal IgG antibodies

Author

Irina Leonardi, Iliyan D. Iliev, Xin Li, William D. Fiers, Anne Puel, Alexa Semon, Itai Doron, Takato Kusakabe, Meghan Bialt-DeCelie, Mélanie Migaud, Woan-Yu Lin, and Iris H. Gao

Subjects
Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Immunoglobulin G, Microbiology, Feces, 03 medical and health sciences, 0302 clinical medicine, Antibody Repertoire, Immunity, Candida albicans, Animals, Humans, Neutralizing antibody, Antibodies, Fungal, 030304 developmental biology, B-Lymphocytes, Phagocytes, 0303 health sciences, Innate immune system, biology, Candidiasis, Germinal center, Germinal Center, biology.organism_classification, CARD Signaling Adaptor Proteins, Gastrointestinal Tract, Mice, Inbred C57BL, biology.protein, Antibody, 030217 neurology & neurosurgery, Mycobiome, Protein Binding, Signal Transduction
Abstract

Summary Antibodies mediate natural and vaccine-induced immunity against viral and bacterial pathogens, whereas fungi represent a widespread kingdom of pathogenic species for which neither vaccine nor neutralizing antibody therapies are clinically available. Here, using a multi-kingdom antibody profiling (multiKAP) approach, we explore the human antibody repertoires against gut commensal fungi (mycobiota). We identify species preferentially targeted by systemic antibodies in humans, with Candida albicans being the major inducer of antifungal immunoglobulin G (IgG). Fungal colonization of the gut induces germinal center (GC)-dependent B cell expansion in extraintestinal lymphoid tissues and generates systemic antibodies that confer protection against disseminated C. albicans or C. auris infection. Antifungal IgG production depends on the innate immunity regulator CARD9 and CARD9+CX3CR1+ macrophages. In individuals with invasive candidiasis, loss-of-function mutations in CARD9 are associated with impaired antifungal IgG responses. These results reveal an important role of gut commensal fungi in shaping the human antibody repertoire through CARD9-dependent induction of host-protective antifungal IgG.

Published
2021

34. Genetic inhibition of CARD9 accelerates the development of atherosclerosis in mice through CD36 dependent-defective autophagy

Author

Yujiao Zhang, Marie Vandestienne, Jean-Rémi Lavillegrand, Jeremie Joffre, Icia Santos-Zas, Aonghus Lavelle, Xiaodan Zhong, Wilfried Le Goff, Maryse Guérin, Rida Al-Rifai, Ludivine Laurans, Patrick Bruneval, Coralie Guérin, Marc Diedisheim, Melanie Migaud, Anne Puel, Fanny Lanternier, Jean-Laurent Casanova, Clément Cochain, Alma Zernecke, Antoine-Emmanuel Saliba, Michal Mokry, Jean-Sebastien Silvestre, Alain Tedgui, Ziad Mallat, Soraya Taleb, Olivia Lenoir, Cécile Vindis, Stéphane M. Camus, Harry Sokol, and Hafid Ait-Oufella

Subjects
Science
Abstract

Abstract Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe -/- mice as well as hematopoietic deletion in Ldlr -/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe -/- Rag2 -/- Card9 -/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1β production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.

Published
2023
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35. 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

36. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations

Author

Jean-Pierre de Villartay, Luigi D. Notarangelo, Caroline Deswarte, Danielle T. Avery, Rubén Martínez-Barricarte, Masao Kobayashi, Claire Soudais, Dina Averbuch, Fabienne Jabot-Hanin, Egídio Torrado, Chizuru Okada, Stuart G. Tangye, Yuval Itan, Despina Moshous, Bertrand Boisson, Cindy S. Ma, Anne Puel, M. Lagos, Capucine Picard, Mohammed Alzahrani, Jamie Rossjohn, Rabih Halwani, Elissa K. Deenick, Jeffrey J. Fountain, Jamal Shamma, Jacinta Bustamante, Mélanie Migaud, Natalie Wong, Dan Engelhard, Daniela Latorre, Aziz Belkadi, Sylvain Breton, Sylvain Latour, Federico Mele, Janet Markle, Marcela Gonzalez, Hiyam Marzouqa, Sophie Hambleton, Stéphanie Boisson-Dupuis, Laurent Abel, James McCluskey, Federica Sallusto, Alessandro Sette, Peter D. Arkwright, Saleh Al-Muhsen, Olivier Lantz, Jean-Laurent Casanova, Lauren A. Henderson, Andrea M. Cooper, Cecilia S. Lindestam Arlehamn, and Satoshi Okada

Subjects
0303 health sciences, Multidisciplinary, biology, T cell, Gene rearrangement, Mucocutaneous Candidiasis, medicine.disease, biology.organism_classification, Chronic Candidiasis, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, RAR-related orphan receptor gamma, Immunity, Immunology, medicine, Chronic mucocutaneous candidiasis, Candida albicans, 030304 developmental biology, 030215 immunology
Abstract

A surprising immune twist for RORC The immune system needs its full array of soldiers—including cells and the molecules they secrete—to optimally protect the host. When this isn't the case, minor infections can become chronic or even deadly. Markle et al. report the discovery of seven individuals carrying loss-of-function mutations in RORC, which encodes the transcription factors RORγ and RORγT. These individuals lacked immune cells that produce the cytokine interleukin-17, causing them to suffer from chronic candidiasis. RORC-deficient individuals also exhibited impaired immunity to mycobacterium, probably due to reduced production of the cytokine interferon-γ, a molecule not known to require RORC for its induction. Science , this issue p. 606

Published
2015

37. Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis

Author

Miguel Galicchio, Yun Ling, Figen Dogu, Aydan Ikinciogullari, Capucine Picard, Anne Puel, Romain Lévy, Yuval Itan, Laurent Abel, Julien Cottineau, Sophie Cypowyj, Yildiz Camcioglu, Jacinta Bustamante, Mélanie Migaud, Nicolas Goudin, Alexandre Bolze, Jean-Laurent Casanova, Serdar Nepesov, Bertrand Boisson, Aziz Belkadi, and Caner Aytekin

Subjects
Adult, Male, Immunology, Mucocutaneous zone, macromolecular substances, Article, Immunity, Candida albicans, Humans, Immunology and Allergy, Medicine, Sex organ, Allele, Chronic mucocutaneous candidiasis, Child, Adaptor Proteins, Signal Transducing, biology, business.industry, Candidiasis, Chronic Mucocutaneous, Homozygote, Interleukin-17, Skin Diseases, Genetic, Receptors, Interleukin, medicine.disease, biology.organism_classification, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Corpus albicans, Female, Interleukin 17, business
Abstract

Autosomal-recessive IL-17RA, IL-17RC, and ACT1 deficiencies and autosomal-dominant IL-17F deficiency in humans underlie susceptibility to chronic mucocutaneous candidiasis., Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nail, oral, and genital mucosae with Candida species, mainly C. albicans. Autosomal-recessive (AR) IL-17RA and ACT1 deficiencies and autosomal-dominant IL-17F deficiency, each reported in a single kindred, underlie CMC in otherwise healthy patients. We report three patients from unrelated kindreds, aged 8, 12, and 37 yr with isolated CMC, who display AR IL-17RC deficiency. The patients are homozygous for different nonsense alleles that prevent the expression of IL-17RC on the cell surface. The defect is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. However, in contrast to what is observed for the IL-17RA– and ACT1-deficient patients tested, the response to IL-17E (IL-25) is maintained in these IL-17RC–deficient patients. These experiments of nature indicate that human IL-17RC is essential for mucocutaneous immunity to C. albicans but is otherwise largely redundant.

Published
2015

38. Gain-of-Function Mutations in STAT1: A Recently Defined Cause for Chronic Mucocutaneous Candidiasis Disease Mimicking Combined Immunodeficiencies

Author

Guzide Aksu, Ezgi Ulusoy Severcan, Ferda Evin Gurkan, Jean-Laurent Casanova, Anne Puel, Elif Azarsiz, Esra Isik, Sanem Eren Akarcan, Mélanie Migaud, Necil Kutukculer, Neslihan Edeer Karaca, and Ege Üniversitesi

Subjects
0301 basic medicine, lcsh:Immunologic diseases. Allergy, medicine.medical_treatment, Immunology, Hypergammaglobulinemia, Case Report, Disease, Hematopoietic stem cell transplantation, Biology, biology.organism_classification, Chronic Candidiasis, medicine.disease, 03 medical and health sciences, Combined immunodeficiencies, 030104 developmental biology, 0302 clinical medicine, medicine, Immunology and Allergy, Chronic mucocutaneous candidiasis, Candida albicans, lcsh:RC581-607, Immunodeficiency, 030215 immunology
Abstract

WOS: 000415059900001, PubMed ID: 29259832, Chronic Mucocutaneous Candidiasis (CMC) is the chronic, recurrent, noninvasive Candida infections of the skin, mucous membranes, and nails. A 26-month-old girl was admitted with the complaints of recurrent oral Candidiasis, diarrhea, and respiratory infections. Candida albicans grew in oral mucosa swab. CMV and EBV DNA titers were elevated. She had hypergammaglobulinemia; IgE level, percentages of lymphocyte subgroups, and in vitro T-cell proliferation responses were normal. She had parenchymal nodules within the lungs and a calcific nodule in the liver. Chronic-recurrent infections with different pathogens leading to significant morbidity suggested combined immunodeficiency, CMC, or Mendelian susceptibility to mycobacterial diseases. Genetic analysis revealed a predefined heterozygous gain-of-function mutation (GOF) (c.1154 C>T, p.Thr385Met) in the gene coding STAT1 molecule. Hematopoietic stem cell transplantation (HSCT) was planned because of severe recurring infections. Patients with STAT1GOFmutations may exhibit diverse phenotypes including infectious and noninfectious findings. HSCT should be considered as an early treatment option before permanent organ damage leading tomorbidity andmortality develops. This case is presented to prompt clinicians to consider STAT1GOFmutations in the differential diagnosis of patientswith chronic Candidiasis and recurrent infections with multiple organisms, since these mutations are responsible for nearly half of CMC cases reported.

Published
2017

39. Tuberculin Skin Test Negativity Is Under Tight Genetic Control of Chromosomal Region 11p14-15 in Settings With Different Tuberculosis Endemicities

Author

Christine Poirier, Alexandre Alcaïs, Anne Boland-Auge, Ghislain Grange, François Corrard, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova, Christophe Delacourt, Erwin Schurr, Laurent Abel, Aurélie Cobat, Eileen G. Hoal, Jacinta Bustamante, and Mélanie Migaud

Subjects
Adult, Male, Linkage disequilibrium, Tuberculosis, Adolescent, Tuberculosis Contact, Tuberculin, tuberculin skin test, human genetics, Genome-wide association study, Locus (genetics), Linkage Disequilibrium, 03 medical and health sciences, Major Articles and Brief Reports, South Africa, Young Adult, tuberculosis infection, genome-wide linkage, Immunology and Allergy, Medicine, Humans, Hypersensitivity, Delayed, Prospective Studies, Child, Genetic Association Studies, 030304 developmental biology, 0303 health sciences, biology, Bacteria, 030306 microbiology, business.industry, Tuberculin Test, Infant, Middle Aged, medicine.disease, biology.organism_classification, bacterial infections and mycoses, 3. Good health, Infectious Diseases, Child, Preschool, Chromosomal region, Immunology, Female, business, Mycobacterium
Abstract

A substantial proportion of subjects exposed to a contagious tuberculosis case display lack of tuberculin skin test (TST) reactivity. We previously mapped a major locus (TST1) controlling lack of TST reactivity in families from an area in South Africa where tuberculosis is hyperendemic. Here, we conducted a household tuberculosis contact study in a French area where the endemicity of tuberculosis is low. A genome-wide analysis of TST negativity identified a significant linkage signal (P3 × 10(-5)) in close vicinity of TST1. Combined analysis of the 2 samples increased evidence of linkage (P = 2.4 × 10(-6)), further implicating genetic factors located on 11p14-15. This region overlaps the TNF1 locus controlling mycobacteria-driven tumor necrosis factor α production.

Published
2014

40. Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

Author

Nobuyuki Hyakuna, Saleh Al Muhsen, Takaki Asano, Caner Aytekin, Didier Bronnimann, Yuval Itan, Erika Della Mina, Figen Dogu, Chittibabu Vatte, Laurent Abel, Amein Al Ali, Caini Liu, Vivien Béziat, Xiaoxia Li, Julie Toubiana, Marie Ferneiny, Romain Lévy, Masao Kobayashi, Anne Puel, Ekrem Unal, Suzan A AlKhater, Cyril Cyrus, Louis Yi Ann Chai, Fatih Celmeli, Fabian Hauck, Satoshi Okada, Stéphanie Boisson-Dupuis, Osamu Ohara, Turkan Patiroglu, Jacinta Bustamante, Mélanie Migaud, Kunihiko Moriya, Matías Oleastro, Jean-Laurent Casanova, Aydan Ikinciogullari, Florian Gothe, Natalia Tahuil, Yildiz Camcioglu, Christoph Klein, Aicha Salhi, Ling Yun, and Serdar Nepesov

Subjects
Male, 0301 basic medicine, T-Lymphocytes, 0302 clinical medicine, Receptors, 2.1 Biological and endogenous factors, Missense mutation, Aetiology, Chronic mucocutaneous candidiasis, Child, Receptor, Immunodeficiency, Skin, Candida, Pediatric, Receptors, Interleukin-17, Multidisciplinary, Interleukin-17, Homozygote, Candidiasis, Bacterial Infections, Pedigree, Transmembrane domain, Infectious Diseases, PNAS Plus, Child, Preschool, Female, Infection, Mucocutaneous zone, Genes, Recessive, Biology, Immunophenotyping, Open Reading Frames, 03 medical and health sciences, Rare Diseases, Clinical Research, Genetics, medicine, Humans, Recessive, Allele, Preschool, Gene, Alleles, Family Health, Cell Membrane, Infant, Newborn, Infant, Fibroblasts, Newborn, medicine.disease, HEK293 Cells, Emerging Infectious Diseases, Good Health and Well Being, 030104 developmental biology, Mycoses, Genes, Mutation, Immunology, immunodeficiency, Genome-Wide Association Study, 030215 immunology
Abstract

Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.

Published
2016

41. Deep Dermatophytosis and Inherited CARD9 Deficiency

Author

Lobna Boussofara, Grégory Jouvion, Aomar Ammar-Khodja, Marie-Elisabeth Bougnoux, Merad Boudia, Mohamed Denguezli, Olivier Lortholary, Jean-Laurent Casanova, Frédérique Jacobs, Sophie Cypowyj, Kinda Schepers, Molka Larif, Saad Pathan, Capucine Picard, Bodo Grimbacher, Luyan Liu, Lynda Taibi, Fabrice Chrétien, Gérard Lefranc, Laurent Abel, Rod Hay, Boumediene Guellil, Jean-Christophe Goffard, Carolina Prando, Laurence Michel, Fanny Lanternier, Sylvie Fraitag, Mélanie Migaud, Anne Puel, Quentin B. Vincent, Hervé Bachelez, Omar Boudghene Stambouli, and Véronique Del Marmol

Subjects
Adult, Male, Genes, Recessive, medicine.disease_cause, Article, 03 medical and health sciences, symbols.namesake, Africa, Northern, Tinea, Humans, Medicine, In patient, Immunodeficiency, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Interleukin-6, 030306 microbiology, business.industry, Homozygote, Deep dermatophytosis, General Medicine, Middle Aged, medicine.disease, Founder Effect, Pedigree, 3. Good health, CARD Signaling Adaptor Proteins, Mutation, Immunology, Mendelian inheritance, symbols, Dermatophyte, Female, North african, business, Founder effect
Abstract

Deep dermatophytosis is a severe and sometimes life-threatening fungal infection caused by dermatophytes. It is characterized by extensive dermal and subcutaneous tissue invasion and by frequent dissemination to the lymph nodes and, occasionally, the central nervous system. The condition is different from common superficial dermatophyte infection and has been reported in patients with no known immunodeficiency. Patients are mostly from North African, consanguineous, multiplex families, which strongly suggests a mendelian genetic cause.We studied the clinical features of deep dermatophytosis in 17 patients with no known immunodeficiency from eight unrelated Tunisian, Algerian, and Moroccan families. Because CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in an Iranian family with invasive fungal infections, we also sequenced CARD9 in the patients.Four patients died, at 28, 29, 37, and 39 years of age, with clinically active deep dermatophytosis. No other severe infections, fungal or otherwise, were reported in the surviving patients, who ranged in age from 37 to 75 years. The 15 Algerian and Tunisian patients, from seven unrelated families, had a homozygous Q289X CARD9 allele, due to a founder effect. The 2 Moroccan siblings were homozygous for the R101C CARD9 allele. Both alleles are rare deleterious variants. The familial segregation of these alleles was consistent with autosomal recessive inheritance and complete clinical penetrance.All the patients with deep dermatophytosis had autosomal recessive CARD9 deficiency. Deep dermatophytosis appears to be an important clinical manifestation of CARD9 deficiency. (Funded by Agence Nationale pour la Recherche and others.).

Published
2013

42. Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases

Author

Capucine Picard, Anastasia Bondarenko, Marjorie Hubeau, Lorena Regairaz, Caroline Deswarte, Imen Ben-Mustapha, Antoine Guérin, Joseph Hertecant, Guillaume Vogt, Rose-Marie Herbigneaux, Fatima Ailal, Davood Mansouri, Guzide Aksu, Antonio Condino-Neto, Laurent Abel, Carolina Prando, Ambre Czarna, Lizbeth Blancas Galicia, Saul Oswaldo Lugo-Reyes, Isil Barlan, Mussaret B. Zaidi, Liliana Bezrodnik, Daniela Di Giovanni, Laura Perez, Laila Ait Baba, Sigifredo Pedraza-Sánchez, Miguel Galicchio, Gehad ElGhazali, Aminata Diabate, Sara Espinosa, Matías Oleastro, Francesca Conti, Necil Kutukculer, Edgar Oliveira, Héctor Eduardo Guidos Morales, Edith Gonzalez Serrano, Fatma Nur Öz, Ahmed Aziz Bousfiha, Jalel Chemli, Özden Anal, Peter Ciznar, Nizar Mahlaoui, Francisco J. Espinosa-Rosales, Silvia Danielian, Gloria G. Guerrero, Saleh Al-Muhsen, Marco Antonio Yamazaki Nakashimada, Nadia Kechout, Ridha Barbouche, Maria Claudia Ortega, Susana Soto Lavin, Liudmyla Chernyshova, Ghassan Dbaibo, Melike Emiroglu, Stéphane Blanche, Jacinta Bustamante, Mélanie Migaud, Jean-Laurent Casanova, Maylis de Suremain, Barik Konte, Neslihan Edeer Karaca, Jianxin He, Stéphanie Ndaga, Nestor Proenza Pérez, Stéphanie Boisson-Dupuis, Eman Al-Idrissi, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Public Health and Cellular Biology [Rome], Università degli Studi di Roma Tor Vergata [Roma], Génétique Humaine des Maladies Infectieuses (Inserm U980), Immunodeficiencies Research Unit [Mexico city], National Institute of Pediatrics, Mexico, Beijing Childrens Hospital, Department of Pediatrics [Izmir], Ege University, Institute of Biomedical Sciences - Department of Immunology [Sao Paulo], University of São Paulo (USP), Laboratory of Biology and Health UARC34–Metabolic and Immunologic Pathology Research Team, Faculté des Sciences Ben M'sik [Casablanca], Université Hassan II [Casablanca] (UH2MC)-Université Hassan II [Casablanca] (UH2MC), Bioinformatics Laboratory [Curitiba], Pelé Pequeno Principe Research Institute, Curitiba, Department of Pediatric Infectious Diseases [Konya], Necmettin Erbakan University, Meram Medical Faculty, Pediatric Infectious Diseases Department [Ankara], Dr Sami Ulus Matern & Childrens Res & Training Ho, Department of Immunology [Mexico City], Natl Inst Pediat, Immunodeficiencies Res Unit, Mexico City, DF, Mexico, Marmara University [Kadıköy - İstanbul], Childrens Hosp Super Sor Maria Ludovica, Allergy and Immunology Unit [San Salvador], Natl Childrens Hosp Benjamin Bloom San Salvador, Immunology Unit [Buenos Aires], Childrens Hosp Ricardo Gutierrez Buenos Aires, Department of Pediatrics [Beirut], American University of Beirut [Beyrouth] (AUB), Clinical Immunology Unit, Casablanca Children's Hospital, Ibn Rochd Hospital King Hassan II University-Aïn Chok, Childrens Hosp Victor J Vilela Rosario, Department of Immunology [Buenos Aires], 'Juan Pedro Garrahan' National Hospital of Pediatrics, Buenos Aires, Department of Pediatrics [Sousse], Sahloul Hospital, Childrens Hosp San Jose Colombia, Concepcion Regional Hospital [Concepción], Department of Pediatrics [Abu Dhabi], Tawam Hospital, Al Ain, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Institut Pasteur d'Algérie, Réseau International des Instituts Pasteur (RIIP), Department of Pediatrics [Riyadh], King Fahad Medical City, Department of Pediatrics Infectious Diseases and Clinical Immunology [Kiev], Department of Pediatrics, Comenius University Medical School [Bratislava], University Children's Hospital, Bratislava, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unit of Biochemistry [Tlalpan], Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Microbiology Research Laboratory, Hospital General O'Horan and Infectious Diseases Research Unit [Merida], Hosp Reg Alta Especialidad Peninsula Yucatan, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur de Tunis, Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], French Reference Center for Primary Immune Deficiencies (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Pediatrics, Prince Naif Center for Immunology Research, College of Medicine, King Saud University [Riyadh] (KSU), F.C. was supported by the Department of Public Health and Cellular Biology, University of Rome Tor Vergata. A.G. was supported by the French National Research Agency (ANR). The Laboratory of Human Genetics of Infectious Diseases is supported by institutional grants from INSERM, University Paris Descartes, the Rockefeller University, and the St Giles Foundation and grants from the French National Research Agency (ANR) under the 'Investments for the Future' program (grant no. ANR-10-IAHU-01) and grant IFNGPHOX (no. ANR13-ISV3-0001-01). E.B.d.O. and A.C.-N. are supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP grants 2012/11757-2, 2010/51814-0, and 2012/51094-2) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ grant 303809/2010-8). S.P.-S. is supported by Consejo Nacional de Ciencia y Tecnología (CONACYT, grant 182817)., Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Rome Tor Vergata, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Dokuz Eylul University, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Shahid Beheshti University of Medical Sciences, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, rockefeller university, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), University of São Paulo ( USP ), Faculty of Science of Ben M'sik, King Hassan II University–Mohammedia, Casablanca, American University of Beirut [Beyrouth], Faculty of Medicine, Dokuz Eylül University, Izmir, Institut Pasteur d'Algérie-Réseau International des Instituts Pasteur ( RIIP ), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Natl Inst Med Sci & Nutr Salvador Zubiran, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur de Tunis-Réseau International des Instituts Pasteur ( RIIP ), and King Saud University [Riyadh] ( KSU )

Subjects
0301 basic medicine, Male, MESH : Retrospective Studies, [SDV]Life Sciences [q-bio], Disease, MESH : Child, Preschool, chronic granulomatous disease, Granulomatous Disease, Chronic, 0302 clinical medicine, Chronic granulomatous disease, MESH : Child, MESH: Granulomatous Disease, Chronic, MESH: Child, Immunology and Allergy, Disseminated disease, MESH : Female, BCG, MESH: Tuberculosis, MESH : BCG Vaccine, Child, biology, MESH: Patient Outcome Assessment, MESH : Infant, Bacterial Infections, MESH : Tuberculosis, MESH: Infant, MESH : Patient Outcome Assessment, 3. Good health, Vaccination, MESH : Bacterial Infections, MESH: BCG Vaccine, tuberculosis, Mycobacterium ulcerans, Child, Preschool, BCG Vaccine, Female, Tuberculosis, MESH: Bacterial Infections, MESH : Male, Immunology, primary immunodeficiency, 03 medical and health sciences, MESH: Mycoses, medicine, Humans, MESH: Mycobacterium Infections, Retrospective Studies, MESH : Mycoses, Mycobacterium Infections, MESH: Humans, [ SDV ] Life Sciences [q-bio], business.industry, MESH : Humans, MESH: Child, Preschool, Infant, Mycobacteria, MESH: Retrospective Studies, medicine.disease, biology.organism_classification, MESH: Male, Patient Outcome Assessment, 030104 developmental biology, Mycoses, MESH : Mycobacterium Infections, Primary immunodeficiency, MESH : Granulomatous Disease, Chronic, business, BCG vaccine, MESH: Female, 030215 immunology
Abstract

International audience; Background : Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients.Objective : Our objective was to assess the effect of mycobacterial disease in patients with CGD.Methods : We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria.Results : Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients.Conclusion : Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.

Published
2016

43. Chronic Mucocutaneous Candidiasis in Humans with Inborn Errors of Interleukin-17 Immunity

Author

Neil M. Wolfman, Jamila El-Baghdadi, Magali Audry, Miguel Galicchio, Jean-Laurent Casanova, Matthew J. Whitters, Luyan Liu, Mary Collins, Christine Bodemer, Hye Kyung Lim, Matthew Gumbleton, Jonathan Brooks, Laurent Abel, Capucine Picard, Saleh Al-Muhsen, Jill F. Wright, Maya Chrabieh, Antoine Toulon, Sophie Cypowyj, Laura Israel, Anne Puel, Jacinta Bustamante, Mélanie Migaud, and Theresa Paradis

Subjects
Male, medicine.medical_treatment, Molecular Sequence Data, Mucocutaneous zone, Genes, Recessive, Immunity, Candida albicans, medicine, Humans, Chronic mucocutaneous candidiasis, Child, Genes, Dominant, Receptors, Interleukin-17, Multidisciplinary, biology, Candidiasis, Chronic Mucocutaneous, Interleukin-17, biology.organism_classification, medicine.disease, Corpus albicans, Pedigree, Cytokine, Child, Preschool, Mutation, Immunology, Th17 Cells, Female, Interleukin 17, Cytokine receptor, Signal Transduction
Abstract

Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, and oral and genital mucosae caused by Candida albicans and, to a lesser extent, Staphylococcus aureus , in patients with no other infectious or autoimmune manifestations. We report two genetic etiologies of CMCD: autosomal recessive deficiency in the cytokine receptor, interleukin-17 receptor A (IL-17RA), and autosomal dominant deficiency of the cytokine interleukin-17F (IL-17F). IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. By contrast, IL-17F deficiency is partial, with mutant IL-17F–containing homo- and heterodimers displaying impaired, but not abolished, activity. These experiments of nature indicate that human IL-17A and IL-17F are essential for mucocutaneous immunity against C. albicans , but otherwise largely redundant.

Published
2011

44. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis

Author

Bernd H. Belohradsky, Miriam Hoernes, Sophie Cypowyj, Janine Reichenbach, Saleh Al-Muhsen, Magali Audry, Joachim Roesler, Amos Etzioni, Francisco Espinosa Rosales, Matías Oleastro, Luyan Liu, Tatiana Kochetkov, Viktor P. Chernyshov, Olivier Lortholary, Cécile Masson, Julie Toubiana, Stéphane Blanche, Caroline Thumerelle, Reinhard Seger, Dan Engelhard, Beáta Tóth, Yuval Itan, Lizbeth Blancas-Galicia, Patrick Nitschke, Gizi Wildbaum, Ludmyla Chernyshova, Avinash Abhyankar, Jérome Flatot, Ellen D. Renner, Ileana Maria Madrigal Beas, Xiao-Fei Kong, Maya Chrabieh, Antoine Toulon, Capucine Picard, Masao Kobayashi, László Maródi, J. Hiller, Alexandra Y. Kreins, Christine Bodemer, Julie Sawalle-Belohradsky, Alexandre Bolze, Claudia Traidl-Hoffmann, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova, Anastasia Bondarenko, Alain Fischer, Emmanuelle Jouanguy, Laurent Abel, Theresia Kusuma, Nathan Karin, Rosa María Cortés Grimaldo, Pierre-Régis Burgel, Alessandro Borghesi, Annette Jansson, Anne Puel, Mélanie Bué, Jacinta Bustamante, Kilian Eyerich, Mélanie Migaud, Carlos Torres Lozano, Stefanie Eyerich, Barbara Drexel, Sara Sebnem Kilic, Klaus Magdorf, Satoshi Okada, Vera Gulácsy, Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı., Kılıç, Sara Şebnem, University of Zurich, and Puel, A

Subjects
Male, Models, Molecular, medicine.medical_treatment, T-Lymphocytes, Job Syndrome, Mucocutaneous Candidiasis, Mutation, Fluorescent Antibody Technique, Interleukin 6, Electrophoretic Mobility Shift Assay, Receptor, Interferon alpha-beta, Gene, Interleukin 22, 0302 clinical medicine, Hyper-ige syndrome, Interleukin 17, Gain of function mutation, T lymphocyte, Immunology and Allergy, Disease, Chronic mucocutaneous candidiasis, Sequencing-based discovery, hyper-ige syndrome, sequencing-based discovery, cd4(+) t-cells, th17 cells, inborn-errors, ifn-gamma, th17-associated cytokines, deficiency, disease, il-27, Phosphorylation, Child, Dominance (genetics), Priority journal, Allele, 0303 health sciences, Heterozygosity, Candidiasis, Chronic Mucocutaneous, Interleukin-17, Flow Cytometry, 3. Good health, Pedigree, Cytokine, STAT1 Transcription Factor, 2723 Immunology and Allergy, Deficiency, Mucocutaneous candidiasis, Female, Cd4(+) t-cells, Inborn-errors, Human, Il-27, Interleukin 17F, Clinical article, Immunology, Immunoblotting, Molecular Sequence Data, Research & experimental medicine, 610 Medicine & health, Enzyme-Linked Immunosorbent Assay, Biology, Chronic disease, Article, 03 medical and health sciences, Interferon-gamma, Germline mutation, Immunity, STAT1 protein, Stat 1 gene, medicine, Autosomal dominant disorder, Humans, Th17-associated cytokines, ddc:610, Th17 cells, Medicine, research & experimental, Germ-Line Mutation, 030304 developmental biology, 2403 Immunology, Base Sequence, Interleukins, Infant, Heterozygote advantage, Sequence Analysis, DNA, medicine.disease, Interleukin 21, 10036 Medical Clinic, Interferons, Ifn-gamma, Sequence Alignment, 030215 immunology
Abstract

Whole-exome sequencing reveals activating STAT1 mutations in some patients with autosomal dominant chronic mucocutaneous candidiasis disease., Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.

Published
2011

45. A homozygous CARD9 mutation in a Brazilian patient with deep dermatophytosis

Author

Fanny Lanternier, Mélanie Migaud, Rosemeire Navickas Constantino-Silva, Nelson Augusto Rosário Filho, Sandra Mitie Ueda Palma, Anete Sevciovic Grumach, Jean-Laurent Casanova, Flavio Queiroz-Telles, and Anne Puel

Subjects
Adult, Cytotoxicity, Immunologic, Male, medicine.medical_specialty, Pathology, Itraconazole, Neutrophils, Immunology, Young Adult, Medical microbiology, Tinea, Candidiasis, Oral, medicine, Immunology and Allergy, Humans, Trichophyton, Genetic Predisposition to Disease, Allele, Child, Sequence Deletion, Skin, biology, business.industry, Deep dermatophytosis, Homozygote, medicine.disease, biology.organism_classification, Dermatology, Pedigree, CARD Signaling Adaptor Proteins, Child, Preschool, Primary immunodeficiency, Terbinafine, Ketoconazole, Female, business, Brazil, medicine.drug
Abstract

Deep dermatophytosis has been described in HIV and immunosuppressed patients. Recently, CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in individuals with deep dermatophytosis previously classified as “immunocompetent”. We report a 24-year-old Brazilian male patient with deep dermatophytosis born to an apparently non-consanguineous family. The symptoms started with oral candidiasis when he was 3 years old, persistent although treated. At 11 years old, well delimited, desquamative and pruriginous skin lesions appeared in the mandibular area; ketoconazole and itraconazole were introduced and maintained for 5 years. At 12 years of age, the lesions, which initially affected the face, started to spread to thoracic and back of the body (15 cm of diameter) and became ulcerative, secretive and painful. Terbinafine was introduced without any improvement. Trichophyton mentagrophytes was isolated from the skin lesions. A novel homozygous mutation in CARD9 (R101L) was identified in the patient, resulting in impaired neutrophil fungal killing. Both parents, one brother (with persistent superficial but not deep dermatophytosis) and one sister were heterozygous for this mutation, while another brother was found to be homozygous for the CARD9 wild-type allele. This is the first report of CARD9 deficiency in Latin America.

Published
2015

46. Inherited CARD9 deficiency in 2 unrelated patients with invasive Exophiala infection

Author

Davood Mansouri, Caroline Galeotti, Parvaneh Adimi, Olivier Lortholary, Laurent Abel, Sébastien Héritier, Mahin Jamshidi, Valeska Bidault, Marie-Elisabeth Bougnoux, Capucine Picard, Jean-Laurent Casanova, Luyan Liu, Elisa Barbati, Stéphane Blanche, Maryline Chomton, Serge Romana, Emmanuel Jacquemin, Vincent Pedergnana, Seyed Alireza Mahdaviani, Fanny Lanternier, Julie Lachenaud, Marie-Louise Frémond, Danielle Canioni, Adela Angoulvant, Ulrich Meinzer, Emmanuel Gonzales, Mélanie Migaud, Anne Puel, Nahal Mansouri, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'infectiologie Necker-Pasteur [CHU Necker], 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), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), AP-HP Hôpital universitaire Robert-Debré [Paris], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), DHU Hepatinov, Centre de Référence des Maladies Auto-Inflammatoires et des Amyloses [Le Kremlin-Bicêtre] (CeRéMAIA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Signalisation calcique et interactions cellulaires dans le foie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier René Dubos [Pontoise], Masih Daneshvari Hospital, Partenaires INRAE, Shahid Beheshti University, Islamic Azad University, Department of Infectious Disease, Hanoï Medical University, Biologie et Pathogénicité fongiques (BPF), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Rockefeller University [New York], Centre National de Référence des Mycoses invasives et antifongiques - Mycologie moléculaire (CNRMA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), The ANR (grant GENCMCD 11-BSV3-005-01, the Jeffrey Modell Foundation, the French government's Investissement d'Avenir program (ANR-10-LABX-62-IBEID), the Clinical and Translational Science Award Program, National Center for Advancing Translational Sciences, National Institutes of Health (grant UL1TR000043), Rockefeller University, including the St. Giles Foundation, INSERM, and Paris Descartes University, ANR-11-BSV3-0005,GENCMCD,Dissection génétique de la candidose cutanéo-muqueuse chronique chez l'homme(2011), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Coordination des Cellules et Morphogenèse / Heart Morphogenesis (Imagine - Institut Pasteur U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Biologie et Pathogénicité fongiques, Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Institut Pasteur [Paris], Institut Pasteur [Paris]-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), ProdInra, Migration, BLANC - Dissection génétique de la candidose cutanéo-muqueuse chronique chez l'homme - - GENCMCD2011 - ANR-11-BSV3-0005 - BLANC - VALID, and Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID

Subjects
medicine.medical_specialty, Pathology, exophiala species, [SDV]Life Sciences [q-bio], Disease, Skin infection, invasive fungal infection, Exophiala, parental unidisomy, medicine, Immunology and Allergy, Allele, Immunodeficiency, biology, osteomyelitis, biology.organism_classification, medicine.disease, central nervous system, Dermatology, Phialophora verrucosa, Uniparental disomy, 3. Good health, [SDV] Life Sciences [q-bio], Infectious Diseases, autosomal recessive CARD9 deficiency, Exophiala dermatitidis
Abstract

International audience; Background. Exophiala species are mostly responsible for skin infections. Invasive Exophiala dermatitidis disease is a rare and frequently fatal infection, with 42 cases reported. About half of these cases had no known risk factors. Similarly, invasive Exophiala spinifera disease is extremely rare, with only 3 cases reported, all in patients with no known immunodeficiency. Autosomal recessive CARD9 deficiency has recently been reported in otherwise healthy patients with severe fungal diseases caused by Candida species, dermatophytes, or Phialophora verrucosa. Methods. We investigated an 8-year-old girl from a nonconsanguineous Angolan kindred, who was born in France and developed disseminated E. dermatitidis disease and a 26 year-old woman from an Iranian consaguineous kindred, who was living in Iran and developed disseminated E. spinifera disease. Both patients were otherwise healthy. Results. We sequenced CARD9 and found both patients to be homozygous for loss-of-function mutations (R18W and E323del). The first patient had segmental uniparental disomy of chromosome 9, carrying 2 copies of the maternal CARD9 mutated allele. Conclusions. These are the first 2 patients with inherited CARD9 deficiency and invasive Exophiala disease to be described. CARD9 deficiency should thus be considered in patients with unexplained invasive Exophiala species disease, even in the absence of other infections.

Published
2015

47. IMMUNODEFICIENCIES. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations

Author

Satoshi, Okada, Janet G, Markle, Elissa K, Deenick, Federico, Mele, Dina, Averbuch, Macarena, Lagos, Mohammed, Alzahrani, Saleh, Al-Muhsen, Rabih, Halwani, Cindy S, Ma, Natalie, Wong, Claire, Soudais, Lauren A, Henderson, Hiyam, Marzouqa, Jamal, Shamma, Marcela, Gonzalez, Rubén, Martinez-Barricarte, Chizuru, Okada, Danielle T, Avery, Daniela, Latorre, Caroline, Deswarte, Fabienne, Jabot-Hanin, Egidio, Torrado, Jeffrey, Fountain, Aziz, Belkadi, Yuval, Itan, Bertrand, Boisson, Mélanie, Migaud, Cecilia S Lindestam, Arlehamn, Alessandro, Sette, Sylvain, Breton, James, McCluskey, Jamie, Rossjohn, Jean-Pierre, de Villartay, Despina, Moshous, Sophie, Hambleton, Sylvain, Latour, Peter D, Arkwright, Capucine, Picard, Olivier, Lantz, Dan, Engelhard, Masao, Kobayashi, Laurent, Abel, Andrea M, Cooper, Luigi D, Notarangelo, Stéphanie, Boisson-Dupuis, Anne, Puel, Federica, Sallusto, Jacinta, Bustamante, Stuart G, Tangye, and Jean-Laurent, Casanova

Subjects
Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, DNA Mutational Analysis, Thymus Gland, Article, Interferon-gamma, Mice, Candida albicans, Animals, Humans, Exome, Child, Tuberculosis, Pulmonary, Alleles, Candidiasis, Chronic Mucocutaneous, Interleukin-17, Immunity, Receptors, Antigen, T-Cell, gamma-delta, Mycobacterium tuberculosis, Nuclear Receptor Subfamily 1, Group F, Member 3, Mycobacterium bovis, Pedigree, Child, Preschool, Mutation, Cattle, Female, Severe Combined Immunodeficiency, Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor, Tuberculosis, Bovine
Abstract

Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORγ and RORγT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORγ- and RORγT-deficient individuals also displayed an impaired IFN-γ response to Mycobacterium. This principally reflected profoundly defective IFN-γ production by circulating γδ T cells and CD4(+)CCR6(+)CXCR3(+) αβ T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORγ, RORγT, or both.

Published
2014

48. Association study of genes controlling IL-12-dependent IFN-γ immunity: STAT4 alleles increase risk of pulmonary tuberculosis in Morocco

Author

Ahmed Abid, Jamila El Baghdadi, Laurent Abel, Ismail Abderrahmani Rhorfi, Anne Boland, Kristel Cosker, Ayoub Sabri, Safa El Azbaoui, Audrey V. Grant, Hicham Janah, Erwin Schurr, Jacinta Bustamante, Mélanie Migaud, Caroline Deswarte, Marianna Orlova, Stéphanie Boisson-Dupuis, Jean-Laurent Casanova, Majid Benkirane, Yasser Gharbaoui, H. Souhi, and Kebir Alaoui-Tahiri

Subjects
Male, Pathogenesis and Host Response, genetic association, STAT4, Genotype, Immunology and Allergy, Child, IFN-γ, education.field_of_study, biology, Middle Aged, STAT4 Transcription Factor, Interleukin-12, 3. Good health, Morocco, Infectious Diseases, IL-12, Child, Preschool, Female, pulmonary tuberculosis, candidate pathway, Adult, Risk, Tuberculosis, Adolescent, Population, Single-nucleotide polymorphism, eQTL, Polymorphism, Single Nucleotide, Mycobacterium tuberculosis, Interferon-gamma, Young Adult, Major Articles and Brief Reports, medicine, Humans, Genetic Predisposition to Disease, Allele, education, Tuberculosis, Pulmonary, Alleles, Genetic association, Aged, Case-control study, Infant, family-based study, medicine.disease, biology.organism_classification, Case-Control Studies, common variant, Immunology, Behcet disease
Abstract

Background. Only a minority of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis. Genetic epidemiological evidence suggests that pulmonary tuberculosis has a strong human genetic component. Previous genetic findings in Mendelian predisposition to more severe mycobacterial infections, including by M. tuberculosis, underlined the importance of the interleukin 12 (IL-12)/interferon γ (IFN-γ) circuit in antimycobacterial immunity. Methods. We conducted an association study in Morocco between pulmonary tuberculosis and a panel of single-nucleotide polymorphisms (SNPs) covering 14 core IL-12/IFN-γ circuit genes. The analyses were performed in a discovery family-based sample followed by replication in a case-control population. Results. Out of 228 SNPs tested in the family-based sample, 6 STAT4 SNPs were associated with pulmonary tuberculosis (P = .0013–.01). We replicated the same direction of association for 1 cluster of 3 SNPs encompassing the promoter region of STAT4. In the combined sample, the association was stronger among younger subjects (pulmonary tuberculosis onset

Published
2014

49. Inherited human OX40 deficiency underlying classic Kaposi sarcoma of childhood

Author

Bernhard Fleckenstein, Lazaro Lorenzo, Martin Olivier, Antoine Gessain, Nur Canpolat, Cindy S. Ma, Vincent Pedergnana, Olivier Cassar, Jinjong Myoung, Michael Croft, Avinash Abhyankar, Jean-Laurent Casanova, Monika Schmidt, Emmanuelle Jouanguy, Laurent Abel, Danielle T. Avery, Ethel Cesarman, Stuart G. Tangye, Capucine Picard, Flore Rozenberg, Arzu Akcay, Gonul Aydogan, Philippe Gros, Jacinta Bustamante, Mélanie Migaud, Minji Byun, Yifang Liu, Umaimainthan Palendira, Hye Kyung Lim, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, rockefeller university, Immunology Program, Garvan Institute of medical research, St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales [Sydney] ( UNSW ), Pediatric Hematology and Oncology, Kanuni Sultan Suleyman Education and Research Hospital, Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Novartis Institutes for BioMedical Research, Department of Pathology and Laboratory Medicine, Weil Cornell Medical College, Institut für Klinische und Molekulare Virologie, Friedrich-Alexander Universität Erlangen-Nürnberg ( FAU ), Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Université Paris Descartes - Paris 5 ( UPD5 ), Department of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University, CHU Necker - Enfants Malades [AP-HP], McGill University, La Jolla Institute for Allergy & Immunology ( LA JOLLA Institute ), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the Institut National de la Santé et de la Recherche Médicale, University Paris Descartes, the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID), the St. Giles Foundation, the National Center for Research Resources and the National Center for Advancing Sciences (NCATS) grant number 8UL1TR000043 from the National Institutes of Health, and the Rockefeller University. M. Byun is supported by the Charles H. Revson Foundation and formerly by the Irvington Institute Fellowship Program of the Cancer Research Institute. C.S. Ma, U. Palendira, and S.G. Tangye are supported by the National Health and Medical Research Council of Australia and Cancer Council New South Wales. E. Cesarman is funded by National Institutes of Health grants R01CA103646 and R01CA154228. J.-L. Casanova is a member of the Sanofi Strategic Development and Scientific Advisory Committee. The authors have no additional conflicting financial interests., ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' ( 2010 ), Ziani, Isma, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], University of New South Wales [Sydney] (UNSW), Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Novartis Institutes for BioMedical Research (NIBR), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Epidémiologie et Physiopathologie des Virus Oncogènes (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), McGill University = Université McGill [Montréal, Canada], La Jolla Institute for Immunology [La Jolla, CA, États-Unis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], Inheritance Patterns, Intracellular Space, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, T-Lymphocyte Subsets, Immunology and Allergy, IL-2 receptor, Age of Onset, Child, [ SDV.GEN.GH ] Life Sciences [q-bio]/Genetics/Human genetics, 0303 health sciences, Homozygote, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Female, Adult, Cell type, T cell, Molecular Sequence Data, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Article, Young Adult, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigen, Immunity, medicine, Humans, Amino Acid Sequence, Cysteine, Lymphocyte Count, Sarcoma, Kaposi, 030304 developmental biology, Classic Kaposi Sarcoma, Base Sequence, [ SDV ] Life Sciences [q-bio], Cell Membrane, HEK 293 cells, biochemical phenomena, metabolism, and nutrition, Receptors, OX40, HEK293 Cells, Amino Acid Substitution, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Antibody Formation, Mutation, Mutant Proteins, Immunologic Memory, CD8, 030215 immunology
Abstract

Human OX40 is necessary for robust CD4+ T cell memory and confers selective protective immunity against HHV-8 infection in endothelial cells., Kaposi sarcoma (KS), a human herpes virus 8 (HHV-8; also called KSHV)–induced endothelial tumor, develops only in a small fraction of individuals infected with HHV-8. We hypothesized that inborn errors of immunity to HHV-8 might underlie the exceedingly rare development of classic KS in childhood. We report here autosomal recessive OX40 deficiency in an otherwise healthy adult with childhood-onset classic KS. OX40 is a co-stimulatory receptor expressed on activated T cells. Its ligand, OX40L, is expressed on various cell types, including endothelial cells. We found OX40L was abundantly expressed in KS lesions. The mutant OX40 protein was poorly expressed on the cell surface and failed to bind OX40L, resulting in complete functional OX40 deficiency. The patient had a low proportion of effector memory CD4+ T cells in the peripheral blood, consistent with impaired CD4+ T cell responses to recall antigens in vitro. The proportion of effector memory CD8+ T cells was less diminished. The proportion of circulating memory B cells was low, but the antibody response in vivo was intact, including the response to a vaccine boost. Together, these findings suggest that human OX40 is necessary for robust CD4+ T cell memory and confers apparently selective protective immunity against HHV-8 infection in endothelial cells.

Published
2013

50. Age-dependent association between pulmonary tuberculosis and common TOX variants in the 8q12-13 linkage region

Author

Erwin Schurr, Marianna Orlova, Ayoub Sabri, Vaomalala Raharimanga, Ahmed Abid, Anne Boland, Yasser Gharbaoui, Safa El Azbaoui, Daniel K. Nolan, Luis B. Barreiro, Laurent Abel, Jamila El Baghdadi, Jean-Laurent Casanova, Majid Benkirane, Satoshi Okada, Ismail Abderrahmani Rhorfi, Voahangy Rasolofo, Jacinta Bustamante, Mélanie Migaud, Vincent Richard, Stéphanie Boisson-Dupuis, Audrey V. Grant, Kebir Alaoui-Tahiri, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Genetics Unit, Military Hospital Mohamed V, Department of Pneumology, Blood Transfusion Center, Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), McGill Centre for the Study of Host Resistance, McGill University = Université McGill [Montréal, Canada], Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Pediatrics, Faculty of Medicine, Sainte-Justine Hospital Research Centre, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, Université Paris Descartes - Paris 5 (UPD5), Pasteur Institute of Paris (Progamme Transversal de Recherche PTR202), Bill and Melinda Gates Foundation, St. Giles Foundation, Jeffrey Modell Foundation and Talecris Biotherapeutics, Rockefeller University Center for Clinical and Translational Science (5UL1RR024143-04) Rockefeller University, and National Institute of Allergy and Infectious Diseases (1R01AI089970-01 and U01AI088685). A.V.G. was partly supported by the Fondation pour la Recherche Médicale and Fondation BNP Paribas. L.B.B. is a scholar of the Fonds de la Recherche en Santé du Québec., Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal]-Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Institut Pasteur de Madagascar-Réseau International des Instituts Pasteur ( RIIP ), The Research Institute of the McGill-University Health Centre, Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, rockefeller university, Université de Montréal-Sainte-Justine Hospital Research Centre, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [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), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), McGill University, and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]

Subjects
Male, Linkage disequilibrium, MESH: Mycobacterium tuberculosis, MESH : Tuberculosis, Pulmonary, Genetic Linkage, [SDV]Life Sciences [q-bio], MESH : Genotype, environment and public health, Linkage Disequilibrium, MESH: Genotype, MESH: Madagascar, MESH : Genetic Loci, MESH : Chromosomes, Human, Pair 8, Genetics(clinical), MESH : Female, Genetics (clinical), Genetics, 0303 health sciences, MESH : Linkage Disequilibrium, MESH : High Mobility Group Proteins, integumentary system, MESH: Polymorphism, Single Nucleotide, MESH : Polymorphism, Single Nucleotide, Age Factors, High Mobility Group Proteins, MESH: Genetic Predisposition to Disease, MESH: European Continental Ancestry Group, MESH : Adult, MESH: Case-Control Studies, 3. Good health, Morocco, MESH: Linkage Disequilibrium, Chromosomal region, Female, Chromosomes, Human, Pair 8, Adult, MESH : Case-Control Studies, Tuberculosis, Genotype, MESH : Madagascar, MESH : Male, MESH: Genetic Linkage, macromolecular substances, Biology, Polymorphism, Single Nucleotide, MESH: Genetic Loci, White People, Genetic determinism, Mycobacterium tuberculosis, MESH : European Continental Ancestry Group, 03 medical and health sciences, MESH : Mycobacterium tuberculosis, Report, Madagascar, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Allele, MESH : Morocco, Tuberculosis, Pulmonary, Genotyping, Alleles, 030304 developmental biology, MESH: Age Factors, MESH: Tuberculosis, Pulmonary, MESH: Humans, [ SDV ] Life Sciences [q-bio], 030306 microbiology, MESH: Alleles, MESH : Humans, MESH: Adult, biology.organism_classification, medicine.disease, MESH: High Mobility Group Proteins, MESH : Genetic Linkage, MESH: Male, Genetic Loci, Case-Control Studies, MESH: Morocco, MESH : Genetic Predisposition to Disease, MESH : Age Factors, MESH : Alleles, MESH: Chromosomes, Human, Pair 8, MESH: Female
Abstract

International audience; Only a small fraction of individuals infected with Mycobacterium tuberculosis develop clinical tuberculosis (TB) in their lifetime. Genetic epidemiological evidence suggests a genetic determinism of pulmonary TB (PTB), but the molecular basis of genetic predisposition to PTB remains largely unknown. We used a positional-cloning approach to carry out ultrafine linkage-disequilibrium mapping of a previously identified susceptibility locus in chromosomal region 8q12-13 by genotyping 3,216 SNPs in a family-based Moroccan sample including 286 offspring with PTB. We observed 44 PTB-associated SNPs (p < 0.01), which were genotyped in an independent set of 317 cases and 650 controls from Morocco. A single signal, consisting of two correlated SNPs close to TOX, rs1568952 and rs2726600 (combined p = 1.1 × 10(-5) and 9.2 × 10(-5), respectively), was replicated. Stronger evidence of association was found in individuals who developed PTB before the age of 25 years (combined p for rs1568952 = 4.4 × 10(-8); odds ratio of PTB for AA versus AG/GG = 3.09 [1.99-4.78]). The association with rs2726600 (p = 0.04) was subsequently replicated in PTB-affected subjects under 25 years in a study of 243 nuclear families from Madagascar. Stronger evidence of replication in Madagascar was obtained for additional SNPs in strong linkage disequilibrium with the two initial SNPs (p = 0.003 for rs2726597), further confirming the signal. We thus identified around rs1568952 and rs2726600 a cluster of SNPs strongly associated with early-onset PTB in Morocco and Madagascar. SNP rs2726600 is located in a transcription-factor binding site in the 3' region of TOX, and further functional explorations will focus on CD4 T lymphocytes.

Published
2013

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