Author: "Lazaro Lorenzo" / Topic: immunology and allergy - Searchworks@Jio Institute Digital Library Search Results

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1. Fulminant viral hepatitis in two siblings with inherited IL-10RB deficiency

Author: Cecilia B. Korol, Serkan Belkaya, Fahad Alsohime, Lazaro Lorenzo, Stéphanie Boisson-Dupuis, Joseph Brancale, Anna-Lena Neehus, Silvia Vilarinho, Alsum Zobaida, Rabih Halwani, Saleh Al-Muhsen, Jean-Laurent Casanova, Emmanuelle Jouanguy, and Belkaya, Serkan
Subjects: Excessive IFN-gamma, Inborn error of immunity, IFN-λ, Immunology, Fulminant viral hepatitis, IL-18BP, Autosomal recessive disease, Inherited IL-10RB deficiency, IL-10, IL-22, Immunology and Allergy, Hepatitis A virus, Early-onset inflammatory bowel disease, IL-18
Abstract: Fulminant viral hepatitis (FVH) caused by hepatitis A virus (HAV) is a life-threatening disease that typically strikes otherwise healthy individuals. The only known genetic etiology of FVH is inherited IL-18BP deficiency, which unleashes IL-18-dependent lymphocyte cytotoxicity and IFN-γ production. We studied two siblings who died from a combination of early-onset inflammatory bowel disease (EOIBD) and FVH due to HAV. The sibling tested was homozygous for the W100G variant of IL10RB previously described in an unrelated patient with EOIBD. We show here that the out-of-frame IL10RB variants seen in other EOIBD patients disrupt cellular responses to IL-10, IL-22, IL-26, and IFN-λs in overexpression conditions and in homozygous cells. By contrast, the impact of in-frame disease-causing variants varies between cases. When overexpressed, the W100G variant impairs cellular responses to IL-10, but not to IL-22, IL-26, or IFN-λ1, whereas cells homozygous for W100G do not respond to IL-10, IL-22, IL-26, or IFN-λ1. As IL-10 is a potent antagonist of IFN-γ in phagocytes, these findings suggest that the molecular basis of FVH in patients with IL-18BP or IL-10RB deficiency may involve excessive IFN-γ activity during HAV infections of the liver. Inherited IL-10RB deficiency, and possibly inherited IL-10 and IL-10RA deficiencies, confer a predisposition to FVH, and patients with these deficiencies should be vaccinated against HAV and other liver-tropic viruses.
Published: 2022

2. A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes

Author: Paul Bastard, Kuang-Chih Hsiao, Qian Zhang, Jeremy Choin, Emma Best, Jie Chen, Adrian Gervais, Lucy Bizien, Marie Materna, Christine Harmant, Maguelonne Roux, Nicola L. Hawley, Daniel E. Weeks, Stephen T. McGarvey, Karla Sandoval, Carmina Barberena-Jonas, Consuelo D. Quinto-Cortés, Erika Hagelberg, Alexander J. Mentzer, Kathryn Robson, Boubacar Coulibaly, Yoann Seeleuthner, Benedetta Bigio, Zhi Li, Gilles Uzé, Sandra Pellegrini, Lazaro Lorenzo, Zineb Sbihi, Sylvain Latour, Marianne Besnard, Tiphaine Adam de Beaumais, Evelyne Jacqz Aigrain, Vivien Béziat, Ranjan Deka, Litara Esera Tulifau, Satupa‘itea Viali, Muagututi‘a Sefuiva Reupena, Take Naseri, Peter McNaughton, Vanessa Sarkozy, Jane Peake, Annaliesse Blincoe, Sarah Primhak, Simon Stables, Kate Gibson, See-Tarn Woon, Kylie Marie Drake, Adrian V.S. Hill, Cheng-Yee Chan, Richard King, Rohan Ameratunga, Iotefa Teiti, Maite Aubry, Van-Mai Cao-Lormeau, Stuart G. Tangye, Shen-Ying Zhang, Emmanuelle Jouanguy, Paul Gray, Laurent Abel, Andrés Moreno-Estrada, Ryan L. Minster, Lluis Quintana-Murci, Andrew C. Wood, Jean-Laurent Casanova, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Rockefeller University [New York], Human genetics of infectious diseases: Complex predisposition (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Département de Pédiatrie et maladies infectieuses [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Howard Hughes Medical Institute (HHMI), University of Auckland [Auckland], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Collège de France - Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Langebio (CINVESTAV), University of New South Wales [Sydney] (UNSW), Sydney Children's hospital, Garvan Institute of medical research, UNSW Faculty of Medicine [Sydney], Institut Louis Malardé [Papeete] (ILM), Institut de Recherche pour le Développement (IRD), Auckland City Hospital, Canterbury Health Laboratories, University of Oxford, University of Queensland [Brisbane], Brown University, Ministry of Health [Samoa], Tupua Tamasese Meaole Hospital (TTM), University of Cincinnati (UC), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Institut Gustave Roussy (IGR), Centre Hospitalier de Polynésie Française, Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), University of Oslo (UiO), National Laboratory of Genomics for Biodiversity (LANGEBIO), Centro de Investigacion y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), Yale University [New Haven], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Shanghai Jiaotong University, Murdoch Children's Research Institute (MCRI), The laboratory of V.-M. Cao-Lormeau is supported by MATAEA grant no. 03557/MED/REC_29/05/2019 (Délégation à la recherche de la Polynésie française). The Laboratory of Human Evolutionary Genetics is supported by Institut Pasteur, Collège de France, the Centre national de la recherche scientifique, Fondation Allianz-Institut de France, the French Government’s Investissement d’Avenir program, Laboratoires d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID) and 'Milieu Intérieur' (ANR-10-LABX-69-01), Fondation de France (grant no. 00106080), and Fondation pour la Recherche Médicale (Equipe FRM DEQ20180339214). The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH, R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences, the NIH Clinical and Translational Science Award program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics, and the Genome Sequencing Program Coordinating Center funded by the National Human Genome Research Institute (UM1HG006504 and U24HG008956), the Yale High-Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM, EQU201903007798), the FRM and ANR GENCOVID project, the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the European Union’s Horizon 2020 research and innovation program under grant agreement 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, INSERM, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), and the University of Paris. P. Bastard was supported by the FRM (EA20170638020) and by the MD-PhD program of the Imagine Institute (with the support of Fondation Bettencourt-Schueller). The National Laboratory of Genomics for Biodiversity (LANGEBIO-CINVESTAV) in Mexico is supported by Consejo Nacional de Ciencia y Technologia (grant number FONCICYT/50/2016), The Newton Fund through the Medical Research Council (grant number MR/N028937/1), and the International Center for Genetic Engineering and Biotechnology grant number CRP/MEX20-01, awarded to A. Moreno-Estrada. S.G. Tangye is supported by a Leadership 3 Investigator Grant awarded by the National Health and Medical Research Council of Australia (1176665) and the Jeffrey Modell Foundation. Clinical Immunogenomics Research Consortium Australasia investigators (K.-C. Hsiao, P. McNaughton, A. Blincoe, J. Peake, S.G. Tangye, and P. Gray) are supported by the John Brown Cook Foundation. This work was supported by the National Institutes of Health grants R01-HL093093 (S.T. McGarvey) and R01-HL133040 (R.L. Minster). Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program were provided by the National Heart, Lung, and Blood Institute (NHLBI). Genome sequencing for the Soifua Manuia study, labeled 'NHLBI TOPMed: Genome-wide Association Study of Adiposity in Samoans' (phs000972.v4.p1) in the dbGaP, was performed at the Northwest Genomics Center (HHSN268201100037C) and the New York Genome Center (HHSN268201500016C). Core support, including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering, was provided by the TOPMed Informatics Research Center (3R01-HL117626-02S1, contract HHSN268201800002I). Core support, including phenotype harmonization, data management, sample-identity QC, and general program coordination, was also provided by the TOPMed Data Coordinating Center (R01-HL120393, U01-HL120393, contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. This research was funded in whole or in part by the French National Research Agency (ANR)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), 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), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Institut Pasteur [Paris]-Université Paris Cité (UPC), University of Oxford [Oxford], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institute for Regenerative Medicine and Biotherapy [Montpellier], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Université Paris Cité (UPC), Garvan Institute of Medical Research [Sydney, Australia], and Chaire Génomique humaine et évolution
Subjects: [SDV.GEN]Life Sciences [q-bio]/Genetics, Infectious disease and host defense, Homozygote, Immunology, Innate immunity and inflammation, Receptor, Interferon alpha-beta, Polynesia, Virus Diseases, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Humans, Immunology and Allergy, Immunodeficiency, Child, Alleles, Human disease genetics
Abstract: International audience; Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-β). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.
Published: 2022
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3. Human BCL10 Deficiency due to Homozygosity for a Rare Allele

Author: Lazaro Lorenzo, Jean-Laurent Casanova, Carolina Cubillos-Zapata, Eduardo López-Collazo, Anne Puel, Silvia Sánchez-Ramón, Amin Safa, Rebeca Pérez de Diego, María Vela, Antonio Pérez-Martínez, Mukesh Desai, Maria J. Recio, Ana Van Den Rym, Prasad Taur, Vijaya Gowri, Ambreen Pandrowala, Rubén Martínez-Barricarte, Pablo Gonzalez-Navarro, and Victor Toledano
Subjects: Male, 0301 basic medicine, T-Lymphocytes, T cell, Immunology, Chromosome Disorders, Biology, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Immunology and Allergy, Lectins, C-Type, Allele, Respiratory Tract Infections, Cells, Cultured, Immunodeficiency, B-Lymphocytes, Mutation, Homozygote, Toll-Like Receptors, Immunologic Deficiency Syndromes, Infant, B-Cell CLL-Lymphoma 10 Protein, medicine.disease, Phenotype, BCL10, Minor allele frequency, 030104 developmental biology, medicine.anatomical_structure, Primary immunodeficiency, Immunologic Memory, 030215 immunology
Abstract: In 2014, a child with broad combined immunodeficiency (CID) who was homozygous for a private BCL10 allele was reported to have complete inherited human BCL10 deficiency. In the present study, we report a new BCL10 mutation in another child with CID who was homozygous for a BCL10 variant (R88X), previously reported as a rare allele in heterozygosis (minor allele frequency, 0.000003986). The mutant allele was a loss-of-expression and loss-of-function allele. As with the previously reported patient, this patient had complete BCL10 deficiency. The clinical phenotype shared features, such as respiratory infections, but differed from that of the previous patient that he did not develop significant gastroenteritis episodes or chronic colitis. Cellular and immunological phenotypes were similar to those of the previous patient. TLR4, TLR2/6, and Dectin-1 responses were found to depend on BCL10 in fibroblasts, and final maturation of T cell and B cell maturation into memory cells was affected. Autosomal-recessive BCL10 deficiency should therefore be considered in children with CID.
Published: 2020
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4. Clinical and Immunological Features of Human BCL10 Deficiency

Author: Blanca Garcia-Solis, Ana Van Den Rym, Jareb J. Pérez-Caraballo, Abdulwahab Al–Ayoubi, Anas M. Alazami, Lazaro Lorenzo, Carolina Cubillos-Zapata, Eduardo López-Collazo, Antonio Pérez-Martínez, Luis M. Allende, Janet Markle, Miguel Fernández-Arquero, Silvia Sánchez-Ramón, Maria J. Recio, Jean-Laurent Casanova, Reem Mohammed, Rubén Martinez-Barricarte, and Rebeca Pérez de Diego
Subjects: mass cytometry, Primary Immunodeficiency Diseases, Nonsense mutation, DNA Mutational Analysis, Immunology, Disease, primary immunodeficiency, BCL10, computational immunology, Immune system, CBM complex, Medicine, Humans, combined immunodeficiency, Immunology and Allergy, Mass cytometry, Lymphocytes, Family history, Child, Original Research, business.industry, Hematopoietic Stem Cell Transplantation, autosomal recessive, RC581-607, medicine.disease, B-Cell CLL-Lymphoma 10 Protein, Transplantation, Haematopoiesis, Codon, Nonsense, Primary immunodeficiency, next-generation sequencing, Female, Immunologic diseases. Allergy, business
Abstract: The CARD-BCL10-MALT1 (CBM) complex is critical for the proper assembly of human immune responses. The clinical and immunological consequences of deficiencies in some of its components such as CARD9, CARD11, and MALT1 have been elucidated in detail. However, the scarcity of BCL10 deficient patients has prevented gaining detailed knowledge about this genetic disease. Only two patients with BCL10 deficiency have been reported to date. Here we provide an in-depth description of an additional patient with autosomal recessive complete BCL10 deficiency caused by a nonsense mutation that leads to a loss of expression (K63X). Using mass cytometry coupled with unsupervised clustering and machine learning computational methods, we obtained a thorough characterization of the consequences of BCL10 deficiency in different populations of leukocytes. We showed that in addition to the near absence of memory B and T cells previously reported, this patient displays a reduction in NK, γδT, Tregs, and TFH cells. The patient had recurrent respiratory infections since early childhood, and showed a family history of lethal severe infectious diseases. Fortunately, hematopoietic stem-cell transplantation (HSCT) cured her. Overall, this report highlights the importance of early genetic diagnosis for the management of BCL10 deficient patients and HSCT as the recommended treatment to cure this disease.
Published: 2021
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5. Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis

Author: Shen-Ying Zhang, Mélodie Aubart, Lazaro Lorenzo, Helen C. Su, Soraya Boucherit, Zhiyong Liu, Danyel Lee, Paul Bastard, Andrea Martín-Nalda, Jie Chen, Laurent Abel, Jeremy Manry, Pere Soler Palacín, Jean-Laurent Casanova, Jacques G. Rivière, Huie Jing, Mary Hasek, Flore Rozenberg, Roger Colobran, Wesley Tung, Université Paris Cité, Equipe HAL, APPEL À PROJETS GÉNÉRIQUE 2018 - Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est - - SEAe-HostFactors2018 - ANR-18-CE15-0020 - AAPG2018 - VALID, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Laboratory of Clinical Immunology and Microbiology [Bethesda, MA, USA] (LCIM), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Vall d’Hebron Research Institute (VHIR), Vall d'Hebron University Hospital [Barcelona], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurochirurgie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), ANR-18-CE15-0020,SEAe-HostFactors,Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est(2018), and ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010)
Subjects: Male, Interferon-Induced Helicase, IFIH1, viruses, Immunology, chemical and pharmacologic phenomena, Interferon alpha-2, Biology, Virus Replication, medicine.disease_cause, Compound heterozygosity, Loss of Function Mutation, Immunity, Enterovirus Infections, medicine, Extracellular, Humans, Immunology and Allergy, Encephalitis, Viral, Cells, Cultured, Enterovirus, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Infant, MDA5, Interferon-beta, Fibroblasts, Virology, Toll-Like Receptor 3, Rhombencephalon, Poly I-C, Cell culture, Child, Preschool, TLR3, Female, Metabolism, Inborn Errors, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Intracellular
Abstract: International audience; Enterovirus (EV) infection rarely results in life-threatening infection of the central nervous system. We report two unrelated children with EV30 and EV71 rhombencephalitis. One patient carries compound heterozygous TLR3 variants (loss-of-function F322fs2* and hypomorphic D280N), and the other is homozygous for an IFIH1 variant (loss-of-function c.1641+1G>C). Their fibroblasts respond poorly to extracellular (TLR3) or intracellular (MDA5) poly(I:C) stimulation. The baseline (TLR3) and EV-responsive (MDA5) levels of IFN-β in the patients’ fibroblasts are low. EV growth is enhanced at early and late time points of infection in TLR3- and MDA5-deficient fibroblasts, respectively. Treatment with exogenous IFN-α2b before infection renders both cell lines resistant to EV30 and EV71, whereas post-infection treatment with IFN-α2b rescues viral susceptibility fully only in MDA5-deficient fibroblasts. Finally, the poly(I:C) and viral phenotypes of fibroblasts are rescued by the expression of WT TLR3 or MDA5. Human TLR3 and MDA5 are critical for cell-intrinsic immunity to EV, via the control of baseline and virus-induced type I IFN production, respectively.
Published: 2021
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6. Inherited IFNAR1 deficiency in otherwise healthy patients with adverse reaction to measles and yellow fever live vaccines

Author: Stephen J. Seligman, Serkan Belkaya, Ruben Pholien, Ismail Reisli, Johan Neyts, Yoann Seeleuthner, Leen Moens, Afshin Shirkani, Scott Drutman, Charles M. Rice, Lazaro Lorenzo-Diaz, Isabelle Meyts, Margaret R. MacDonald, Emersom Ciclini Mesquita, Dick Zijlmans, Denise Cristina de Souza Matos, Nicholas Hernandez, Sheila Maria Barbosa de Lima, Maria de Lourdes de Sousa Maia, Alain Lefevre-Utile, Dirk Jochmans, Paul J. Hertzog, Tamiris Azamor da Costa Barros, Marilda M. Siqueira, Esra Hazar Sayar, Hans Heinrich Hoffmann, Xavier Bossuyt, Nico Marr, Qian Zhang, Patrícia Mouta Nunes de Oliveira, Laura Pöyhönen, Emmanuelle Jouanguy, Giorgia Bucciol, Andrea Jurado, Shen-Ying Zhang, Aurélie Cobat, Robbert Boudewijns, Hassan Rokni-Zadeh, Jérémie Le Pen, Ekaterini Goudouris, Rik Gijsbers, Ian Tietjen, Chibuzo U Enemchukwu, Reinaldo de Menezes Martins, Laurent Abel, Majid Changi-Ashtiani, Jean-Laurent Casanova, Mohammad Shahrooei, Mana Momenilandi, and Akira Homma
Subjects: Male, 0301 basic medicine, Adolescent, Measles-Mumps-Rubella Vaccine, Measles Vaccine, Immunology, Inheritance Patterns, Yellow fever vaccine, Receptor, Interferon alpha-beta, Rubella, Measles, Article, 03 medical and health sciences, 0302 clinical medicine, Immunity, medicine, Humans, Immunology and Allergy, Child, Research Articles, Alleles, business.industry, Yellow Fever Vaccine, Yellow fever, Infant, medicine.disease, Virology, Pedigree, 3. Good health, Vaccination, 030104 developmental biology, Interferon Type I, Mutation, Female, Mutant Proteins, Measles vaccine, business, Signal Transduction, 030215 immunology, medicine.drug
Abstract: We describe two unrelated patients with inherited IFNAR1 deficiency who suffered from life-threatening infections following measles or yellow fever virus vaccination and were otherwise healthy., Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients’ fibroblast phenotypes are rescued with WT IFNAR1. Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.
Published: 2019
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7. Inherited GATA2 deficiency is dominant by haploinsufficiency and displays incomplete clinical penetrance

Author: Rubén Martínez-Barricarte, Guillaume Vogt, Gabriela López-Herrera, Lidia Branco, Laurent Abel, Patricia Mariá O.Farrill Romanillos, Anna-Lena Neehus, Manon Roynard, Bengü Gerçeker, Júlia Vasconcelos, José Luis Franco Restrepo, Franck Rapaport, Sairaj Munavar Sajjath, Caroline Deswarte, Jean Donadieu, Christine Bellanné-Chantelot, Fatma Omur Ardeniz, Antoine Guérin, Antonio Condino-Neto, Noé Ramirez Alejo, A. S. Brunel, Caroline Thomas, Claire Lozano, Alexis Cuffel, Laura Berrón-Ruiz, Rebeca Pérez de Diego, Carmen Oleaga-Quintas, Kang Liu, Elise Launay, Mónica Martínez-Gallo, Vanesa Cunill Monjo, Marlène Pasquet, Laura Marques, D.B. Lew, Claire Fieschi, Fethi Mellouli, Tom Le Voyer, Carlos Rodríguez-Gallego, Luiz Fernando Job Jobim, Nora Hilda Segura Méndez, Eric Jeziorski, Yu Jerry Zhou, Andrés Augusto Arias, Stéphanie Boisson-Dupuis, Marie-Gabrielle Vigué, Anne Puel, Stéphane Marot, Aurélie Cobat, Kacy A Ramirez, Nuria Fernández-Hidalgo, Jacinta Bustamante, Jérémie Rosain, Lazaro Lorenzo-Diaz, Mariana Jobim, Regis A. Campos, Torsten Witte, Roger Colobran, Jean-Laurent Casanova, Marcela Moncada-Vélez, Edgar Borges de Oliveira-Júnior, and Ege Üniversitesi
Subjects: Adult, Male, Adolescent, Genotype, GATA2 Deficiency, mycobacteria, DNA Mutational Analysis, Immunology, Penetrance, Context (language use), Locus (genetics), Kaplan-Meier Estimate, Monocytopenia, Asymptomatic, Article, Cell Line, Young Adult, Databases, Genetic, Outcome Assessment, Health Care, Exome Sequencing, medicine, GATA2, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Child, Alleles, Genetic Association Studies, Germ-Line Mutation, Genes, Dominant, Mycobacterium Infections, Primary immunodeficiency, FENÓTIPOS, business.industry, Middle Aged, medicine.disease, Hematologic Diseases, Pedigree, haploinsufficiency, Phenotype, tuberculosis, Female, medicine.symptom, business, Haploinsufficiency
Abstract: Purpose Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. Methods We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. Results We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. Conclusion Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus., INSERM, University of Paris; Rockefeller University; St. Giles Foundation; National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R37AI095983]; French National Research Agency (ANR) under the "Investments for the future" programFrench National Research Agency (ANR) [ANR-10-IAHU-01, ANR13-ISV3-0001-01, ANR-16-CE17-0005-01]; ECOS-NORD [C19S01-63407, SRC2017]; ANRHGDIFDFrench National Research Agency (ANR) [ANR-14-CE15-006-01]; ANR-IFNGPHOX [ANR-13-ISV3-0001-01]; GENMSMD [ANR-16-CE17-0005-01]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2012/11757-2, 2010/51814-0, 2012/51094-2]; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ)National Council for Scientific and Technological Development (CNPq) [303809/2010-8]; Instituto de Salud Carlos IIIInstituto de Salud Carlos IIIEuropean Commission [PI11/01086, PI14/00405]; European Regional Development Fund (ERDF)European Commission; Colombia-France (ECOS-NORD/COLCIENCIAS/MEN/ICETEX) [619-2013]; Diana Garcia de Olarte foundation PID; ColcienciasDepartamento Administrativo de Ciencia, Tecnologia e Innovacion Colciencias [713-2016, 111574455633]; "Poste d'accueil" INSERMInstitut National de la Sante et de la Recherche Medicale (Inserm); Imagine Institute, The Laboratory of Human Genetics of Infectious Diseases is supported in part by institutional grants from INSERM, University of Paris, The Rockefeller University and the St. Giles Foundation, the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) (R37AI095983), and grants from the French National Research Agency (ANR) under the "Investments for the future" program (ANR-10-IAHU-01) and IFNGPHOX (ANR13-ISV3-0001-01 for JB and ACN), GENMSMD (ANR-16-CE17-0005-01 for JB) grants, ECOS-NORD (C19S01-63407 for JB and JFR), and SRC2017 (for JB). CO-Q is supported by ANRHGDIFD (ANR-14-CE15-006-01). AG was supported by the ANR-IFNGPHOX (ANR-13-ISV3-0001-01), GENMSMD (ANR-16-CE17-0005-01), and the Imagine Institute. AC-N and EBO-J are supported by Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP grants 2012/11757-2, 2010/51814-0, and 2012/51094-2) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ grant 303809/2010-8). MMG and RC are supported by Instituto de Salud Carlos III, grants PI11/01086 and PI14/00405, co-financed by the European Regional Development Fund (ERDF). JFR and AAA are supported by Colombia-France (ECOS-NORD/COLCIENCIAS/MEN/ICETEX; 619-2013, Diana Garcia de Olarte foundation PID and Colciencias grant 713-2016 #111574455633). JR was supported by "Poste d'accueil" INSERM and Imagine Institute.
Published: 2021

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

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

9. Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis

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

10. The human CIB1–EVER1–EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses

Author: Matthieu Bouaziz, Sirous Zeinali, Vignesh Gunasekharan, Fabienne Jabot-Hanin, Sarah Jill De Jong, Peter Itin, Nessa Aghazadeh, Xavier Rueda Cadena, E. Imahorn, Aurelia D’Amico, Amandine Crequer, Irina Matos, Elaine Fuchs, Bettina Burger, Janet Markle, David Hum, Etienne Patin, Florian Full, Bayaki Saka, Amir Hossein Saeidian, Laurent Abel, James G. Krueger, Nataly Portilla Maya, Claire Q.F. Wang, Jouni Uitto, Emmanuelle Jouanguy, Leila Youssefian, Hassan Vahidnezhad, Armin Ensser, Andrés Augusto Arias, Leslie V. Parise, Tina M. Leisner, Jean-Laurent Casanova, Lou Laimins, Lazaro Lorenzo, Gérard Orth, José Luis Franco, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Northwestern University [Evanston], 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), University of Basel (Unibas), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Institut Pasteur d'Iran, Réseau International des Instituts Pasteur (RIIP), Sidney Kimmel Medical College [Philadelphia], Jefferson (Philadelphia University + Thomas Jefferson University), Tehran University of Medical Sciences (TUMS), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Fundación Universitaria de Ciencias de la Salud = University Foundation of Health Sciences [Bogotá, Colombia] (FUCS), Instituto Nacional de Cancerologia = National Cancer Institute [Bogotá], Université de Lomé [Togo], Kawsar Human Genetics Research Center, Kawsar Genomics and Biotech Cente, University Hospital Basel [Basel], Département de Virologie - Department of Virology, Institut Pasteur [Paris], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), The Laboratory of Human Genetics of Infectious Diseases is supported by grants from the National Institutes of Health (grant 5 R21 AI107508-02) and the French Cancer Institute (grant 2013-1-PL BIO-11-1). L.V. Parise and T.M. Leisner are supported by National Institutes of Health grant R41 CA200189. S.J. de Jong was supported by the German Research Foundation (Jo 1151-1), funds from the Women Science Fellowship program at The Rockefeller University, and the National Institutes of Health Clinical and Translational Science Award program (UL1 TR001866). J.L. Franco and A.A. Arias were supported by the Fundación Diana Garcia de Olarte FIP and Colciencias Programa de Intercambio de investigadores e innovadores Colombia-Francia (ECOS-NORD/COLCIENCIAS/MEN/ICETEX, 619-2013 and Colciencias contract 713-2016 code 111574455633)., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)
Subjects: 0301 basic medicine, Intrinsic immunity, Mutation, Chemistry, TMC6, Immunology, Epidermodysplasia verruciformis, medicine.disease, medicine.disease_cause, Molecular biology, 3. Good health, 03 medical and health sciences, 030104 developmental biology, medicine.anatomical_structure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunity, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunology and Allergy, TMC8, Keratinocyte, Gene
Abstract: International audience; Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of TMC6 (encoding EVER1) or TMC8 (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human β-papillomaviruses (β-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the CIB1 gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are not dependent on CIB1, and CIB1 deficiency does not impair keratinocyte adhesion or migration. In keratinocytes, the CIB1 protein interacts with the HPV E5 and E8 proteins encoded by α-HPV16 and γ-HPV4, respectively, suggesting that this protein acts as a restriction factor against HPVs. Collectively, these findings suggest that the disruption of CIB1-EVER1-EVER2-dependent keratinocyte-intrinsic immunity underlies the selective susceptibility to β-HPVs of EV patients.
Published: 2018
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11. Dual T cell– and B cell–intrinsic deficiency in humans with biallelic RLTPR mutations

Author: Stuart G. Tangye, Marie Malissen, Caroline Deswarte, Lluis Quintana-Murci, Lazaro Lorenzo, Marianne Leruez-Ville, Capucine Picard, Jean-Laurent Casanova, Yi Wang, Anne Puel, Yun Ling, Vivien Béziat, Aziz Bousfiha, Aziz Belkadi, Fatima Ailal, Gaspard Kerner, Romain Roncagalli, Kathryn Payne, Marie-Alexandra Alyanakian, Quentin B. Vincent, Elena Crestani, Serge Jacquot, Etienne Patin, Laurent Abel, Luigi D. Notarangelo, Maya Chrabieh, Bernard Malissen, Stéphanie Boisson-Dupuis, Sylvie Fraitag, Jacinta Bustamante, Bernhard Fleckenstein, Ingrid Müller-Fleckenstein, Cindy S. Ma, Alain Hovnanian, Yildiz Camcioglu, and Emmanuelle Jouanguy
Subjects: CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, T-Lymphocytes, Interleukin 21, 0302 clinical medicine, Leukocytes, Immunology and Allergy, Cytotoxic T cell, IL-2 receptor, Child, Research Articles, B-Lymphocytes, ZAP70, Microfilament Proteins, NF-kappa B, Cell Differentiation, Natural killer T cell, Pedigree, 3. Good health, Phenotype, medicine.anatomical_structure, Child, Preschool, Female, Dimerization, Signal Transduction, Adult, Adolescent, Cell Survival, T cell, Immunology, Naive B cell, Receptors, Antigen, B-Cell, Biology, Article, Immunophenotyping, Young Adult, 03 medical and health sciences, Th2 Cells, CD28 Antigens, medicine, Humans, Alleles, B cell, Cell Proliferation, Base Sequence, HEK293 Cells, 030104 developmental biology, Mutation, Th17 Cells, Immunologic Memory, 030215 immunology
Abstract: In two complementary papers, Casanova, Malissen, and collaborators report the discovery of human RLTPR deficiency, the first primary immunodeficiency of the human CD28 pathway in T cells. Together, the two studies highlight the important and largely (but not completely) overlapping roles of RLTPR in T and B cells of humans and mice., Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell–intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4+ T cells are reduced. Their CD4+ T cells do not respond to CD28 stimulation. Their CD4+ T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients’ B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.
Published: 2016
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12. Severe influenza pneumonitis in children with inherited TLR3 deficiency

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

13. A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression

Author: Thomas Harrer, Simone Bertz, Abbas Agaimy, Lazaro Lorenzo, Lucy Best, Carolyn C. Jackson, J. Wacker, and Jean-Laurent Casanova
Subjects: Adult, Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Turkey, DNA Mutational Analysis, Immunology, Mutant, Lymphangiectasia, Immunofluorescence, medicine.disease_cause, Article, Craniofacial Abnormalities, Consanguinity, Young Adult, 03 medical and health sciences, Western blot, Mutant protein, medicine, Humans, Immunology and Allergy, Lymphedema, Mutation, medicine.diagnostic_test, business.industry, Siblings, Tumor Suppressor Proteins, Calcium-Binding Proteins, Homozygote, Protein losing enteropathy, medicine.disease, Pedigree, Hennekam syndrome, 030104 developmental biology, Gene Expression Regulation, Female, business, Lymphangiectasis, Intestinal
Abstract: Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1) bi-allelic mutations have been associated with syndromes of widespread congenital lymphatic dysplasia, including Hennekam Syndrome (HS). HS is characterized by lymphedema, lymphangiectasia, and intellectual disability. CCBE1 encodes a putative extracellular matrix protein but the HS-causing mutations have not been studied biochemically. We report two HS siblings, born to consanguineous parents of Turkish ancestry, whose clinical phenotype also includes protein losing enteropathy, painful relapsing chylous ascites, and hypogammaglobulinemia. We identified by whole exome and Sanger sequencing the homozygous CCBE1 C174Y mutation in both siblings. This mutation had been previously reported in another HS kindred from the Netherlands. In over-expression studies, we found increased intracellular expression of all forms (monomers, dimers, trimers) of the CCBE1 C174Y mutant protein, by Western blot, despite mutant mRNA levels similar to wild-type (WT). In addition, we detected increased secretion of the mutant CCBE1 protein by ELISA. We further found the mutant and WT proteins to be evenly distributed in the cytoplasm, by immunofluorescence and confocal microscopy. Finally, we found a strong decrease of lymphatic vessels, with a corresponding diminished expression of CCBE1, by immunohistochemistry of the patients’ intestinal biopsies. In contrast, mucosal blood vessels and muscularis mucosae showed normal CCBE1 staining. Our findings show that the mutant CCBE1 C174Y protein is not loss-of-function by loss-of-expression.
Published: 2015
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14. Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency

Author: Man Chun Leung, Laurent Abel, Bertrand Boisson, Jeffrey Danielson, Huie Jing, Susie S.Y. Huang, Vimel Rattina, Serkan Belkaya, Lisa S. Mathew, Nicholas Hernandez, Yanick J. Crow, Silvia Giliani, Stephen J. Elledge, Michael J. Ciancanelli, Yoann Rose, Damien Chaussabel, Lazaro Lorenzo-Diaz, Tanwir Habib, Isabelle Melki, Qian Zhang, Helen C. Su, Jean-Laurent Casanova, Shen-Ying Zhang, Marie-Noëlle Lebras, Luigi D. Notarangelo, Nico Marr, Stéphanie Boisson-Dupuis, Mathieu P Rodero, Scott Drutman, Naoki Kitabayashi, Tomasz Kula, Cécile Dumaine, Anais Boulai, Stéphane Blanche, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sidra Medicine [Doha, Qatar], Imagine - Institut des maladies génétiques (IMAGINE - U1163), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Immunology, Pneumonia, Viral, Interferon alpha-2, medicine.disease_cause, Virus, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Immunity, Influenza, Human, Influenza A virus, medicine, Immunology and Allergy, Gene silencing, Humans, STAT1, Research Articles, Alleles, ComputingMilieux_MISCELLANEOUS, biology, Homozygote, virus diseases, Infant, medicine.disease, Orthomyxoviridae, Virology, Interferon-Stimulated Gene Factor 3, gamma Subunit, 3. Good health, Pneumonia, 030104 developmental biology, Viral replication, 030220 oncology & carcinogenesis, biology.protein, Female
Abstract: We report a child with inherited, complete IRF9 deficiency who suffered from life-threatening influenza pneumonitis. IRF9 deficiency disrupts the activation of ISGF3 and impairs but does not abolish cellular responses to type I IFNs, as some ISGs are induced., Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient’s cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient’s cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV.
Published: 2018
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15. Double-strand break repair through homologous recombination in autosomal-recessive BCL10 deficiency

Author: Amin Safa, Lazaro Lorenzo, Maria J. Recio, Pablo Gonzalez-Navarro, E. Martin-Arranz, Eduardo López-Collazo, Carolina Cubillos-Zapata, Rubén Martínez-Barricarte, Ana Van Den Rym, María Vela, Victor Toledano, Sonia García-Gómez, Antonio Pérez-Martínez, Rebeca Pérez de Diego, María Dolores Martín-Arranz, Jean-Laurent Casanova, Silvia Sánchez-Ramón, and Rebeca Chaparro
Subjects: DNA Repair, DNA repair, Immunology, Hydrogen Peroxide, Fibroblasts, Biology, B-Cell CLL-Lymphoma 10 Protein, Molecular biology, Double Strand Break Repair, BCL10, Cell Line, Dna breaks, Humans, Hydroxyurea, Immunology and Allergy, DNA Breaks, Double-Stranded, Homologous Recombination, Homologous recombination, Double stranded
Published: 2019
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16. Recurrent Staphylococcal Cellulitis and Subcutaneous Abscesses in a Child with Autoantibodies against IL-6

Author: Capucine Picard, Lazaro Lorenzo, Dominique Gendrel, Maya Chrabieh, Emmanuelle Jouanguy, Maria Mamani-Matsuda, Charlotte Pons, Jean-Laurent Casanova, Anne Puel, and Mathie Lorrot
Subjects: Male, Immunology, Inflammation, Staphylococcal infections, Immunoglobulin G, Recurrence, Immunity, Cell Line, Tumor, medicine, Humans, Immunology and Allergy, Lymphocytes, Abscess, Autoantibodies, Skin, biology, Interleukin-6, business.industry, C-reactive protein, Autoantibody, Cellulitis, Staphylococcal Infections, medicine.disease, C-Reactive Protein, Child, Preschool, biology.protein, medicine.symptom, business
Abstract: We investigated an otherwise healthy patient presenting two episodes of staphylococcal cellulitis and abscesses, accompanied by high fever and biological signs of inflammation but, paradoxically, with no detectable increase in serum levels of C-reactive protein (CRP), an IL-6-responsive protein synthesized in the liver. Following in vitro activation of whole blood cells from the patient with multiple cytokines, TLR agonists, heat-killed bacteria, and mitogens, we observed a profound and specific impairment of IL-6 secretion. However, the patient’s PBMCs, activated in the same conditions but in the absence of the patient’s plasma, secreted IL-6 normally. The patient’s serum contained high titers of IgG1 autoantibodies against IL-6, which specifically neutralized IL-6 production by control PBMCs as well as IL-6 responses in the human hepatocellular carcinoma cell line Hep3B. These anti-IL-6 autoantibodies were detected over a period of 4 years, in the absence of any other autoantibodies. Our results indicate that these Abs probably prevented an increase in CRP concentration during infection and that impaired IL-6-mediated immunity may have contributed to staphylococcal disease. Patients with severe bacterial infections and low serum CRP concentrations should be tested for anti-IL-6 autoantibodies, especially in the presence of other clinical and biological signs of inflammation.
Published: 2008
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17. 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
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18. Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood

Author: Damien Chaussabel, Yi Hung Ou, Flore Rozenberg, Rebeca Pérez de Diego, Pierre Lebon, Laurent Abel, Shen-Ying Zhang, Melina Herman, Marc Tardieu, Annabelle Cardon, Vanessa Sancho-Shimizu, Elisabeth Israelsson, Maja Klaudel-Dreszler, Yiqi Guo, Elodie Pauwels, Michael A. White, Jean-Laurent Casanova, Avinash Abhyankar, Michael J. Ciancanelli, Lazaro Lorenzo, and Edyta Heropolitańska-Pliszka
Subjects: Male, viruses, animal diseases, Immunology, Herpesvirus 1, Human, Biology, Protein Serine-Threonine Kinases, Article, 03 medical and health sciences, Mice, 0302 clinical medicine, fluids and secretions, TANK-binding kinase 1, Immunity, Immunology and Allergy, Animals, Humans, Kinase activity, Allele, Child, Cells, Cultured, 030304 developmental biology, Dominance (genetics), Genes, Dominant, 0303 health sciences, Cell Death, fungi, technology, industry, and agriculture, food and beverages, Heterozygote advantage, Interferon-beta, Vesiculovirus, Fibroblasts, Phenotype, Virology, 3. Good health, Toll-Like Receptor 3, Poly I-C, Viral replication, Mutation, Female, Encephalitis, Herpes Simplex, 030217 neurology & neurosurgery
Abstract: Two unrelated children with HSE carry distinct heterozygous mutations in the gene encoding TANK-binding kinase 1., Childhood herpes simplex virus-1 (HSV-1) encephalitis (HSE) may result from single-gene inborn errors of TLR3 immunity. TLR3-dependent induction of IFN-α/β or IFN-λ is crucial for protective immunity against primary HSV-1 infection in the central nervous system (CNS). We describe here two unrelated children with HSE carrying different heterozygous mutations (D50A and G159A) in TBK1, the gene encoding TANK-binding kinase 1, a kinase at the crossroads of multiple IFN-inducing signaling pathways. Both mutant TBK1 alleles are loss-of-function but through different mechanisms: protein instability (D50A) or a loss of kinase activity (G159A). Both are also associated with an autosomal-dominant (AD) trait but by different mechanisms: haplotype insufficiency (D50A) or negative dominance (G159A). A defect in polyinosinic-polycytidylic acid–induced TLR3 responses can be detected in fibroblasts heterozygous for G159A but not for D50A TBK1. Nevertheless, viral replication and cell death rates caused by two TLR3-dependent viruses (HSV-1 and vesicular stomatitis virus) were high in fibroblasts from both patients, and particularly so in G159A TBK1 fibroblasts. These phenotypes were rescued equally well by IFN-α2b. Moreover, the IFN responses to the TLR3-independent agonists and viruses tested were maintained in both patients’ peripheral blood mononuclear cells and fibroblasts. The narrow, partial cellular phenotype thus accounts for the clinical phenotype of these patients being limited to HSE. These data identify AD partial TBK1 deficiency as a new genetic etiology of childhood HSE, indicating that TBK1 is essential for the TLR3- and IFN-dependent control of HSV-1 in the CNS.
Published: 2012

19. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity

Author: Laia Alsina, Melina Herman, Elodie Pauwels, Pierre Lebon, Laurent Abel, Shen-Ying Zhang, Vanessa Sancho-Shimizu, Zafitsara Zo Andrianirina, Guillaume Vogt, Damien Chaussabel, Lazaro Lorenzo, Frederic Geissmann, Jean-Laurent Casanova, Joana Azevedo, Rebeca Pérez de Diego, Yiqi Guo, Valérie Doireau, Flore Rozenberg, Magali Audry, Annabelle Cardon, Marc Tardieu, Michael J. Ciancanelli, Esperanza Anguiano, Paul Bastard Philippe, Emmanuelle Jouanguy, Capucine Picard, and Sabine Plancoulaine
Subjects: Male, Simplexvirus, food.ingredient, viruses, CD14, DNA Mutational Analysis, Immunology, chemical and pharmacologic phenomena, Biology, medicine.disease_cause, Compound heterozygosity, Peripheral blood mononuclear cell, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, food, Immunity, medicine, Humans, Immunology and Allergy, Cells, Cultured, 030304 developmental biology, 0303 health sciences, virus diseases, hemic and immune systems, Fibroblasts, medicine.disease, Virology, Pedigree, Toll-Like Receptor 3, 3. Good health, Poly I-C, Herpes simplex virus, Viral replication, Mutation, Myeloid Differentiation Factor 88, Leukocytes, Mononuclear, Encephalitis, Herpes Simplex, Encephalitis, Genome-Wide Association Study, 030215 immunology
Abstract: A new autosomal recessive form of complete TLR3 deficiency reveals that human TLR3 is nonredundant in immunity against herpes simplex virus 1 in the central nervous system (CNS) but redundant in host defense against viruses outside the CNS., Autosomal dominant TLR3 deficiency has been identified as a genetic etiology of childhood herpes simplex virus 1 (HSV-1) encephalitis (HSE). This defect is partial, as it results in impaired, but not abolished induction of IFN-β and -λ in fibroblasts in response to TLR3 stimulation. The apparently normal resistance of these patients to other infections, viral illnesses in particular, may thus result from residual TLR3 responses. We report here an autosomal recessive form of complete TLR3 deficiency in a young man who developed HSE in childhood but remained normally resistant to other infections. This patient is compound heterozygous for two loss-of-function TLR3 alleles, resulting in an absence of response to TLR3 activation by polyinosinic-polycytidylic acid (poly(I:C)) and related agonists in his fibroblasts. Moreover, upon infection of the patient’s fibroblasts with HSV-1, the impairment of IFN-β and -λ production resulted in high levels of viral replication and cell death. In contrast, the patient’s peripheral blood mononuclear cells responded normally to poly(I:C) and to all viruses tested, including HSV-1. Consistently, various TLR3-deficient leukocytes from the patient, including CD14+ and/or CD16+ monocytes, plasmacytoid dendritic cells, and in vitro derived monocyte-derived macrophages, responded normally to both poly(I:C) and HSV-1, with the induction of antiviral IFN production. These findings identify a new genetic etiology for childhood HSE, indicating that TLR3-mediated immunity is essential for protective immunity to HSV-1 in the central nervous system (CNS) during primary infection in childhood, in at least some patients. They also indicate that human TLR3 is largely redundant for responses to double-stranded RNA and HSV-1 in various leukocytes, probably accounting for the redundancy of TLR3 for host defense against viruses, including HSV-1, outside the CNS.
Published: 2011

20. NEMO is a key component of NF-κB- and IRF-3-dependent TLR3-mediated immunity to herpes simplex virus

Author: Kun Yang, Shen-Ying Zhang, Michael J. Ciancanelli, Tim Niehues, Emmanuelle Jouanguy, Lazaro Lorenzo, Vanessa Sancho-Shimizu, Huey Hsuan Chang, Janine Reichenbach, Anne Puel, Xiao Xia Li, Alain Israël, Laurent Abel, Jean-Laurent Casanova, Aurélie Cobat, and Magali Audry
Subjects: UNC93B1, viruses, Immunology, medicine.disease_cause, Article, medicine, Immunology and Allergy, Humans, Simplexvirus, Electrophoretic mobility shift assay, biology, NF-kappa B, Fibroblasts, biology.organism_classification, NFKB1, Virology, Molecular biology, I-kappa B Kinase, Toll-Like Receptor 3, Herpes simplex virus, Vesicular stomatitis virus, TNF Receptor-Associated Factor 3, Child, Preschool, Mutation, STAT protein, Interferon Regulatory Factor-3, Encephalitis, Herpes Simplex, Interferon regulatory factors, Signal Transduction
Abstract: Background Children with germline mutations in Toll-like receptor 3 (TLR3) , UNC93B1 , TNF receptor–associated factor 3, and signal transducer and activator of transcription 1 are prone to herpes simplex virus-1 encephalitis, owing to impaired TLR3-triggered, UNC-93B-dependent, IFN-α/β, and/or IFN-λ-mediated signal transducer and activator of transcription 1-dependent immunity. Objective We explore here the molecular basis of the pathogenesis of herpes simplex encephalitis in a child with a hypomorphic mutation in nuclear factor-κB (NF-κB) essential modulator, which encodes the regulatory subunit of the inhibitor of the Iκβ kinase complex. Methods The TLR3 signaling pathway was investigated in the patient's fibroblasts by analyses of IFN-β, IFN-λ, and IL-6 mRNA and protein levels, by quantitative PCR and ELISA, respectively, upon TLR3 stimulation (TLR3 agonists or TLR3-dependent viruses). NF-κB activation was assessed by electrophoretic mobility shift assay and interferon regulatory factor 3 dimerization on native gels after stimulation with a TLR3 agonist. Results The patient's fibroblasts displayed impaired responses to TLR3 stimulation in terms of IFN-β, IFN-λ, and IL-6 production, owing to impaired activation of both NF-κB and IRF-3. Moreover, vesicular stomatitis virus, a potent IFN-inducer in human fibroblasts, and herpes simplex virus-1, induced only low levels of IFN-β and IFN-λ in the patient's fibroblasts, resulting in enhanced viral replication and cell death, as reported for UNC-93B-deficient fibroblasts. Conclusion Herpes simplex encephalitis may occur in patients carrying NF-κB essential modulator mutations, due to the impairment of NF-κB- and interferon regulatory factor 3-dependent-TLR3-mediated antiviral IFN production.
Published: 2010

21. Immunity to virus infection (excluding retroviruses) 1 (WS-025a)

Author: Christian P. Larsen, Lazaro Lorenzo, Annabelle Cardon, T. Frenz, M. Kweon, Shen-Ying Zhang, M. J. Crane, F. Arisawa, T. Rodriguez-Calvo, G. Sutter, R. Perez de Diego, Jean-Laurent Casanova, P. Aichele, Masahito Kamanaka, Y. Mori, Tadahiro Suenaga, Jérome Maluenda, Laurent Abel, G. S. Yap, P. J. Gaddi, Shivaprakash Gangappa, Peter M. Manders, N. J. C. King, H. Kwon, Koichi Araki, S. Lim, U. Kalinke, A. Alejo, Rafi Ahmed, Z. Waibler, Richard A. Flavell, S. Seo, M. Tovey, P. Somboonthum, Barry T. Rouse, N. Sevilla, J. Song, Boris Reizis, R. L. Terry, Emmanuelle Jouanguy, V. Sancho Shimizu, D. R. Getts, Iain L. Campbell, M. T. Getts, Anne Puel, Hisashi Arase, Markus J. Hofer, and T. P. Salazar-Mather
Subjects: Immunity, Immunology, Immunology and Allergy, General Medicine, Biology, Virology, Virus
Published: 2010
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22. Exome sequencing identifies novel mutations in the Toll-like receptor 3 pathway contributing to herpes simplex encephalitis susceptibility (P1403)

Author: Vanessa Sancho Shimizu, Bayarchimeg Mashbat, Yuval Itan, Lazaro Lorenzo, Shen-Ying Zhang, Anne Puel, Michael Levin, and Jean Laurent Casanova
Subjects: Immunology, Immunology and Allergy
Abstract: Herpes simplex encephalitis is a rare manifestation of herpes simplex virus-1 infection. Mutations in genes of the toll-like receptor 3-interferon pathway have been shown to predispose to childhood herpes simplex encephalitis, including UNC93B1, TLR3, TRIF, TRAF3 and TBK1. We investigated herpes simplex encephalitis patients with impaired toll-like receptor 3 signaling for whom the involvement of the known genetic etiologies have been excluded. Exome sequencing was used to identify other mutations underlying herpes simplex encephalitis, paying particular attention to the toll-like receptor 3-interferon pathway by employing a candidate gene based ‘connectome’ approach. One patient in particular carried a novel heterozygous missense mutation in a known gene in the nuclear factor-κB / toll-like receptor 3 pathway. The patient’s cells showed a decrease in interferon regulatory factor-3 dimerization and reduced nuclear translocation of nuclear factor-κB consistent with the lack of type I interferon and IL6 production following toll-like receptor 3 stimulation. The patients’ cells were also more susceptible upon viral infections. Further characterization of the mutation and its impact on type I interferon signaling in the context of herpes simplex virus-1 infection will provide a better understanding of the etiology of childhood herpes simplex encephalitis.
Published: 2013
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23. CS16-7. A novel autosomal recessive and autosomal dominant deficiency in the TLR3 pathway underlying susceptibility to Herpes Simplex Encephalitis

Author: Sylvie Fabrega, Rebeca Perez, Laurent Abel, Anne Puel, Lazaro Lorenzo, Saleh Al-Muhsen, Jean-Laurent Casanova, Shen-Ying Zhang, Annabelle Cardon, Vanessa Sancho Shimizu, and Rabih Halwani
Subjects: Genetics, Immunology, TLR3, medicine, Immunology and Allergy, Hematology, Biology, medicine.disease, Molecular Biology, Biochemistry, Encephalitis
Published: 2011
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24. Inherited IL-18BP deficiency in human fulminant viral hepatitis

Author: Emmanuelle Jouanguy, Julie Bruneau, Yoon Seung Lee, Jean-Laurent Casanova, Lazaro Lorenzo-Diaz, Mohammad Kabbani, Eleftherios Michailidis, Serkan Belkaya, Scott Drutman, Laurent Abel, Soraya Boucherit, Cecilia B. Korol, Mylène Sebagh, Vivien Béziat, Aurélie Cobat, Ype P. de Jong, Bertrand Boisson, Nicholas Hernandez, Charles M. Rice, Paul Bastard, Jean-François Emile, Eric Vivier, Emmanuel Jacquemin, Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), 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)-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 d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'anatomie et cythologie pathologique, CHU Necker - Enfants Malades [AP-HP], 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, The Rockefeller University, Département de Pathologie [Villejuif], Hôpital Paul Brousse, Physiopathogenèse et Traitement des Maladies du Foie [Villejuif], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Intéractions cellulaires et physiopathologie hépathique (Orsay, Essonne) UMRS 1174 (ICPH ), Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire épidémiologie et oncogénèse des tumeurs digestives, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Laboratory of Virology and Infectious Disease [New York], Rockefeller University [New York], Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Physiopathogénèse et Traitement des Maladies du Foie, and Hôpital Paul Brousse-Université Paris-Saclay
Subjects: 0301 basic medicine, Hepatitis, Mutation, business.industry, Fulminant, Immunology, medicine.disease, medicine.disease_cause, Virology, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immunity, 030220 oncology & carcinogenesis, Immunology and Allergy, Medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interleukin 18, business, Viral hepatitis, Exome sequencing, IL18BP
Abstract: Fulminant viral hepatitis (FVH) is a devastating and unexplained condition that strikes otherwise healthy individuals during primary infection with common liver-tropic viruses. We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepatitis by unleashing IL-18. These findings provide proof-of-principle that FVH can be caused by single-gene inborn errors that selectively disrupt liver-specific immunity. They also show that human IL-18 is toxic to the liver and that IL-18BP is its antidote.
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24 results on '"Lazaro Lorenzo"'

1. Fulminant viral hepatitis in two siblings with inherited IL-10RB deficiency

2. A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes

3. Human BCL10 Deficiency due to Homozygosity for a Rare Allele

4. Clinical and Immunological Features of Human BCL10 Deficiency

5. Inborn errors of TLR3- or MDA5-dependent type I IFN immunity in children with enterovirus rhombencephalitis

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

7. Inherited GATA2 deficiency is dominant by haploinsufficiency and displays incomplete clinical penetrance

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

9. Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis

10. The human CIB1–EVER1–EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses

11. Dual T cell– and B cell–intrinsic deficiency in humans with biallelic RLTPR mutations

12. Severe influenza pneumonitis in children with inherited TLR3 deficiency

13. A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression

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

15. Double-strand break repair through homologous recombination in autosomal-recessive BCL10 deficiency

16. Recurrent Staphylococcal Cellulitis and Subcutaneous Abscesses in a Child with Autoantibodies against IL-6

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

18. Heterozygous TBK1 mutations impair TLR3 immunity and underlie herpes simplex encephalitis of childhood

19. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity

20. NEMO is a key component of NF-κB- and IRF-3-dependent TLR3-mediated immunity to herpes simplex virus

21. Immunity to virus infection (excluding retroviruses) 1 (WS-025a)

22. Exome sequencing identifies novel mutations in the Toll-like receptor 3 pathway contributing to herpes simplex encephalitis susceptibility (P1403)

23. CS16-7. A novel autosomal recessive and autosomal dominant deficiency in the TLR3 pathway underlying susceptibility to Herpes Simplex Encephalitis

24. Inherited IL-18BP deficiency in human fulminant viral hepatitis

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