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1. Case Report of Two Independent Moroccan Families with Syndromic Epidermodysplasia Verruciformis and STK4 Deficiency

Author: Assiya El Kettani, Hind Ouair, Farida Marnissi, Jalila El Bakkouri, Rémi Chevalier, Lazaro Lorenzo, Halima Kholaiq, Vivien Béziat, Emmanuelle Jouanguy, Jean-Laurent Casanova, and Ahmed Aziz Bousfiha
Subjects: epidermodysplasia verruciformis, human papillomavirus, STK4 deficiency, CD4+ T cells, Microbiology, QR1-502
Abstract: Epidermodysplasia verruciformis (EV) is a rare genodermatosis caused by β-human papillomaviruses (HPV) in immunodeficient patients. EV is characterized by flat warts and pityriasis-like lesions and might be isolated or syndromic, associated with some other infectious manifestations. We report here three patients from two independent families, with syndromic EV for both of them. By whole exome sequencing, we found that the patients carry new homozygous variants in STK4, both leading to a premature stop codon. STK4 deficiency causes a combined immunodeficiency characterized by a broad infectious susceptibility to bacteria, viruses, and fungi. Auto-immune manifestations were also reported. Deep immunophenotyping revealed multiple cytopenia in the three affected patients, in particular deep CD4+ T cells deficiency. We report here the fourth and the fifth cases of the syndromic EV due to STK4 deficiency.
Published: 2024
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2. 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: primary immunodeficiency, combined immunodeficiency, BCL10, autosomal recessive, mass cytometry, computational immunology, Immunologic diseases. Allergy, RC581-607
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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3. Identification of an Endoglin Variant Associated With HCV-Related Liver Fibrosis Progression by Next-Generation Sequencing

Author: Frédégonde About, Stéphanie Bibert, Emmanuelle Jouanguy, Bertrand Nalpas, Lazaro Lorenzo, Vimel Rattina, Mohammed Zarhrate, Sylvain Hanein, Mona Munteanu, Beat Müllhaupt, David Semela, Nasser Semmo, Jean-Laurent Casanova, Ioannis Theodorou, Philippe Sultanik, Thierry Poynard, Stanislas Pol, Pierre-Yves Bochud, Aurélie Cobat, Laurent Abel, The Swiss Hepatitis C Cohort Study Group, The French ANRS HC EP 26 Genoscan Study Group, Francesco Negro, Antoine Hadengue, Laurent Kaiser, Laura Rubbia-Brandt, Darius Moradpour, Cristina Cellerai, Martin Rickenbach, Andreas Cerny, Gladys Martinetti, Jean-François Dufour, Meri Gorgievski, Virginie Masserey Spicher, Markus Heim, Hans Hirsch, Beat Helbling, Stephan Regenass, Raffaele Malinverni, Guenter Dollenmaier, and Gieri Cathomas
Subjects: endoglin, HCV-related liver fibrosis, exome sequencing, TGF-beta, rare-variant association study, Genetics, QH426-470
Abstract: Despite the astonishing progress in treating chronic hepatitis C virus (HCV) infection with direct-acting antiviral agents, liver fibrosis remains a major health concern in HCV infected patients, in particular due to the treatment cost and insufficient HCV screening in many countries. Only a fraction of patients with chronic HCV infection develop liver fibrosis. While there is evidence that host genetic factors are involved in the development of liver fibrosis, the common variants identified so far, in particular by genome-wide association studies, were found to have limited effects. Here, we conducted an exome association study in 88 highly selected HCV-infected patients with and without fibrosis. A strategy focusing on TGF-β pathway genes revealed an enrichment in rare variants of the endoglin gene (ENG) in fibrosis patients. Replication studies in additional cohorts (617 patients) identified one specific ENG variant, Thr5Met, with an overall odds ratio for fibrosis development in carriers of 3.04 (1.39–6.69). Our results suggest that endoglin, a key player in TGF-β signaling, is involved in HCV-related liver fibrogenesis.
Published: 2019
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4. Microdeletion on chromosome 8p23.1 in a familial form of severe Buruli ulcer.

Author: Quentin B Vincent, Aziz Belkadi, Cindy Fayard, Estelle Marion, Ambroise Adeye, Marie-Françoise Ardant, Christian R Johnson, Didier Agossadou, Lazaro Lorenzo, Julien Guergnon, Christine Bole-Feysot, Jeremy Manry, Patrick Nitschké, Ioannis Theodorou, Jean-Laurent Casanova, Laurent Marsollier, Annick Chauty, Laurent Abel, Alexandre Alcaïs, and Franco-Beninese Buruli Research Group
Subjects: Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract: Buruli ulcer (BU), the third most frequent mycobacteriosis worldwide, is a neglected tropical disease caused by Mycobacterium ulcerans. We report the clinical description and extensive genetic analysis of a consanguineous family from Benin comprising two cases of unusually severe non-ulcerative BU. The index case was the most severe of over 2,000 BU cases treated at the Centre de Dépistage et de Traitement de la Lèpre et de l'Ulcère de Buruli, Pobe, Benin, since its opening in 2003. The infection spread to all limbs with PCR-confirmed skin, bone and joint infections. Genome-wide linkage analysis of seven family members was performed and whole-exome sequencing of both patients was obtained. A 37 kilobases homozygous deletion confirmed by targeted resequencing and located within a linkage region on chromosome 8 was identified in both patients but was absent from unaffected siblings. We further assessed the presence of this deletion on genotyping data from 803 independent local individuals (402 BU cases and 401 BU-free controls). Two BU cases were predicted to be homozygous carriers while none was identified in the control group. The deleted region is located close to a cluster of beta-defensin coding genes and contains a long non-coding (linc) RNA gene previously shown to display highest expression values in the skin. This first report of a microdeletion co-segregating with severe BU in a large family supports the view of a key role of human genetics in the natural history of the disease.
Published: 2018
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5. Encephalitis and poor neuronal death–mediated control of herpes simplex virus in human inherited RIPK3 deficiency

Author: Zhiyong Liu, Eduardo J. Garcia Reino, Oliver Harschnitz, Hongyan Guo, Yi-Hao Chan, Noopur V. Khobrekar, Mary L. Hasek, Kerry Dobbs, Darawan Rinchai, Marie Materna, Daniela Matuozzo, Danyel Lee, Paul Bastard, Jie Chen, Yoon Seung Lee, Seong K. Kim, Shuxiang Zhao, Param Amin, Lazaro Lorenzo, Yoann Seeleuthner, Remi Chevalier, Laure Mazzola, Claire Gay, Jean-Louis Stephan, Baptiste Milisavljevic, Soraya Boucherit, Flore Rozenberg, Rebeca Perez de Diego, Richard D. Dix, Nico Marr, Vivien Béziat, Aurelie Cobat, Mélodie Aubart, Laurent Abel, Stephane Chabrier, Gregory A. Smith, Luigi D. Notarangelo, Edward S. Mocarski, Lorenz Studer, Jean-Laurent Casanova, and Shen-Ying Zhang
Subjects: Immunology, General Medicine
Abstract: Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422*) and frameshift (P493fs9*) RIPK3 variants. Receptor-interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis. In vitro, the R422* and P493fs9* RIPK3 proteins impaired cellular apoptosis and necroptosis upon TLR3, TLR4, or TNFR1 stimulation and ZBP1/DAI-mediated necroptotic cell death after HSV-1 infection. The patient’s fibroblasts displayed no detectable RIPK3 expression. After TNFR1 or TLR3 stimulation, the patient’s cells did not undergo apoptosis or necroptosis. After HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-β and IFN-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient’s human pluripotent stem cell (hPSC)–derived cortical neurons displayed impaired cell death and enhanced viral growth after HSV-1 infection, as did isogenic RIPK3-knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE by impairing the cell death–dependent control of HSV-1 in cortical neurons but not their production of or response to type I IFNs.
Published: 2023
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6. 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
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7. 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

8. A computational approach for detecting physiological homogeneity in the midst of genetic heterogeneity

Author: Peng Zhang, Shen-Ying Zhang, Laurent Abel, Clémentine Boccon-Gibod, Yuval Itan, Jean-Laurent Casanova, Burkhard Stüve, Cigdem Sevim Bayrak, Lazaro Lorenzo, Louis Vallée, Daniela Matuozzo, Yoon-Seung Lee, Soraya Boucherit, Yiming Wu, Aurélie Cobat, Aayushee Jain, and Stéphane Chabrier
Subjects: Candidate gene, Computational biology, Biology, Article, DNA sequencing, Genetic Heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, Gene cluster, Genetics, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Genetic heterogeneity, Computational Biology, Fibroblasts, Phenotype, Penetrance, Toll-Like Receptor 3, Case-Control Studies, Encephalitis, Herpes Simplex, 030217 neurology & neurosurgery, Biological network
Abstract: The human genetic dissection of clinical phenotypes is complicated by genetic heterogeneity. Gene burden approaches that detect genetic signals in case-control studies are underpowered in genetically heterogeneous cohorts. We therefore developed a genome-wide computational method, network-based heterogeneity clustering (NHC), to detect physiological homogeneity in the midst of genetic heterogeneity. Simulation studies showed our method to be capable of systematically converging genes in biological proximity on the background biological interaction network, and capturing gene clusters harboring presumably deleterious variants, in an efficient and unbiased manner. We applied NHC to whole-exome sequencing data from a cohort of 122 individuals with herpes simplex encephalitis (HSE), including 13 individuals with previously published monogenic inborn errors of TLR3-dependent IFN-α/β immunity. The top gene cluster identified by our approach successfully detected and prioritized all causal variants of five TLR3 pathway genes in the 13 previously reported individuals. This approach also suggested candidate variants of three reported genes and four candidate genes from the same pathway in another ten previously unstudied individuals. TLR3 responsiveness was impaired in dermal fibroblasts from four of the five individuals tested, suggesting that the variants detected were causal for HSE. NHC is, therefore, an effective and unbiased approach for unraveling genetic heterogeneity by detecting physiological homogeneity.
Published: 2021
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9. 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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10. 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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11. Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency

Author: Fatima Al Ali, Laurent Abel, Jean-François Emile, Davood Mansouri, Mahbuba Rahman, Franck Rapaport, Stéphanie Boisson-Dupuis, Nicholas Hernandez, Taushif Khan, Anna-Lena Neehus, David Hum, Benedetta Bigio, Vivien Béziat, Nico Marr, Jean-Laurent Casanova, Scott Drutman, Jacinta Bustamante, Emmanuelle Jouanguy, Majid Marjani, Robert Fisch, Ruslana Bryk, Nahal Mansouri, Serkan Belkaya, Lazaro Lorenzo-Diaz, Carl Nathan, and Seyed Alireza Mahdaviani
Subjects: Male, Genotype, Congenital cytomegalovirus infection, Nitric Oxide Synthase Type II, Severe disease, macromolecular substances, 030204 cardiovascular system & hematology, Nitric Oxide, Article, 03 medical and health sciences, Fatal Outcome, 0302 clinical medicine, Loss of Function Mutation, parasitic diseases, Exome Sequencing, medicine, Humans, 030212 general & internal medicine, Frameshift Mutation, business.industry, Homozygote, fungi, food and beverages, virus diseases, General Medicine, Middle Aged, medicine.disease, Pedigree, Multiple infections, Cytomegalovirus infection, Cytomegalovirus Infections, Immunology, Female, business
Abstract: BACKGROUND: Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 (Nos2) are susceptible to the related murine CMV infection. METHODS: We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally. RESULTS: We found a homozygous frameshift mutation in NOS2 encoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, all NOS2 variants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001. CONCLUSIONS: These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.)
Published: 2020
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12. 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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13. Clinical and Immunological Features of Human BCL10 Deficiency

Author: Blanca Garcia Solis, Ana Van Den Rym, Jareb J. Pérez-Caraballo, Abdulwahab Al –Ayoubi, Lazaro Lorenzo, Carolina Cubillos-Zapata, Eduardo López-Collazo, Janet Markle, Miguel Fernández-Arquero, Silvia Sanchez-Ramon, Maria J. Recio, Jean-Laurent Casanova, Reem Mohammed, Rubén Martinez-Barricarte, and Rebeca Perez de Diego
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 prevented gaining that knowledge for this genetic disease. Only two patients with BCL10 deficiency have been reported to date. Here we describe in more depth an additional patient with autosomal recessive BCL10 complete 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 almost absence of memory B and T cells reported before, this patient display a reduction in NK, gdT, Tregs, and TFH cells. The patient suffered from recurrent respiratory infections since early in life, 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 cured this disease.
Published: 2021
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14. 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

15. 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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16. TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons

Author: Isabelle Meyts, Xin Mu, Emmanuelle Jouanguy, Daxing Gao, Aurélie Cobat, Lazaro Lorenzo, Mary Hasek, Damien Chaussabel, Luigi D. Notarangelo, Darragh Duffy, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Lorenz Studer, Gregory A. Smith, Sun Hur, Jie Chen, Peng Zhang, Michael J. Ciancanelli, Jessica L. McAlpine, Gabriele Ciceri, Shen-Ying Zhang, Oliver Harschnitz, Yuval Itan, Michael S. Diamond, Benedetta Bigio, Vincent Bondet, Esperanza Anguiano, Laurent Abel, Rockefeller University [New York], University of Science and Technology of China [Hefei] (USTC), Turnstone Biologics [New York], Memorial Sloane Kettering Cancer Center [New York], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Harvard Medical School [Boston] (HMS), Icahn School of Medicine at Mount Sinai [New York] (MSSM), 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), Imperial College London, Baylor Institute for Immunology Research (BIIR), Benaroya Research Institute [Seattle] (BRI), Sidra Medicine [Doha, Qatar], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), University Hospitals Leuven [Leuven], Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Feinberg School of Medicine, Northwestern University [Evanston], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Howard Hughes Medical Institute (HHMI), This work was funded in part by the National Center for Advancing Translational Sciences, NIH Clinical and Translational Science Award program (UL1TR001866), NIH (R01NS072381, R01AI088364, and R21AI151663), the French National Research Agency (ANR) under the 'Investments for the future' program (ANR-10-IAHU-01), Integrative Biology of Emerging Infectious Diseases Laboratoire d’Excellence (ANR-10-LABX-62-IBEID), and grants ANR-14-CE14-0008-01 and ANR-18-CE15-0020-02, The Rockefeller University, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Descartes University, and the St. Giles Foundation. DG is supported by the Charles H. Revson Senior Fellowship in Biomedical Sciences and the National Natural Science Foundation of China (grant 31970855). IM is supported by KU Leuven C1 grant C16/18/007 and Fonds Wetenschappelijk Onderzoek Vlaanderen grant G0C8517N., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle?(2014), ANR-18-CE15-0020,SEAe-HostFactors,Facteurs de susceptibilité de l'hôte à l'encéphalite pédiatrique en Asie du Sud Est(2018), Institut Pasteur [Paris] (IP), and 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)
Subjects: 0301 basic medicine, viruses, NF-KAPPA-B, Herpesvirus 1, Human, Research & Experimental Medicine, RIG-I, Mice, 0302 clinical medicine, ADAPTER PROTEIN, Induced pluripotent stem cell, GENE-EXPRESSION, Cerebral Cortex, Mice, Knockout, Neurons, Innate immunity, Infectious disease, biology, virus diseases, VESICULAR STOMATITIS-VIRUS, General Medicine, 3. Good health, Cell biology, INTERFERON-ALPHA/BETA, Medicine, Research & Experimental, Vesicular stomatitis virus, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESSENGER-RNA, Life Sciences & Biomedicine, Research Article, HERPES-SIMPLEX ENCEPHALITIS, Immunology, chemical and pharmacologic phenomena, DOUBLE-STRANDED-RNA, Cell Line, 03 medical and health sciences, Immunity, Animals, Humans, Secretion, Messenger RNA, Science & Technology, Innate immune system, TOLL-LIKE RECEPTOR-3, Interferon-beta, Vesiculovirus, Fibroblasts, biology.organism_classification, Embryonic stem cell, Toll-Like Receptor 3, 030104 developmental biology, TLR3
Abstract: Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-β secretion and ISG mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-β immunity. ispartof: JOURNAL OF CLINICAL INVESTIGATION vol:131 issue:1 ispartof: location:United States status: published
Published: 2021
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17. Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

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

19. 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

20. 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

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

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

22. Human SNORA31 variations impair cortical neuron-intrinsic immunity to HSV-1 and underlie herpes simplex encephalitis

Author: Zobaida Alsum, Soraya Boucherit, Lluis Quintana-Murci, Peng Zhang, Luigi D. Notarangelo, Joseph A. Church, Daxing Gao, Rabih Halwani, Lazaro Lorenzo, Thomas M. Carlile, Maria F. Rojas-Duran, Ahmed Aziz Bousfiha, Yuval Itan, Laurent Abel, Flore Rozenberg, Fabien G. Lafaille, Wendy V. Gilbert, Jean-Laurent Casanova, Vimel Rattina, Marc Tessier-Lavigne, Lorenz Studer, Trine H. Mogensen, Bastian Zimmer, Benoit Henry, Søren R. Paludan, Shen-Ying Zhang, Franck Rapaport, Gregory A. Smith, Saleh Al-Muhsen, Michael J. Ciancanelli, Gaspard Kerner, Jessica L. McAlpine, Kerry Dobbs, Madalina E. Carter-Timofte, Laura Marques, Oliver Harschnitz, Osefame Ewaleifoh, Mary Hasek, Dominik Paquet, Marc Tardieu, Naima Amenzoui, Yoon Seung Lee, Dylan Kwart, Rockefeller University [New York], Memorial Sloane Kettering Cancer Center [New York], 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Northwestern University Feinberg School of Medicine, Aarhus University Hospital, National Institutes of Health [Bethesda] (NIH), Yale University [New Haven], Service de Virologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Sharjah, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ibn Rochd University Hospital of Casablanca, University Hassan II of Casablanca, Morocco., King Saud University [Riyadh] (KSU), Centro Hospitalar do Porto, University of Southern California (USC), Service de neurologie pédiatrique et maladies métaboliques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Stanford University, This work was funded in part by the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Clinical and Translational Science Award program (grant nos. UL1TR000043 and UL1TR001866), NIH grants (nos. R01AI088364 to J.L.C. and S.Y.Z., R01NS072381 to J.-L.C. and S.-Y.Z. and R01GM101316 to W.G.), a grant from the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (no. ANR-10-LABX-62-IBEID to L.A.) and the French National Research Agency (ANR) under the ‘Investments for the future’ program (no. ANR-10-IAHU-01 to L.A.), the ANR grant IEIHSEER (no. ANR-14-CE14-0008-01 to S.-Y.Z.), the Lundbeck Foundation (grant no. R268-2016-3927 to S.R.P.), the Rockefeller University, INSERM, Paris Descartes University and the St Giles Foundation., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-CE14-0008,IEIHSEER,L'encéphalite Herpétique de l'enfant résulte de déficits héréditaires d'immunité contre l'HSV-1: une exception ou une règle?(2014), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Hôpital Cochin [AP-HP], Service des maladies infectieuses et tropicales [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Southern California [Los Angeles, CA, USA], Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Central Nervous System, Male, 0301 basic medicine, Intrinsic immunity, viruses, Central nervous system, Herpesvirus 1, Human, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Interferon, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Humans, RNA, Small Nucleolar, Genetic Predisposition to Disease, Small nucleolar RNA, Neurons, Immunity, Infant, RNA, General Medicine, Middle Aged, 3. Good health, Cell biology, 030104 developmental biology, medicine.anatomical_structure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Child, Preschool, 030220 oncology & carcinogenesis, Forebrain, Metagenome, Female, Encephalitis, Herpes Simplex, Small nuclear RNA, medicine.drug
Abstract: International audience; Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is typically sporadic. Inborn errors of TLR3- and DBR1-mediated central nervous system cell-intrinsic immunity can account for forebrain and brainstem HSE, respectively. We report five unrelated patients with forebrain HSE, each heterozygous for one of four rare variants of SNORA31, encoding a small nucleolar RNA of the H/ACA class that are predicted to direct the isomerization of uridine residues to pseudouridine in small nuclear RNA and ribosomal RNA. We show that CRISPR/Cas9-introduced bi- and monoallelic SNORA31 deletions render human pluripotent stem cell (hPSC)-derived cortical neurons susceptible to HSV-1. Accordingly, SNORA31-mutated patient hPSC-derived cortical neurons are susceptible to HSV-1, like those from TLR3- or STAT1-deficient patients. Exogenous interferon (IFN)-β renders SNORA31- and TLR3- but not STAT1-mutated neurons resistant to HSV-1. Finally, transcriptome analysis of SNORA31-mutated neurons revealed normal responses to TLR3 and IFN-α/β stimulation but abnormal responses to HSV-1. Human SNORA31 thus controls central nervous system neuron-intrinsic immunity to HSV-1 by a distinctive mechanism.
Published: 2019
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23. 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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24. T-cell Responses to HSV-1 in Persons Who Have Survived Childhood Herpes Simplex Encephalitis

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

Author: Lazaro Lorenzo, Annick Chauty, Marie-Françoise Ardant, Ioannis Theodorou, Quentin B. Vincent, Maya Chrabieh, Alexandre Alcaïs, Jeremy Manry, Laurent Marsollier, Christian Johnson, Estelle Marion, and Laurent Abel
Subjects: Buruli ulcer, 0303 health sciences, biology, Hazard ratio, Genome-wide association study, Odds ratio, medicine.disease, biology.organism_classification, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Mycobacterium ulcerans, Immunology, medicine, Missense mutation, Allele, ATG16L1, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Buruli ulcer, caused by Mycobacterium ulcerans, is the third mycobacterial disease worldwide characterized by devastating necrotizing skin lesions. The role of host genetics in susceptibility to Buruli ulcer has long been suggested. We conduct the first genome-wide association study of Buruli ulcer on a combined sample of 1,524 well characterized patients and controls from rural Benin. Two-stage analyses identify two novel associated loci located within lincRNA genes: rs9814705 in ENSG00000240095.1 (P = 2.85×10−7; odds ratio = 1.80 [1.43-2.27]), and rs76647377 in LINC01622 (P = 9.85×10−8; hazard ratio = 0.41 [0.28-0.60]). Furthermore, we replicate the protective effect of allele G of a missense variant located in ATG16L1, and previously shown to decrease bacterial autophagy (rs2241880, P = 0.003; odds ratio = 0.31 [0.14-0.68]). Our results suggest lincRNAs and the autophagy pathway as critical factors in the development of Buruli ulcer.
Published: 2019
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26. Genome-wide association study of Buruli ulcer in rural Benin highlights role of two LncRNAs and the autophagy pathway

Author: Lazaro Lorenzo, Laurent Marsollier, Ioannis Theodorou, Marie-Françoise Ardant, Christian Johnson, Maya Chrabieh, Quentin B. Vincent, Alexandre Alcaïs, Estelle Marion, Laurent Abel, Jeremy Manry, Annick Chauty, Gestionnaire, Hal Sorbonne Université, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université d’Abomey-Calavi = University of Abomey Calavi (UAC), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Apoptosis and Tumor Progression (CRCINA-ÉQUIPE 9), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Rockefeller University [New York], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), University of Abomey Calavi (UAC), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE)
Subjects: 0301 basic medicine, Buruli ulcer, Male, Medicine (miscellaneous), Autophagy-Related Proteins, Genome-wide association study, Genome-wide association studies, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Risk Factors, Missense mutation, Benin, Child, ATG16L1, lcsh:QH301-705.5, Buruli Ulcer, biology, 3. Good health, Phenotype, Mycobacterium ulcerans, Host-Pathogen Interactions, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, RNA, Long Noncoding, General Agricultural and Biological Sciences, Adult, Adolescent, Mutation, Missense, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Polymorphism, Single Nucleotide, Risk Assessment, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Young Adult, medicine, Autophagy, Humans, Genetic Predisposition to Disease, Allele, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Odds ratio, [SDV.MHEP.DERM] Life Sciences [q-bio]/Human health and pathology/Dermatology, biology.organism_classification, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, lcsh:Biology (General), Case-Control Studies, Immunology, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Bacterial infection, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Buruli ulcer, caused by Mycobacterium ulcerans and characterized by devastating necrotizing skin lesions, is the third mycobacterial disease worldwide. The role of host genetics in susceptibility to Buruli ulcer has long been suggested. We conduct the first genome-wide association study of Buruli ulcer on a sample of 1524 well characterized patients and controls from rural Benin. Two-stage analyses identify two variants located within LncRNA genes: rs9814705 in ENSG00000240095.1 (P = 2.85 × 10−7; odds ratio = 1.80 [1.43–2.27]), and rs76647377 in LINC01622 (P = 9.85 × 10−8; hazard ratio = 0.41 [0.28–0.60]). Furthermore, we replicate the protective effect of allele G of a missense variant located in ATG16L1, previously shown to decrease bacterial autophagy (rs2241880, P = 0.003; odds ratio = 0.31 [0.14–0.68]). Our results suggest LncRNAs and the autophagy pathway as critical factors in the development of Buruli ulcer., Jeremy Manry, Quentin Vincent et al. report a genome-wide association study for susceptibility to Buruli ulcer in a rural population from the West African country of Benin. They identify two independently associated variants within LncRNA genes and confirm the protective effect of a missense variant in the bacterial autophagy gene ATG16L1.
Published: 2019
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27. Homozygous

Author: Scott B, Drutman, Filomeen, Haerynck, Franklin L, Zhong, David, Hum, Nicholas J, Hernandez, Serkan, Belkaya, Franck, Rapaport, Sarah Jill, de Jong, David, Creytens, Simon J, Tavernier, Katrien, Bonte, Sofie, De Schepper, Jutte, van der Werff Ten Bosch, Lazaro, Lorenzo-Diaz, Andy, Wullaert, Xavier, Bossuyt, Gérard, Orth, Vincent R, Bonagura, Vivien, Béziat, Laurent, Abel, Emmanuelle, Jouanguy, Bruno, Reversade, and Jean-Laurent, Casanova
Subjects: Keratinocytes, Male, Inflammasomes, Siblings, Homozygote, Papillomavirus Infections, Infant, NLR Proteins, Syndrome, Biological Sciences, Pedigree, Child, Preschool, Gain of Function Mutation, Cytokines, Humans, Female, Apoptosis Regulatory Proteins, Respiratory Tract Infections, Adaptor Proteins, Signal Transducing
Abstract: Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation.
Published: 2019

28. Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis

Author: Sarah Jill De Jong, Sofie De Schepper, Jean-Laurent Casanova, Jutte van der Werff ten Bosch, David Hum, Emmanuelle Jouanguy, Franklin L. Zhong, Vincent R. Bonagura, Scott Drutman, Nicholas Hernandez, David Creytens, Gérard Orth, Katrien Bonte, Andy Wullaert, Franck Rapaport, Filomeen Haerynck, Laurent Abel, Serkan Belkaya, Xavier Bossuyt, Vivien Béziat, Lazaro Lorenzo-Diaz, Bruno Reversade, Simon Tavernier, Center for Reproductive Medicine, ACS - Diabetes & metabolism, ARD - Amsterdam Reproduction and Development, ACS - Heart failure & arrhythmias, Clinical sciences, Growth and Development, Pediatrics, Reversade, Bruno, Drutman, Scott B., Haerynck, Filomeen, Zhong, Franklin L., Hum, David, Hernandez, Nicholas J., Belkaya, Serkan, Rapaport, Franck, de Jong, Sarah Jill, Creytens, David, Tavernier, Simon J., Bonte, Katrien, De Schepper, Sofie, ten Bosch, Jutte van der Werff, Lorenzo-Diaz, Lazaro, Wullaert, Andy, Bossuyt, Xavier, Orth, Gerard, Bonagura, Vincent R., Beziat, Vivien, Abel, Laurent, Jouanguy, Emmanuelle, Laurent-Casanova, Jean, School of Medicine, and Department of Medical Genetics
Subjects: Medicine(all), Mutation, Human papillomavirus, Multidisciplinary, Medicine, Medical genetics, Genetics, Inflammasome, NLRP1, Recurrent respiratory papillomatosis, Biology, medicine.disease_cause, Phenotype, Pyrin domain, symbols.namesake, inflammasome, Immunology, medicine, Mendelian inheritance, symbols, genetics, Recurrent Respiratory Papillomatosis, Allele, Inflammasome complex, recurrent respiratory papillomatosis, medicine.drug
Abstract: Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation., United States Department of Health and Human Services; National Institutes of Health (NIH); NIH National Center for Advancing Translational Sciences (NCATS); French National Research Agency (ANR); Integrative Biology of Emerging Infectious Diseases Laboratoire d'Excellence; French Cancer Institute; Strategic Positioning Fund on Genetic Orphan Diseases from A* STAR, Singapore; Jeffrey Modell Foundation; Bijzonder Onderzoeksfonds-Tenure Grant; Cure-AID; European Union ERA-Net for Research Programmes on Rare Diseases; H2020; European Union (European Union); National Research Foundation; St. Giles Foundation; Rockefeller University; Institut National de la Sante et de la Recherche Medicale (Inserm); Paris Descartes University; Shapiro-Silverberg Fund for the Advancement of Translational Research; American Philosophical Society Daland Fellowship in Clinical Investigation; NIH National Center for Research Resources (NCRR)
Published: 2019

29. 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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30. 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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31. Severe influenza pneumonitis in children with inherited TLR3 deficiency

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

32. Inborn Errors of RNA Lariat Metabolism in Humans with Brainstem Viral Infection

Author: Anat Biran, Masad J. Damha, Michael J. Ciancanelli, Kerry Dobbs, Amos Etzioni, Osamu Ohara, Luísa Diogo, Mary Hasek, Stacy A. Hussong, Fabien G. Lafaille, Jean-Laurent Casanova, Yuval Itan, Lorenz Studer, Satoshi Okada, William G. Fairbrother, Lazaro Lorenzo, Veronica Galvan, Saleh Al-Muhsen, Gregory A. Smith, Rabih Halwani, Alexandra Dinis, Allison J Taggart, Aurélie Cobat, Nathaniel E. Clark, P. John Hart, Eduardo J. Garcia Reino, Brad R. Rosenberg, Luigi D. Notarangelo, Nicholas DeRosa, Adam Katolik, Emília Faria, Sonoko Sakata, Rie Fukuhara, Paula Garcia, Candice E. Van Skike, Maki Hyodo, Masao Kobayashi, Bastian Zimmer, Karen McCammon, Catherine A. Freije, Shen-Ying Zhang, Hanna Mandel, Jef D. Boeke, Miyuki Tsumura, Jingchuan Luo, Stephen P. Holloway, Elodie Pauwels, Laurent Abel, and Stefano Volpi
Subjects: 0301 basic medicine, Male, Genetics and Molecular Biology (all), viruses, Mutant, viral encephalitis, Herpesvirus 1, Human, Biology, medicine.disease_cause, Virus Replication, Biochemistry, General Biochemistry, Genetics and Molecular Biology, Virus, Article, brainstem, 03 medical and health sciences, Mice, Open Reading Frames, Immunity, medicine, Escherichia coli, DBR1, Animals, Humans, Amino Acid Sequence, Encephalitis, Viral, Allele, Alleles, RNA lariat debranching, Biochemistry, Genetics and Molecular Biology (all), RNA, Brain Diseases, Metabolic, Inborn, RNA Nucleotidyltransferases, Fibroblasts, Virology, Introns, Pedigree, Toll-Like Receptor 3, 030104 developmental biology, Herpes simplex virus, Mutation, Lariat debranching enzyme, Female, Mutant Proteins, Brainstem, Interferons, Brain Stem
Abstract: Viruses that are typically benign sometimes invade the brainstem in otherwise healthy children. We report bi-allelic DBR1 mutations in unrelated patients from different ethnicities, each of whom had brainstem infection due to herpes simplex virus 1 (HSV1), influenza virus, or norovirus. DBR1 encodes the only known RNA lariat debranching enzyme. We show that DBR1 expression is ubiquitous, but strongest in the spinal cord and brainstem. We also show that all DBR1 mutant alleles are severely hypomorphic, in terms of expression and function. The fibroblasts of DBR1-mutated patients contain higher RNA lariat levels than control cells, this difference becoming even more marked during HSV1 infection. Finally, we show that the patients’ fibroblasts are highly susceptible to HSV1. RNA lariat accumulation and viral susceptibility are rescued by wild-type DBR1. Autosomal recessive, partial DBR1 deficiency underlies viral infection of the brainstem in humans through the disruption of tissue-specific and cell-intrinsic immunity to viruses.
Published: 2018

33. 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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34. Human adaptive immunity rescues an inborn error of innate immunity

Author: Maya Chrabieh, Ying Wang, Sandra K. Weller, Elisabeth Israelsson, Katarzyna Bulek, Damien Chaussabel, Nicole Lemmens, Vincent Pedergnana, Laura Israel, Michael Levin, Jethro Herberg, Théo Lasseau, Carolina Prando, Andrew Moran, Vanessa Sancho-Shimizu, Zhao Zhang, François Vandenesch, Leonard E. Weisman, Jean-Laurent Casanova, Ling Yun, Erika Della Mina, Aziz Belkadi, Yuval Itan, Marc Descatoire, Lazaro Lorenzo, Willem J. B. van Wamel, Bruce Beutler, Avinash Abhyankar, Capucine Picard, Xiaoxia Li, Anne Puel, Peter D. Arkwright, Laurent Abel, Frédéric Batteux, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Texas Southwestern Medical Center [Dallas], Cleveland Clinic, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Imperial College London, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Benaroya Research Institute [Seattle] (BRI), Manchester Royal Infirmary, University of Manchester [Manchester], Texas Children's Hospital [Houston, USA], Hospices Civils de Lyon (HCL), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], 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), Herrada, Anthony, and Medical Microbiology & Infectious Diseases
Subjects: incomplete clinical penetrance, Lipopolysaccharides, Male, 0301 basic medicine, Proband, TIRAP, [SDV]Life Sciences [q-bio], MESH: Membrane Glycoproteins, MESH: Protein Isoforms, Adaptive Immunity, MESH: Monocytes, MESH: Phagocytes, Monocytes, MESH: Antibodies, Monoclonal, 0302 clinical medicine, MESH: Child, TLR2, Protein Isoforms, CRYSTAL-STRUCTURE, Child, PYOGENIC BACTERIAL-INFECTIONS, Phagocytes, Membrane Glycoproteins, Toll-Like Receptors, MESH: Toll-Like Receptor 2, Antibodies, Monoclonal, 11 Medical And Health Sciences, Staphylococcal Infections, respiratory system, Acquired immune system, Penetrance, Pedigree, [SDV] Life Sciences [q-bio], MYD88 DEFICIENCY, lipoteichoic acid, LTA, MESH: Immunity, Innate, Female, lipids (amino acids, peptides, and proteins), Life Sciences & Biomedicine, MESH: Toll-Like Receptors, MESH: Myeloid Differentiation Factor 88, staphylococcus aureus, Biochemistry & Molecular Biology, MESH: Pedigree, MESH: Staphylococcal Infections, SIGNAL-TRANSDUCTION, Biology, MESH: Receptors, Interleukin-1, primary immunodeficiency, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immunity, TIR DOMAIN, medicine, Humans, Point Mutation, MESH: Point Mutation, STAPHYLOCOCCUS-AUREUS, MESH: Humans, Science & Technology, CUTTING EDGE, PRIMARY IMMUNODEFICIENCIES, Macrophages, MESH: Macrophages, Receptors, Interleukin-1, Cell Biology, 06 Biological Sciences, Fibroblasts, medicine.disease, GENE, MESH: Male, Immunity, Innate, Toll-Like Receptor 2, Teichoic Acids, carbohydrates (lipids), stomatognathic diseases, 030104 developmental biology, toll-like receptors, MESH: Fibroblasts, MESH: Teichoic Acids, Myeloid Differentiation Factor 88, Immunology, anti-LTA antibodies, Primary immunodeficiency, TLR4, MESH: Lipopolysaccharides, MESH: Female, MESH: Adaptive Immunity, Developmental Biology, 030215 immunology
Abstract: International audience; The molecular basis of the incomplete penetrance of monogenic disorders is unclear. We describe here eight related individuals with autosomal recessive TIRAP deficiency. Life-threatening staphylococcal disease occurred during childhood in the proband, but not in the other seven homozygotes. Responses to all Toll-like receptor 1/2 (TLR1/2), TLR2/6, and TLR4 agonists were impaired in the fibroblasts and leukocytes of all TIRAP-deficient individuals. However, the whole-blood response to the TLR2/6 agonist staphylococcal lipoteichoic acid (LTA) was abolished only in the index case individual, the only family member lacking LTA-specific antibodies (Abs). This defective response was reversed in the patient, but not in interleukin-1 receptor-associated kinase 4 (IRAK-4)-deficient individuals, by anti-LTA monoclonal antibody (mAb). Anti-LTA mAb also rescued the macrophage response in mice lacking TIRAP, but not TLR2 or MyD88. Thus, acquired anti-LTA Abs rescue TLR2-dependent immunity to staphylococcal LTA in individuals with inherited TIRAP deficiency, accounting for incomplete penetrance. Combined TIRAP and anti-LTA Ab deficiencies underlie staphylococcal disease in this patient.
Published: 2017
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35. Synthesis and characterization of Ruthenium polypyridyl complexes for alkene epoxidation catalysis

Author: Rico Lazaro, Lorenzo, Universitat de Girona. Facultat de Ciències, and Romero García, Isabel
Subjects: Lligands, Alquens, Catàlisi, Ruthenium compounds, Ruteni -- Compostos, Alkenes, Ligands, Catalysis
Abstract: In this dissertation work we have developed and optimized a synthetic route to obtain different ruthenium complexes with N-donor type ligands, afterwards, we have evaluated the efficiency of an aqua-complex as catalyst for the epoxidation of alkenes. Initially we have synthesized one of the non-commercial N-donor ligand (pypz-H), and the starting product cis,cis-[RuCl2(dmso)2(pypz-H)] 2, this mononuclear complex reacts further with the ligand trpy to generate a mixture of the chloro-complex cis, trans[RuCl(trpy)(pypz-H)](PF6) 3b and 3a. Afterwards, from this one we have synthesized and characterized the correspondent aqua-complex trans-[Ru(trpy)(pypzH)(OH2)](PF6)2 4a. All the compounds have been characterized in solution throught spectroscopic techniques (RMN, UV-Visible) and some of them by X-ray difraction, confirming that they maintain their structure in solid state. The redox properties of the compounds have been studied by CV and DPV. The Pourbaix diagram displayed by the complex trans-[Ru(trpy)(pypz-H)(OH2)](PF6)2 4a allowed to obtain data about the redox equilibriums as well as have allowed to know the correspondent pKa values of the RuII and RuIII species. Finally, we have evaluated the catalytic activity of the complex trans-[Ru(trpy)(pypzH)(OH2)](PF6)2 4a in the alkene epoxidation, using PhI(OAc)2 as oxidant. The results obtained shown good conversion values for the compounds tested as well as excellent selectivity values
Published: 2017

36. 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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37. Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis

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

38. 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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39. Herpes Simplex Virus Encephalitis in Human UNC-93B Deficiency

Author: Armanda Casrouge, Cyril Mignot, Capucine Picard, Lazaro Lorenzo, Nora Mahfoufi, Frederic Geissmann, Laurent Abel, Bruce Beutler, Brigitte Senechal, Alexandre Alcaïs, Pierre Lebon, Jean-Laurent Casanova, Nathalie Nicolas, Kasper Hoebe, Bénédicte Héron, Sabine Plancoulaine, Marc Tardieu, Thierry Billette de Villemeur, Celine Eidenschenk, Xin Du, Koichi Tabeta, Emmanuelle Jouanguy, Flore Rozenberg, Shen-Ying Zhang, Anne Puel, Richard L. Miller, Kun Yang, and Olivier Dulac
Subjects: Male, UNC93B1, Herpesvirus 1, Human, Biology, medicine.disease_cause, Virus, Herpesviridae, Interferon-gamma, Immunity, medicine, Humans, Genetic Predisposition to Disease, Immunodeficiency, Multidisciplinary, Viral encephalitis, Toll-Like Receptors, Infant, Interferon-alpha, Membrane Transport Proteins, Interferon-beta, medicine.disease, Virology, Pedigree, Toll-Like Receptor 3, Child, Preschool, Mutation, Immunology, Leukocytes, Mononuclear, Cytokines, Female, Encephalitis, Herpes Simplex, Interferons, Viral disease, Encephalitis, Signal Transduction
Abstract: Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is the most common form of sporadic viral encephalitis in western countries. Its pathogenesis remains unclear, as it affects otherwise healthy patients and only a small minority of HSV-1–infected individuals. Here, we elucidate a genetic etiology for HSE in two children with autosomal recessive deficiency in the intracellular protein UNC-93B, resulting in impaired cellular interferon-α/β and -λ antiviral responses. HSE can result from a single-gene immunodeficiency that does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies. Other severe infectious diseases may also reflect monogenic disorders of immunity.
Published: 2006
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40. TLR3 deficiency in herpes simplex encephalitis: High allelic heterogeneity and recurrence risk

Author: Marc Tardieu, Xin Cai, Shen-Ying Zhang, Yuval Itan, Lazaro Lorenzo, Emmanuelle Jouanguy, Anne Vergison, Anders Paetau, Minji Byun, Reina Roivainen, Laurent Abel, Elodie Pauwels, Pierre Lebon, Pentti J. Tienari, Mikko Seppänen, Timo Hautala, Hye Kyung Lim, Alisan Yildiran, Ylva Rönnelid, Soraya Boucherit, Fabien G. Lafaille, Flore Rozenberg, Jean-Laurent Casanova, Michael J. Ciancanelli, Amos Etzioni, William Dell, and OMÜ
Subjects: Male, Adolescent, viruses, chemical and pharmacologic phenomena, Biology, medicine.disease_cause, Genetic analysis, Article, Genotype-phenotype distinction, Gene Frequency, Recurrence, Risk Factors, medicine, Humans, Allele, Child, Allele frequency, Cells, Cultured, Genetics, Mutation, virus diseases, Infant, hemic and immune systems, medicine.disease, Pedigree, Toll-Like Receptor 3, Minor allele frequency, Child, Preschool, Immunology, Allelic heterogeneity, Female, Neurology (clinical), Encephalitis, Herpes Simplex, Encephalitis
Abstract: Boucherit, Soraya/0000-0002-8819-7594; Lorenzo, Lazaro/0000-0001-6648-8684; Jouanguy, Emmanuelle/0000-0002-7358-9157; Zhang, Shen-Ying/0000-0002-9449-3672; Abel, Laurent/0000-0001-7016-6493; Seppanen, Mikko/0000-0001-9733-3650; Ciancanelli, Michael/0000-0002-4623-852X; Hautala, Timo/0000-0001-7889-1614; Casanova, Jean-Laurent/0000-0002-7782-4169; Byun, Minji/0000-0002-2830-4079 WOS: 000345301000005 PubMed: 25339207 Objective: To determine the proportion of children with herpes simplex encephalitis (HSE) displaying TLR3 deficiency, the extent of TLR3 allelic heterogeneity, and the specific clinical features of TLR3 deficiency. Methods: We determined the sequence of all exons of TLR3 in 110 of the 120 patients with HSE enrolled in our study who do not carry any of the previously described HSE-predisposing mutations of TLR3 pathway genes (TLR3, UNC93B1, TRIF, TRAF3, and TBK1). All the new mutant TLR3 alleles detected were characterized experimentally in-depth to establish the causal relationship between the genotype and phenotype. Results: In addition to the 3 previously reported TLR3-deficient patients from the same cohort, 6 other children or young adults with HSE carry 1 of 5 unique or extremely rare (minor allele frequency
Published: 2014

41. Assembly of Truncated HCV Core Antigen into Virus-like Particles in Escherichia coli

Author: Viviana Falcón, Lazaro Lorenzo, Ernesto González, Ivón Menéndez, Juan Morales, Maria Cristina De Rosa, Santiago Dueñas-Carrera, and Nelson Acosta-Rivero
Subjects: viruses, Hepatitis C virus, Blotting, Western, Size-exclusion chromatography, Biophysics, Hepacivirus, medicine.disease_cause, Biochemistry, Virus, law.invention, law, Escherichia, Escherichia coli, medicine, Microscopy, Immunoelectron, Molecular Biology, Differential centrifugation, biology, Viral Core Proteins, Cell Biology, biology.organism_classification, Molecular biology, Yeast, Recombinant DNA, Electrophoresis, Polyacrylamide Gel, Hepatitis C Antigens
Abstract: Core protein is one of the most conserved and immunogenic of the hepatitis C virus proteins. Several pieces of experimental evidence suggest its ability for formation of virus like particles alone or in association with other viral proteins in mammalian or yeast cells with great similarity to those detected in patient sera and liver extract. In this work we report an Escherichia coli-derived truncated hepatitis C core protein that is able to aggregate. SDS–PAGE and size exclusion chromatography patterns bring to mind the aggregation of monomers of recombinant protein Co.120. The Co.120 protein migrated with buoyant density of 1.28 g/cm3 when analyzed using CsCl density gradient centrifugation. Spherical structures with an average diameter of 30 nm were observed using electron microscopy. We report here that VLPs are generated when the first 120 aa of HCV core protein are expressed in E. coli.
Published: 2001
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42. A truncated variant of the hepatitis C virus core induces a slow but potent immune response in mice following DNA immunization

Author: Lazaro Lorenzo, Antonieta Herrera, Juan Morales, Santiago Dueñas-Carrera, Julio César Alvarez-Obregón, Liz Alvarez-Lajonchere, and Dagmara Pichardo
Subjects: Viral Hepatitis Vaccines, Cellular immunity, T-Lymphocytes, Hepatitis C virus, Enzyme-Linked Immunosorbent Assay, Hepacivirus, In Vitro Techniques, Lymphocyte Activation, medicine.disease_cause, Binding, Competitive, Virus, law.invention, Mice, Immune system, law, Vaccines, DNA, medicine, Animals, Humans, Immunity, Cellular, Mice, Inbred BALB C, General Veterinary, General Immunology and Microbiology, biology, Viral Core Proteins, Immunogenicity, Public Health, Environmental and Occupational Health, Hepatitis C Antibodies, Virology, Molecular biology, Peptide Fragments, Infectious Diseases, Humoral immunity, biology.protein, Recombinant DNA, Molecular Medicine, Female, Antibody, Plasmids
Abstract: Vaccination of BALB/c mice with pIDKCo, a plasmid containing the coding sequence for the first 176 amino acids of the hepatitis C virus (HCV) core protein, induced both humoral and cellular specific immune responses. Particularly, the level of anti-core antibodies increased slowly with time up to a mean value above 1:8000 that was generally superior than that found in anti-HCV positive individuals. Six out of nine anti-HCV positive human sera were able to inhibit at different extent the binding of mouse anti-core sera to a recombinant capsid protein. Our results show that it is possible to elicit a potent humoral and cellular immune response against the HCV core antigen in mice following DNA immunization.
Published: 2000
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43. 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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44. 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

45. Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency

Author: Sylvie Fabrega, Pierre Lebon, Jean-Laurent Casanova, Vanessa Sancho-Shimizu, Michael J. Ciancanelli, Megumi Tatematsu, Tsukasa Seya, Anne Puel, Lazaro Lorenzo, Saleh Al-Muhsen, Jérome Maluenda, Capucine Picard, Shen-Ying Zhang, Abdullah A. Alangari, Annabelle Cardon, Misako Matsumoto, Nima Rezaei, Flore Rozenberg, Farhad Mahvelati, Laurent Abel, Sabine Plancoulaine, Soraya Boucherit, Yiqi Guo, Marc Tardieu, Emmanuelle Jouanguy, Rabih Halwani, Elisabeth Israelsson, Rebeca Pérez de Diego, Melina Herman, Ata Ghadiri, Zobaida Alsum, Damien Chaussabel, Nouf Alkhamis, and Abdulkarim S. Al-Makadma
Subjects: Male, Genotype, Nonsense mutation, Molecular Sequence Data, Mutation, Missense, Saudi Arabia, Genes, Recessive, Disease, Herpesvirus 1, Human, Biology, DEAD-box RNA Helicases, Consanguinity, Genetic Heterogeneity, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Amino Acid Sequence, Genes, Dominant, Sequence Homology, Amino Acid, Viral encephalitis, Infant, Interferon-alpha, General Medicine, medicine.disease, Penetrance, Virology, Pedigree, Toll-Like Receptor 3, Toll-Like Receptor 4, Adaptor Proteins, Vesicular Transport, TRIF, Codon, Nonsense, Child, Preschool, Immunology, Female, Encephalitis, Herpes Simplex, Signal transduction, Sequence Alignment, Encephalitis, Research Article, Genome-Wide Association Study, Signal Transduction
Abstract: Herpes simplex encephalitis (HSE) is the most common sporadic viral encephalitis of childhood. Autosomal recessive (AR) UNC-93B and TLR3 deficiencies and autosomal dominant (AD) TLR3 and TRAF3 deficiencies underlie HSE in some children. We report here unrelated HSE children with AR or AD TRIF deficiency. The AR form of the disease was found to be due to a homozygous nonsense mutation that resulted in a complete absence of the TRIF protein. Both the TLR3- and the TRIF-dependent TLR4 signaling pathways were abolished. The AD form of disease was found to be due to a heterozygous missense mutation, resulting in a dysfunctional protein. In this form of the disease, the TLR3 signaling pathway was impaired, whereas the TRIF-dependent TLR4 pathway was unaffected. Both patients, however, showed reduced capacity to respond to stimulation of the DExD/H-box helicases pathway. To date, the TRIF-deficient patients with HSE described herein have suffered from no other infections. Moreover, as observed in patients with other genetic etiologies of HSE, clinical penetrance was found to be incomplete, as some HSV-1–infected TRIF-deficient relatives have not developed HSE. Our results provide what we believe to be the first description of human TRIF deficiency and a new genetic etiology for HSE. They suggest that the TRIF-dependent TLR4 and DExD/H-box helicase pathways are largely redundant in host defense. They further demonstrate the importance of TRIF for the TLR3-dependent production of antiviral IFNs in the CNS during primary infection with HSV-1 in childhood.
Published: 2011

46. 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

47. 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

48. EV3 deficiency - a new genetic etiology predisposing to severe beta-HPV infection and non-melanoma skin cancer

Author: Sarah Jill, De Jong, primary, Amandine, Crequer, additional, Lazaro, Lorenzo, additional, Andres, Arias, additional, Nataly, Portilla Maya, additional, Xavier, Rueda Cadena, additional, Jose, Franco, additional, Elias, Imahorn, additional, Bettina, Burger, additional, Gerard, Orth, additional, Emmanuelle, Jouanguy, additional, and Jean-Laurent, Casanova, additional
Published: 2015
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49. Age-dependent Mendelian predisposition to herpes simplex virus type 1 encephalitis in childhood

Author: Olivier Dulac, Lazaro Lorenzo, Louis Vallée, Thierry Blanc, Nora Mahfoufi, Vanessa Sancho-Shimizu, Cécile Bost-Bru, Patrick Berquin, Leila Lazaro, Flore Rozenberg, Emmanuelle Jouanguy, Nathalie Nicolas, Philippe Evrard, Yiqi Guo, D. Obach, Sabine Plancoulaine, Annabelle Cardon, Alexandre Alcaïs, Daniel Amsallem, Bénédicte Héron, Laurent Abel, Jean-Laurent Casanova, Josette Mancini, Soraya Boucherit, Marc Tardieu, Brigitte Chabrol, François Rivier, Thomas Clozel, Stéphane Chabrier, Shen-Ying Zhang, Emmanuel Cheuret, Pierre Lebon, and Jean-Michel Pedespan
Subjects: Male, Pediatrics, medicine.medical_specialty, Adolescent, Acyclovir, medicine.disease_cause, Antiviral Agents, Herpesviridae, symbols.namesake, Young Adult, Risk Factors, medicine, Humans, Simplexvirus, Genetic Predisposition to Disease, Aciclovir, Family history, Age of Onset, Child, business.industry, Age Factors, Genetic Variation, Infant, medicine.disease, Penetrance, Toll-Like Receptor 3, Herpes simplex virus, El Niño, Child, Preschool, Pediatrics, Perinatology and Child Health, Immunology, Mendelian inheritance, symbols, Female, Encephalitis, Herpes Simplex, business, Encephalitis, medicine.drug
Abstract: Objective To test the hypothesis that predisposition to childhood herpes simplex virus (HSV) type 1 encephalitis (HSE) may be determined in part by human genetic factors. Study design A genetic epidemiologic survey of childhood HSE (onset at age 3 months to 15 years) over a 20-year period (1985-2004) was conducted throughout France (comprising 29 university hospital neuropediatric centers). A total of 85 children fulfilled the diagnostic criteria for inclusion. Family and personal histories were obtained by face-to-face interview for 51 patients. Results No familial cases of HSE were identified in our survey; however, a high proportion (20%) of the children interviewed had a relevant family history: parental consanguinity (12% of patients), early-onset herpetic keratitis in a first-degree relative (6%), or both (2%). The narrow window of high susceptibility to HSE before age 3 years (62% of patients) further indicates that predisposition to HSE is tightly age-dependent. Conclusions This survey suggests that childhood HSE, although sporadic, may result from Mendelian predisposition (from autosomal recessive susceptibility in particular), at least in some children. There likely is incomplete penetrance, however, which may reflect, at least in part, the impact of age at the time of HSV-1 infection.
Published: 2009

50. TLR3 deficiency in patients with herpes simplex encephalitis

Author: Vanessa Sancho-Shimizu, Armanda Casrouge, Pedro Romero, Flore Rozenberg, Capucine Picard, Anne Puel, Lluis Quintana-Murci, Asma Smahi, Bénédicte Héron, Frederic Geissmann, Lazaro Lorenzo, Joshua N. Leonard, Jean-Laurent Casanova, Matthias Titeux, Louis Vallée, Luis B. Barreiro, Eric Vivier, Céline Cognet, Horst von Bernuth, Alain Hovnanian, Gaelle Elain, Marc Tardieu, David J. Segal, Shen-Ying Zhang, Emmanuelle Jouanguy, Claire Hamilton, Cheng-Lung Ku, Pierre Lebon, Ariane Chapgier, Laurent Abel, Sophie Ugolini, Sabine Plancoulaine, Xin Xin Zhang, Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Chirurgie, Assistance Publique - Hôpitaux de Marseille ( APHM ) -Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Génétique Humaine des Maladies Infectieuses (Inserm U980), 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)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Assistance Publique - Hôpitaux de Marseille (APHM)-Hospices Civiles de Marseille-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )
Subjects: Keratinocytes, MESH : Cell Line, viruses, MESH : Toll-Like Receptor 3, MESH : Immunity, Natural, Herpesvirus 1, Human, CD8-Positive T-Lymphocytes, MESH : Child, Preschool, medicine.disease_cause, 0302 clinical medicine, MESH : Interferons, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH: Interferons, MESH : Female, Genes, Dominant, MESH: Heterozygote, 0303 health sciences, Toll-like receptor, Multidisciplinary, MESH: Dendritic Cells, MESH : Keratinocytes, MESH: Encephalitis, Herpes Simplex, virus diseases, hemic and immune systems, MESH : Infant, MESH : Genes, Dominant, MESH: Toll-Like Receptor 3, MESH : CD8-Positive T-Lymphocytes, MESH: CD8-Positive T-Lymphocytes, MESH: Infant, MESH: Keratinocytes, 3. Good health, Killer Cells, Natural, MESH: Leukocytes, Mononuclear, MESH: Herpesvirus 1, Human, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Killer Cells, Natural, MESH : Mutation, Encephalitis, MESH : Poly I-C, MESH: Killer Cells, Natural, UNC93B1, Heterozygote, MESH : Heterozygote, MESH: Mutation, chemical and pharmacologic phenomena, Biology, MESH: Poly I-C, Virus, Herpesviridae, Cell Line, 03 medical and health sciences, Immunity, MESH : Fibroblasts, medicine, Humans, Alleles, 030304 developmental biology, MESH: Immunity, Natural, Innate immune system, MESH: Humans, MESH: Alleles, MESH: Child, Preschool, MESH : Humans, Infant, Dendritic Cells, Fibroblasts, medicine.disease, Virology, MESH : Herpesvirus 1, Human, Immunity, Innate, MESH : Encephalitis, Herpes Simplex, Toll-Like Receptor 3, MESH: Cell Line, MESH : Leukocytes, Mononuclear, Herpes simplex virus, Poly I-C, MESH: Fibroblasts, MESH : Dendritic Cells, Immunology, Mutation, Leukocytes, Mononuclear, Encephalitis, Herpes Simplex, Interferons, MESH: Genes, Dominant, MESH : Alleles, MESH: Female, 030215 immunology
Abstract: International audience; Some Toll and Toll-like receptors (TLRs) provide immunity to experimental infections in animal models, but their contribution to host defense in natural ecosystems is unknown. We report a dominant-negative TLR3 allele in otherwise healthy children with herpes simplex virus 1 (HSV-1) encephalitis. TLR3 is expressed in the central nervous system (CNS), where it is required to control HSV-1, which spreads from the epithelium to the CNS via cranial nerves. TLR3 is also expressed in epithelial and dendritic cells, which apparently use TLR3-independent pathways to prevent further dissemination of HSV-1 and to provide resistance to other pathogens in TLR3-deficient patients. Human TLR3 appears to be redundant in host defense to most microbes but is vital for natural immunity to HSV-1 in the CNS, which suggests that neurotropic viruses have contributed to the evolutionary maintenance of TLR3.
Published: 2007
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