Author: "Jérémie Rosain" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Jérémie Rosain"' showing total 70 results

Start Over Author "Jérémie Rosain"

70 results on '"Jérémie Rosain"'

1. Interferon Gamma in Sickness Predisposing to Mycobacterial Infectious Diseases

Author: Betül Gemici Karaaslan, Jérémie Rosain, Jacinta Bustamante, and Ayça Kıykım
Subjects: Medicine
Abstract: In recent decades, the prevalence of inborn errors of immunity has increased, necessitating the development of more effective treatment and care options for these highly morbid conditions. Due to these “experiments of nature,” the complicated nature of the immune system is being revealed. Based on the functional and molecular tests, targeted therapies are now being developed which offer a more effective approach and reduce damage. This study aimed to investigate a key cytokine of the cellular immune response, interferon‐gamma (IFN-γ), which is linked to Mendelian susceptibility to Mycobacterial disease, and its potential as a therapeutic option for IFN-γ deficiency.
Published: 2024
Full Text: View/download PDF

2. Study of the potential role of CASPASE-10 mutations in the development of autoimmune lymphoproliferative syndrome

Author: Filippo Consonni, Solange Moreno, Blanca Vinuales Colell, Marie-Claude Stolzenberg, Alicia Fernandes, Mélanie Parisot, Cécile Masson, Nathalie Neveux, Jérémie Rosain, Sarah Bamberger, Marie-Gabrielle Vigue, Marion Malphettes, Pierre Quartier, Capucine Picard, Frédéric Rieux-Laucat, and Aude Magerus
Subjects: Cytology, QH573-671
Abstract: Abstract Autoimmune lymphoproliferative syndrome (ALPS) is a primary disorder of lymphocyte homeostasis, leading to chronic lymphoproliferation, autoimmune cytopenia, and increased risk of lymphoma. The genetic landscape of ALPS includes mutations in FAS, FASLG, and FADD, all associated with apoptosis deficiency, while the role of CASP10 defect in the disease remains debated. In this study, we aimed to assess the impact of CASP10 variants on ALPS pathogenesis. We benefit from thousands of genetic analysis datasets performed in our Institute’s genetic platform to identify individuals carrying CASP10 variants previously suspected to be involved in ALPS outcome: p.C401LfsX15, p.V410I and p.Y446C, both at heterozygous and homozygous state. Clinical and laboratory features of the six included subjects were variable but not consistent with ALPS. Two individuals were healthy. Comprehensive analyses of CASP10 protein expression and FAS-mediated apoptosis were conducted and compared to healthy controls and ALPS patients with FAS mutations. Missense CASP10 variants (p.V410I and p.Y446C), which are common in the general population, did not disrupt CASP10 expression, nor FAS-mediated apoptosis. In contrast, homozygous p.C401LfsX15 CASP10 variant lead to a complete abolished CASP10 expression but had no impact on FAS-mediated apoptosis function. At heterozygous state, this p.C401LfsX15 variant lead to a reduced CASP10 protein levels but remained associated with a normal FAS-mediated apoptosis function. These findings demonstrate that CASPASE 10 is dispensable for FAS-mediated apoptosis. In consequences, CASP10 defect unlikely contribute to ALPS pathogenesis, since they did not result in an impairment of FAS-mediated apoptosis nor in clinical features of ALPS in human. Moreover, the absence of FAS expression up-regulation in subjects with CASP10 variants rule out any compensatory mechanisms possibly involved in the normal apoptosis function observed. In conclusion, this study challenges the notion that CASP10 variants contribute to the development of ALPS.
Published: 2024
Full Text: View/download PDF

3. Partial human Janus kinase 1 deficiency predominantly impairs responses to interferon gamma and intracellular control of mycobacteria

Author: Vanessa Daza-Cajigal, Adriana S. Albuquerque, Dan F. Young, Michael J. Ciancanelli, Dale Moulding, Ivan Angulo, Valentine Jeanne-Julien, Jérémie Rosain, Ekaterina Minskaia, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Richard E. Randall, Timothy D. McHugh, Adrian J. Thrasher, and Siobhan O. Burns
Subjects: JAK1, IFN immunity, immunodeficiency, mycobacterial disease, viral susceptibility, Immunologic diseases. Allergy, RC581-607
Abstract: PurposeJanus kinase-1 (JAK1) tyrosine kinase mediates signaling from multiple cytokine receptors, including interferon alpha/beta and gamma (IFN-α/β and IFN-γ), which are important for viral and mycobacterial protection respectively. We previously reported autosomal recessive (AR) hypomorphic JAK1 mutations in a patient with recurrent atypical mycobacterial infections and relatively minor viral infections. This study tests the impact of partial JAK1 deficiency on cellular responses to IFNs and pathogen control.MethodsWe investigated the role of partial JAK1 deficiency using patient cells and cell models generated with lentiviral vectors expressing shRNA.ResultsPartial JAK1 deficiency impairs IFN-γ-dependent responses in multiple cell types including THP-1 macrophages, Epstein-Barr Virus (EBV)-transformed B cells and primary dermal fibroblasts. In THP-1 myeloid cells, partial JAK1 deficiency reduced phagosome acidification and apoptosis and resulted in defective control of mycobacterial infection with enhanced intracellular survival. Although both EBV-B cells and primary dermal fibroblasts with partial JAK1 deficiency demonstrate reduced IFN-α responses, control of viral infection was impaired only in patient EBV-B cells and surprisingly intact in patient primary dermal fibroblasts.ConclusionOur data suggests that partial JAK1 deficiency predominantly affects susceptibility to mycobacterial infection through impact on the IFN-γ responsive pathway in myeloid cells. Susceptibility to viral infections as a result of reduced IFN-α responses is variable depending on cell type. Description of additional patients with inherited JAK1 deficiency will further clarify the spectrum of bacterial and viral susceptibility in this condition. Our results have broader relevance for anticipating infectious complications from the increasing use of selective JAK1 inhibitors.
Published: 2022
Full Text: View/download PDF

4. Challenges in Rare Diseases Diagnostics: Incontinentia Pigmenti with Heterozygous GBA Mutation

Author: Snežana Minić, Dušan Trpinac, Ivana Novaković, Nataša Cerovac, Danijela Dobrosavljević Vukojević, and Jérémie Rosain
Subjects: Incontinentia pigmenti, Gaucher disease, IKBKG gene mutations, GBA gene mutations, rare disease diagnostics, neurodegeneration, Medicine (General), R5-920
Abstract: Rare diseases represent a diagnostic challenge due to their number, variety of clinical phenomena, and possibility of a simultaneous presence of two or more diseases. An illustration of this challenge is an occurrence of a late diagnosis of a proband initially diagnosed with West syndrome, later revealed to be caused by Incontinentia pigmenti (IP). Furthermore, 20 years later, it was discovered that the proband was also a carrier of a heterozygous GBA gene mutation. The methods used in diagnostics were as follows: IKBKG gene analysis, the X-chromosome inactivation assay, analyses of the genes relevant for neurodegeneration, WES analysis, analysis of biochemical parameters typical for Gaucher disease (GD), and autoantibodies including IFN-α2a and IFN-ω. To avoid overlooking IP and other possible rare disease diagnoses, carefully searching for dermatological signs in these conditions is recommended. It is important that the diagnostic criteria are based on quality and extensive data from multiple studies of each rare disease. Establishing precise diagnostic criteria for as many rare diseases as possible and establishing a publicly accessible database of rare diseases with a search possibility according to phenotypic abnormalities and genetic mutations would greatly facilitate and speed up the establishment of an accurate diagnosis.
Published: 2022
Full Text: View/download PDF

5. Clinical and Genetic Spectrum of a Large Cohort With Total and Sub-total Complement Deficiencies

Author: Carine El Sissy, Jérémie Rosain, Paula Vieira-Martins, Pauline Bordereau, Aurélia Gruber, Magali Devriese, Loïc de Pontual, Muhamed-Kheir Taha, Claire Fieschi, Capucine Picard, and Véronique Frémeaux-Bacchi
Subjects: complement, genetic variants, meningococcal infections, deficiency, auto immune diseases, Immunologic diseases. Allergy, RC581-607
Abstract: The complement system is crucial for defense against pathogens and the removal of dying cells or immune complexes. Thus, clinical indications for possible complete complement deficiencies include, among others, recurrent mild or serious bacterial infections as well as autoimmune diseases (AID). The diagnostic approach includes functional activity measurements of the classical (CH50) and alternative pathway (AP50) and the determination of the C3 and C4 levels, followed by the quantitative analysis of individual components or regulators. When biochemical analysis reveals the causal abnormality of the complement deficiency (CD), molecular mechanisms remains frequently undetermined. Here, using direct sequencing analysis of the coding region we report the pathogenic variants spectrum that underlie the total or subtotal complement deficiency in 212 patients. We identified 107 different hemizygous, homozygous, or compound heterozygous pathogenic variants in 14 complement genes [C1Qβ (n = 1), C1r (n = 3), C1s (n = 2), C2 (n = 12), C3 (n = 5), C5 (n = 12), C6 (n = 9), C7 (n = 17), C8 β (n = 7), C9 (n = 3), CFH (n = 7), CFI (n = 18), CFP (n = 10), CFD (n = 2)]. Molecular analysis identified 17 recurrent pathogenic variants in 6 genes (C2, CFH, C5, C6, C7, and C8). More than half of the pathogenic variants identified in unrelated patients were also found in healthy controls from the same geographic area. Our study confirms the strong association of meningococcal infections with terminal pathway deficiency and highlights the risk of pneumococcal and auto-immune diseases in the classical and alternative pathways. Results from this large genetic investigation provide evidence of a restricted number of molecular mechanisms leading to complement deficiency and describe the clinical potential adverse events of anti-complement therapy.
Published: 2019
Full Text: View/download PDF

6. Copy number variations and founder effect underlying complete IL-10Rβ deficiency in Portuguese kindreds.

Author: Fabienne Charbit-Henrion, Bernadette Bègue, Anaïs Sierra, Sylvain Hanein, Marie-Claude Stolzenberg, Zhi Li, Sandra Pellegrini, Nicolas Garcelon, Marc Jeanpierre, Bénédicte Neven, Isabelle Loge, Capucine Picard, Jérémie Rosain, Jacinta Bustamante, Marc Le Lorc'h, Bénédicte Pigneur, Alicia Fernandes, GENIUS Group, Frédéric Rieux-Laucat, Jorge Amil Dias, Frank M Ruemmele, and Nadine Cerf-Bensussan
Subjects: Medicine, Science
Abstract: Mutations in interleukin-10 receptor (IL-10R) genes are one cause of very early-onset inflammatory bowel disease with perianal lesions, which can be cured by hematopoietic stem cell transplantation. Using a functional test, which assesses responsiveness of peripheral monocytes to IL-10, we identified three unrelated Portuguese patients carrying two novel IL-10RB mutations. In the three patients, sequencing of genomic DNA identified the same large deletion of exon 3 which precluded protein expression. This mutation was homozygous in two patients born from consanguineous families and heterozygous in the third patient born from unrelated parents. Microsatellite analysis of the IL10RB genomic region revealed a common haplotype in the three Portuguese families pointing to a founder deletion inherited from a common ancestor 400 years ago. In the third patient, surface expression of IL-10R was normal but signaling in response to IL-10 was impaired. Complementary DNA sequencing and next-generation sequencing of IL10RB locus with custom-made probes revealed a ≈ 6 Kb duplication encompassing the exon 6 which leads to a frameshift mutation and a loss of the TYK2-interacting Box 2 motif. Altogether, we describe two novel copy number variations in IL10RB, one with founder effect and one preserving cell surface expression but abolishing signaling.
Published: 2018
Full Text: View/download PDF

7. Mutations in the adaptor-binding domain and associated linker region of p110δ cause Activated PI3K-δ Syndrome 1 (APDS1)

Author: Lucie Heurtier, Hicham Lamrini, Loïc Chentout, Marie-Céline Deau, Amine Bouafia, Jérémie Rosain, Jean-Marc Plaza, Mélanie Parisot, Benoit Dumont, Delphine Turpin, Etienne Merlin, Despina Moshous, Nathalie Aladjidi, Bénédicte Neven, Capucine Picard, Marina Cavazzana, Alain Fischer, Anne Durandy, Jean-Louis Stephan, and Sven Kracker
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2017
Full Text: View/download PDF

8. Human IL-23 is essential for IFN-γ–dependent immunity to mycobacteria

Author: Quentin Philippot, Masato Ogishi, Jonathan Bohlen, Julia Puchan, Andrés Augusto Arias, Tina Nguyen, Marta Martin-Fernandez, Clement Conil, Darawan Rinchai, Mana Momenilandi, Seyed Alireza Mahdaviani, Mohammad Keramatipour, Jérémie Rosain, Rui Yang, Taushif Khan, Anna-Lena Neehus, Marie Materna, Ji Eun Han, Jessica Peel, Federico Mele, Marc Weisshaar, Sandra Jovic, Paul Bastard, Romain Lévy, Tom Le Voyer, Peng Zhang, Majistor Raj Luxman Maglorius Renkilaraj, Carlos A. Arango-Franco, Simon Pelham, Yoann Seeleuthner, Mathieu Pochon, Manar Mahmoud Ahmad Ata, Fatima Al Ali, Mélanie Migaud, Camille Soudée, Tatiana Kochetkov, Anne Molitor, Raphael Carapito, Seiamak Bahram, Bertrand Boisson, Claire Fieschi, Davood Mansouri, Nico Marr, Satoshi Okada, Mohammad Shahrooei, Nima Parvaneh, Zahra Chavoshzadeh, Aurélie Cobat, Dusan Bogunovic, Laurent Abel, Stuart G. Tangye, Cindy S. Ma, Vivien Béziat, Federica Sallusto, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Jean-Laurent Casanova, and Anne Puel
Subjects: Immunology, General Medicine
Abstract: Patients with autosomal recessive (AR) IL-12p40 or IL-12Rβ1 deficiency display Mendelian susceptibility to mycobacterial disease (MSMD) due to impaired IFN-γ production and, less commonly, chronic mucocutaneous candidiasis (CMC) due to impaired IL-17A/F production. We report six patients from four kindreds with AR IL-23R deficiency. These patients are homozygous for one of four different loss-of-function IL23R variants. All six patients have a history of MSMD, but only two suffered from CMC. We show that IL-23 induces IL-17A only in MAIT cells, possibly contributing to the incomplete penetrance of CMC in patients unresponsive to IL-23. By contrast, IL-23 is required for both baseline and Mycobacterium -inducible IFN-γ immunity in both Vδ2 + γδ T and MAIT cells, probably contributing to the higher penetrance of MSMD in these patients. Human IL-23 appears to contribute to IL-17A/F–dependent immunity to Candida in a single lymphocyte subset but is required for IFN-γ–dependent immunity to Mycobacterium in at least two lymphocyte subsets.
Published: 2023

9. 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

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

Author: Tom Le Voyer, Adrian Gervais, Jérémie Rosain, Audrey Parent, Axel Cederholm, Darawan Rinchai, Lucy Bizien, Gonca Hancioglu, Quentin Philippot, Mame Sokhna Gueye, Majistor Raj Luxman, Maglorius Renkilaraj, Masato Ogishi, Camille Soudée, Mélanie Migaud, Flore Rozenberg, Mana Momenilandi, Quentin Riller, Luisa Imberti, Ottavia Delmonte, Gabriele Müller, Bärbel Keller, Julio Orrego, William Alexander Gallego, Tamar Rubin, Melike Emiroglu, Nima Parvaneh, Daniel Eriksson, Maribel Aranda-Guillen, David I Berrios, Linda Vong, Connie H Katelaris, Peter Mustillo, Johannes Rädler, Jonathan Bohlen, Jale Bengi Celik, Camila Astudillo, Sarah Winter, Audrey Guichard, Vivien Béziat, Jacinta Bustamante, Qiang Pan-Hammarström, Yu Zhang, Lindsey B Rosen, Steve M Holland, Heather Kenney, Kaan Boztuğ, Nizar Mahlaoui, Sylvain Latour, Roshini Abraham, Vassilios Lougaris, Fabian Hauck, Anna Sediva, Faranaz Atschekzei, M Cecilia Poli, Mary A Slatter, Boaz Palterer, Michael D Keller, Alberto Pinzon-Charry, Anna Sullivan, Luke Droney, Daniel Suan, Nathalie Aladjidi, Miguel Hie, Estibaliz Lazaro, Jose Franco, Sevgi Keles, Marion Malphette, Marlene Pasquet, Maria Elena Maccari, Andrea Meinhardt, Aydan Ikinciogullari, Mohammad Shahrooei, Fatih Celmeli, Patrick Frosk, Christopher C Goodnow, Paul E Gray, Alexandre Belot, Hye Sun Kuehn, Sergio D Rosenzweig, Francesco Licciardi, Amélie Servettaz, Vincent Barlogis, Guillaume Le Guenno, Vera-Maria Herrmann, Taco Kuijpers, Grégoire Ducoux, Françoise Sarrot-Reynauld, Catharina Schuetz, Charlotte Cunningham-Rundles, Frédéric Rieux-Laucat, Stuart G Tangye, Cristina Sobacchi, Rainer Doffinger, Klaus Warnatz, Bodo Grimbacher, Claire Fieschi, Laureline Berteloot, Vanessa Bryant, Sophie Trouillet Assant, Luigi D Notarangelo, Helen Su, Benedicte Neven, Laurent Abel, Qian Zhang, Bertrand Boisson, Aurélie Cobat, Emmanuelle Jouanguy, Olle Kampe, Paul Bastard, Chaim Roifman, Nils Landegren, Mark S Anderson, Jean-Laurent Casanova, and Anne Puel
Abstract: Patients with inborn errors of the alternative NF-κB pathway have low thymic AIRE expression, leading to the development of auto-Abs neutralizing type I IFNs, and severe viral diseases.
Published: 2023

11. Human T-bet governs the generation of a distinct subset of CD11c high CD21 low B cells

Author: Rui Yang, Danielle T. Avery, Katherine J. L. Jackson, Masato Ogishi, Ibtihal Benhsaien, Likun Du, Xiaofei Ye, Jing Han, Jérémie Rosain, Jessica N. Peel, Marie-Alexandra Alyanakian, Bénédicte Neven, Sarah Winter, Anne Puel, Bertrand Boisson, Kathryn J. Payne, Melanie Wong, Amanda J. Russell, Yoko Mizoguchi, Satoshi Okada, Gulbu Uzel, Christopher C. Goodnow, Sylvain Latour, Jalila El Bakkouri, Aziz Bousfiha, Kahn Preece, Paul E. Gray, Baerbel Keller, Klaus Warnatz, Stéphanie Boisson-Dupuis, Laurent Abel, Qiang Pan-Hammarström, Jacinta Bustamante, Cindy S. Ma, Jean-Laurent Casanova, and Stuart G. Tangye
Subjects: B-Lymphocytes, Lipoproteins, Plasma Cells, Immunology, General Medicine, Lymphocyte Activation, Article, CD11c Antigen, Mice, Gene Expression Regulation, Immunoglobulin G, Animals, Humans, Adaptor Proteins, Signal Transducing
Abstract: High-level expression of the transcription factor T-bet characterizes a phenotypically distinct murine B cell population known as “age-associated B cells” (ABCs). T-bet–deficient mice have reduced ABCs and impaired humoral immunity. We describe a patient with inherited T-bet deficiency and largely normal humoral immunity including intact somatic hypermutation, affinity maturation and memory B cell formation in vivo, and B cell differentiation into Ig-producing plasmablasts in vitro. Nevertheless, the patient exhibited skewed class switching to IgG1, IgG4, and IgE, along with reduced IgG2, both in vivo and in vitro. Moreover, T-bet was required for the in vivo and in vitro development of a distinct subset of human B cells characterized by reduced expression of CD21 and the concomitantly high expression of CD19, CD20, CD11c, FCRL5, and T-bet, a phenotype that shares many features with murine ABCs. Mechanistically, human T-bet governed CD21 lo CD11c hi B cell differentiation by controlling the chromatin accessibility of lineage-defining genes in these cells: FAS , IL21R , SEC61B , DUSP4 , DAPP1 , SOX5 , CD79B , and CXCR4 . Thus, human T-bet is largely redundant for long-lived protective humoral immunity but is essential for the development of a distinct subset of human CD11c hi CD21 lo B cells.
Published: 2022

12. Lymphoma as an Exclusion Criteria for CVID Diagnosis Revisited

Author: Vincent Allain, Virginie Grandin, Véronique Meignin, Rémi Bertinchamp, David Boutboul, Claire Fieschi, Lionel Galicier, Laurence Gérard, Marion Malphettes, Jacinta Bustamante, Mathieu Fusaro, Nathalie Lambert, Jérémie Rosain, Christelle Lenoir, Sven Kracker, Frédéric Rieux-Laucat, Sylvain Latour, Jean-Pierre de Villartay, Capucine Picard, and Eric Oksenhendler
Subjects: Immunology, Immunology and Allergy
Abstract: Hypogammaglobulinemia in a context of lymphoma is usually considered as secondary and prior lymphoma remains an exclusion criterion for a common variable immunodeficiency (CVID) diagnosis. We hypothesized that lymphoma could be the revealing symptom of an underlying primary immunodeficiency (PID), challenging the distinction between primary and secondary hypogammaglobulinemia.Within a French cohort of adult patients with hypogammaglobulinemia, patients who developed a lymphoma either during follow-up or before the diagnosis of hypogammaglobulinemia were identified. These two chronology groups were then compared. For patients without previous genetic diagnosis, a targeted next-generation sequencing of 300 PID-associated genes was performed.A total of forty-seven patients had developed 54 distinct lymphomas: non-Hodgkin B cell lymphoma (67%), Hodgkin lymphoma (26%), and T cell lymphoma (7%). In 25 patients, lymphoma developed prior to the diagnosis of hypogammaglobulinemia. In this group of patients, Hodgkin lymphoma was overrepresented compared to the group of patients in whom lymphoma occurred during follow-up (48% versus 9%), whereas MALT lymphoma was absent (0 versus 32%). Despite the histopathological differences, both groups presented with similar characteristics in terms of age at hypogammaglobulinemia diagnosis, consanguinity rate, or severe T cell defect. Overall, genetic analyses identified a molecular diagnosis in 10/47 patients (21%), distributed in both groups and without peculiar gene recurrence. Most of these patients presented with a late onset combined immunodeficiency (LOCID) phenotype.Prior or concomitant lymphoma should not be used as an exclusion criteria for CVID diagnosis, and these patients should be investigated accordingly.
Published: 2022

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

Author: Tom Le Voyer, Adrian Gervais, Jérémie Rosain, Audrey V. Parent, Axel Cederholm, Chaim Roifman, Nils Landegren, Mark S. Anderson, Jean-Laurent Casanova, and Anne Puel
Subjects: Immunology, Immunology and Allergy
Published: 2023

14. Inborn errors of human transcription factors governing IFN-γ antimycobacterial immunity

Author: Masato Ogishi, Rui Yang, Jérémie Rosain, Jacinta Bustamante, Jean-Laurent Casanova, and Stéphanie Boisson-Dupuis
Subjects: Immunology, Immunology and Allergy
Published: 2023

15. Two Novel Homozygous Mutations in Phosphoglucomutase 3 Leading to Severe Combined Immunodeficiency, Skeletal Dysplasia, and Malformations

Author: Maria Veiga-da-Cunha, Aline Vincent, Jérémie Rosain, Martin Castelle, Jill Serre, Laurent Renesme, Valérie Cormier-Daire, Takfarinas Kentache, Benjamin Fournier, Sophie Blesson, Nathalie Aladjidi, Despina Moshous, Mathieu Fusaro, Eulalie Lasseaux, Capucine Picard, Fanny Morice Picard, Nathalie Seta, Bénédicte Neven, Anne-Lise Delezoide, Catherine Fallet-Bianco, Emile Van Schaftingen, and UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique
Subjects: Male, 0301 basic medicine, Immunology, Limb Deformities, Congenital, macromolecular substances, Disease, Virus, N-Acetylphosphoglucosamine, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Immunology and Allergy, Missense mutation, Congenital disorders of glycosylation, Abnormalities, Multiple, Bone Diseases, Developmental, Severe combined immunodeficiency, Primary immunodeficiency, business.industry, Infant, Newborn, Infant, Phosphoglucomutase 3, medicine.disease, PGM3, 030104 developmental biology, Phosphoglucomutase, Dysplasia, Child, Preschool, Face, Skeletal dysplasia, Female, Severe Combined Immunodeficiency, Nervous System Diseases, business, Congenital disorder of glycosylation, 030215 immunology
Abstract: Phosphoglucomutase 3 (PGM3) deficiency is a rare congenital disorder of glycosylation. Most of patients with autosomal recessive hypomorphic mutations in PGM3 encoding for phosphoglucomutase 3 present with eczema, skin and lung infections, elevated serum IgE, as well as neurological and skeletal features. A few PGM3-deficient patients suffer from a more severe disease with nearly absent T cells and severe skeletal dysplasia. We performed targeted next-generation sequencing on two kindred to identify the underlying genetic etiology of a severe combined immunodeficiency with developmental defect. We report here two novel homozygous missense variants (p.Gly359Asp and p.Met423Thr) in PGM3 identified in three patients from two unrelated kindreds with severe combined immunodeficiency, neurological impairment, and skeletal dysplasia. Both variants segregated with the disease in the two families. They were predicted to be deleterious by in silico analysis. PGM3 enzymatic activity was found to be severely impaired in primary fibroblasts and Epstein-Barr virus immortalized B cells from the kindred carrying the p.Met423Thr variant. Our findings support the pathogenicity of these two novel variants in severe PGM3 deficiency.
Published: 2021

16. A partial form of inherited human USP18 deficiency underlies infection and inflammation

Author: Marta Martin-Fernandez, Sofija Buta, Tom Le Voyer, Zhi Li, Lasse Toftdal Dynesen, Françoise Vuillier, Lina Franklin, Fatima Ailal, Alice Muglia Amancio, Louise Malle, Conor Gruber, Ibtihal Benhsaien, Jennie Altman, Justin Taft, Caroline Deswarte, Manon Roynard, Alejandro Nieto-Patlan, Kunihiko Moriya, Jérémie Rosain, Nathalie Boddaert, Aziz Bousfiha, Yanick J. Crow, Dragana Jankovic, Alan Sher, Jean-Laurent Casanova, Sandra Pellegrini, Jacinta Bustamante, Dusan Bogunovic, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Human genetics of infectious diseases : Mendelian 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), Signalisation des Cytokines - Cytokine Signaling, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalo-universitaire Averroes [Casablanca], Université Hassan II [Casablanca] (UH2MC), National Institutes of Health [Bethesda] (NIH), Fundação Cristiano Varella [Muriaé/MG, Brasil] (FCV), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie et imagerie médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], School of Mathematics - University of Edinburgh, University of Edinburgh, Rockefeller University [New York], 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 research was in part supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases (grant numbers R01AI127372, R01AI148963, R01AI151029, 5R01AI089970, and 5R37AI095983), the National Center for Research Resources and the National Center for Advancing Sciences of the National Institutes of Health (grant number 8UL1TR000043), The Rockefeller University, the St. Giles Foundation, The Yale Center for Mendelian Genomics funded by the National Human Genome Research Institute (UM1HG006504), INSERM, University of Paris, 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 (grant number ANR-10-IAHU-01), and GENMSMD (ANR-16-CE17-0005-01 for J. Bustamante). T. LeVoyer is supported by the MD-PhD program of the Imagine Institute with the support of the Bettancourt-Schueller Foundation. Work in Institut Pasteur was supported by grants from Association de la Recherche sur le Cancer (ARC no. 20141201864) and Fondation pour la Recherche Médicale (grant DEQ. 2017033741) and by institutional funding from Institut Pasteur and INSERM. Z. Li was supported by Centre national de la recherche scientifique. L.T. Dynesen was supported by the EU Erasmus+ program. L. Franklin was supported by la Fondation de France (Prix Thérèse Lebrasseur to S. Pellegrini). L. Malle and C. Gruber were supported by National Institute of Child Health and Human Development-Interdisciplinary Training in Systems and Developmental Biology and Birth Defects T32HD075735., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), Vuillier, Françoise, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, and Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme - - GENMSMD2016 - ANR-16-CE17-0005 - AAPG2016 - VALID
Subjects: MESH: Inflammation, MESH: Interleukin-12, MESH: Interleukin-23, Inflammation, MESH: Cytokines, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Ubiquitin Thiolesterase, Interleukin-12, Interleukin-23, [SDV] Life Sciences [q-bio], MESH: Ubiquitins, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Humans, Immunology and Allergy, Ubiquitin Thiolesterase, Ubiquitins
Abstract: International audience; Human USP18 is an interferon (IFN)-stimulated gene product and a negative regulator of type I IFN (IFN-I) signaling. It also removes covalently linked ISG15 from proteins, in a process called deISGylation. In turn, ISG15 prevents USP18 from being degraded by the proteasome. Autosomal recessive complete USP18 deficiency is life-threatening in infancy owing to uncontrolled IFN-I–mediated autoinflammation. We report three Moroccan siblings with autoinflammation and mycobacterial disease who are homozygous for a new USP18 variant. We demonstrate that the mutant USP18 (p.I60N) is normally stabilized by ISG15 and efficient for deISGylation but interacts poorly with the receptor-anchoring STAT2 and is impaired in negative regulation of IFN-I signaling. We also show that IFN-γ–dependent induction of IL-12 and IL-23 is reduced owing to IFN-I–mediated impairment of myeloid cells to produce both cytokines. Thus, insufficient negative regulation of IFN-I signaling by USP18-I60N underlies a specific type I interferonopathy, which impairs IL-12 and IL-23 production by myeloid cells, thereby explaining predisposition to mycobacterial disease.
Published: 2022

17. Inherited human IFN-γ deficiency underlies mycobacterial disease

Author: Jérémie Rosain, Bernhard Fleckenstein, Chih-Yu Chi, Cheng-Lung Ku, Nico Marr, Rui Yang, Jacinta Bustamante, Flore Rozenberg, Carmen Oleaga-Quintas, Vivien Béziat, Yoann Seeleuthner, Rubén Martínez-Barricarte, Franck Rapaport, Jing-Ya Ding, Michel J. Massaad, Stéphanie Boisson-Dupuis, Raif S. Geha, Fatima Al Ali, Antoine Guérin, Laurent Abel, Taushif Khan, Gaspard Kerner, Waleed Al-Herz, Mahbuba Rahman, Jean-Laurent Casanova, Caroline Deswarte, Manon Roynard, Diane S. T. Garcia, Ahmad Al-Khabaz, and Valentine Jeanne-Julien
Subjects: 0301 basic medicine, medicine.medical_treatment, Biology, Frameshift mutation, Interferon-gamma, 03 medical and health sciences, symbols.namesake, Negative selection, 0302 clinical medicine, Immunity, medicine, Humans, Gene, Loss function, Receptors, Interferon, Sequence Deletion, Genetics, Mycobacterium Infections, Base Sequence, Homozygote, Genetic Diseases, Inborn, General Medicine, Mycobacterium bovis, Phenotype, 030104 developmental biology, Cytokine, 030220 oncology & carcinogenesis, Mendelian inheritance, symbols, Female, Research Article
Abstract: Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to clinical disease caused by the Bacille Calmette-Guérin (BCG) vaccine and environmental mycobacteria. The known genetic etiologies of MSMD are inborn errors of IFN-γ immunity due to mutations of 15 genes controlling the production of or response to IFN-γ. Since the first MSMD-causing mutations were reported in 1996, biallelic mutations in the genes encoding IFN-γ receptor 1 (IFN-γR1) and IFN-γR2 have been reported in many patients of diverse ancestries. Surprisingly, mutations of the gene encoding the IFN-γ cytokine itself have not been reported, raising the remote possibility that there might be other agonists of the IFN-γ receptor. We describe 2 Lebanese cousins with MSMD, living in Kuwait, who are both homozygous for a small deletion within the IFNG gene (c.354_357del), causing a frameshift that generates a premature stop codon (p.T119Ifs4*). The mutant allele is loss of expression and loss of function. We also show that the patients’ herpesvirus Saimiri–immortalized T lymphocytes did not produce IFN-γ, a phenotype that can be rescued by retrotransduction with WT IFNG cDNA. The blood T and NK lymphocytes from these patients also failed to produce and secrete detectable amounts of IFN-γ. Finally, we show that human IFNG has evolved under stronger negative selection than IFNGR1 or IFNGR2, suggesting that it is less tolerant to heterozygous deleterious mutations than IFNGR1 or IFNGR2. This may account for the rarity of patients with autosomal-recessive, complete IFN-γ deficiency relative to patients with complete IFN-γR1 and IFN-γR2 deficiencies.
Published: 2020

18. Pulmonary Alveolar Proteinosis and Multiple Infectious Diseases in a Child with Autosomal Recessive Complete IRF8 Deficiency

Author: Jérémie Rosain, Andrea Bernasconi, Emma Prieto, Lucia Caputi, Tom Le Voyer, Guadalupe Buda, Marcelo Marti, Jonathan Bohlen, Anna-Lena Neehus, Claudio Castaños, Rosario Gallagher, Karim Dorgham, Matias Oleastro, Laura Perez, Silvia Danielian, Jose Edgardo Dipierri, Jean-Laurent Casanova, Jacinta Bustamante, and Mariana Villa
Subjects: Male, DNA, Complementary, Immunology, Interferon Regulatory Factors, Immunology and Allergy, Humans, Infant, Pulmonary Alveolar Proteinosis, Child, Communicable Diseases, Monocytes
Abstract: Background Autosomal recessive (AR) complete IRF8 deficiency is a rare severe inborn error of immunity underlying an absence of blood myeloid mononuclear cells, intracerebral calcifications, and multiple infections. Only three unrelated patients have been reported. Materials and Methods We studied an Argentinian child with multiple infectious diseases and severe pulmonary alveolar proteinosis (PAP). We performed whole-exome sequencing (WES) and characterized his condition by genetic, immunological, and clinical means. Results The patient was born and lived in Argentina. He had a history of viral pulmonary diseases, disseminated disease due to bacillus Calmette-Guérin (BCG), PAP, and cerebral calcifications. He died at the age of 10 months from refractory PAP. WES identified two compound heterozygous variants in IRF8: c.55del and p.R111*. In an overexpression system, the p.R111* cDNA was loss-of-expression, whereas the c.55del cDNA yielded a protein with a slightly lower molecular weight than the wild-type protein. The mutagenesis of methionine residues downstream from c.55del revealed a re-initiation of translation. However, both variants were loss-of-function in a luciferase assay, suggesting that the patient had AR complete IRF8 deficiency. The patient had no blood monocytes or dendritic cells, associated with neutrophilia, and normal counts of NK and other lymphoid cell subsets. Conclusion We describe the fourth patient with AR complete IRF8 deficiency. This diagnosis should be considered in children with PAP, which is probably due to the defective development or function of alveolar macrophages.
Published: 2021

19. Autoantibodies against type I IFNs in patients with Ph-negative myeloproliferative neoplasms

Author: Oscar Borsani, Paul Bastard, Jérémie Rosain, Adrian Gervais, Emanuela Sant’Antonio, Daniele Vanni, Ilaria Carola Casetti, Daniela Pietra, Chiara Trotti, Silvia Catricalà, Virginia Valeria Ferretti, Luca Malcovati, Luca Arcaini, Jean-Laurent Casanova, Alessandro Borghesi, Elisa Rumi, University of Pavia, 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 (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), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], 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), Azienda Usl Toscana centro [Firenze], Fondazione IRCCS Policlinico San Matteo [Pavia], Università di Pavia, Howard Hughes Medical Institute (HHMI), Ecole Polytechnique Fédérale de Lausanne (EPFL), Studies performed at the Department of Hematology, Fondazione IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia were supported by grants from the Italian Ministry of Health for young researchers (GR-2016-02361272) (E.R.) and by Associazione Italiana per la Ricerca sul Cancro (AIRC: IG 2021 ID 25703) through the project 'Actionable targets in clonal progression and systemic spreading of myeloid neoplasms,' (IG 2021 ID 25703) (E.R.) MYNERVA project (Project Code: 21267) (E.R. and L.M.). This work was supported by The European Union’s Horizon 2020 research and innovation program (ATAC, 101003650), the Center for Innovative Medicine at Karolinska Institutet, the Swedish Research Council, the Knut and Alice Wallenberg Foundation (KAW). 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 Institute of Allergy and Infectious Diseases (NIAID) (grants R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health Clinical and Translational Science Award (CTSA) program (UL1TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01), ANR grants (ANR-14-CE14-0008-01, ANR-18-CE15-0020-02, ANR-20-CE93-003, ANR-20-CO11-000,1 and ANR-21-COVR-0039), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANR-20-COVI-0003), ANRS Nord-Sud (ANRS-COV05), the European Union’s Horizon 2020 Research and Innovation Program (grant agreement no. 824110) (EASI-Genomics), the Square Foundation, Grandir-Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, Fondation du Souffle, Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM, and the University of Paris. P.B. received support from the French Foundation for Medical Research (FRM, EA20170638020) and was supported by the PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller)., 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), 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), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), Università degli Studi di Pavia = University of Pavia (UNIPV), 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), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Subjects: MESH: Interferon Type I, MESH: Humans, Myeloproliferative Disorders, [SDV]Life Sciences [q-bio], Immunology, Cell Biology, Hematology, Biochemistry, Neoplasms, Interferon Type I, MESH: Autoantibodies, Humans, MESH: Neoplasms, ComputingMilieux_MISCELLANEOUS, risk, MESH: Myeloproliferative Disorders, Autoantibodies
Abstract: International audience
Published: 2021

20. Autoantibodies Neutralizing Type I Interferons in 20% of COVID-19 Deaths in a French Hospital

Author: Paul Bastard, Adrian Gervais, Emmanuelle Jouanguy, Antoine Servajean, Angelique Chauvineau-Grenier, Aurélie Cobat, Benjamin Rossi, Jean-Laurent Casanova, Jérémie Rosain, Hôpital Robert Ballanger [Aulnay-sous-Bois], 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), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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 the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the 'Investments for the Future' program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANR-20-COVI-0003), ANRS Nord-Sud (ANRS-COV05), ANR GENVIR (ANR-20-CE93-003) and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the European Union’s Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir—Fonds de solidarité pour l’enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, Institut National de la Santé et de la Recherche Médicale (INSERM), and the University of Paris. PB was supported by the French Foundation for Medical Research (FRM, EA20170638020). PB and JR were supported by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt-Schueller)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), 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), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité, Equipe HAL, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé - - GENCOVID2020 - ANR-20-COVI-0003 - COVID-19 - VALID, 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 - - GENVIR2020 - ANR-20-CE93-0003 - AAPG2020 - VALID, Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19. - - AABIFNCOV2020 - ANR-20-CO11-0001 - COVID-19 - VALID, and European Advanced infraStructure for Innovative Genomics - EASI-Genomics - - H2020-INFRAIA-2018-12019-02-01 - 2023-07-31 - 824110 - VALID
Subjects: 2019-20 coronavirus outbreak, medicine.medical_specialty, [SDV.IMM] Life Sciences [q-bio]/Immunology, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, Article, Immunity, Internal medicine, medicine, Type I interferons, Immunology and Allergy, Humans, Autoantibodies, business.industry, SARS-CoV-2, Autoantibody, COVID-19, medicine.disease, mortality, Hospitals, Pneumonia, Increased risk, Cohort, Interferon Type I, [SDV.IMM]Life Sciences [q-bio]/Immunology, Original Article, business
Abstract: Recent studies reported the presence of pre-existing autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) in at least 15% of patients with critical or severe COVID-19 pneumonia. In one study, these auto-Abs were found in almost 20% of deceased patients across all ages. We aimed to assess the prevalence and clinical impact of the auto-Abs to type I IFNs in Seine-Saint-Denis district, which was one of the most affected areas by COVID-19 in France during the first wave. We tested for the presence of auto-Abs neutralizing type I IFNs in a cohort of patients admitted for critical COVID-19 pneumonia during the first wave in the spring of 2020 in medicine departments at Robert Ballanger Hospital, Aulnay sous Bois. We found circulating auto-Abs that neutralized 100 pg/mL IFN-α2 and/or IFN-ω in plasma 1/10 in 7.9% (11 of 139) of patients hospitalized for critical COVID-19. The presence of neutralizing auto-Abs was associated with an increased risk of mortality as these auto-Abs were detected in 21% of patients who died from COVID-19 pneumonia. Deceased patients with and without auto-Abs did not present overt clinical differences. These results confirm both the importance of IFN-I immunity in host defense against SARS-CoV-2 infection and the usefulness of detection of auto-Abs neutralizing type I IFNs in the management of patients.
Published: 2021

21. Pulmonary non-tuberculous mycobacterial infection in patients without predisposing condition, morphological and immunological overview of a french cohort

Author: Hélène Salvator, Geneviève Le Bourdelles, Elisabeth Rivaud, Valentine Jeanne-Julien, Philippe Devilliers, Evelyne Balloul, Capucine Picard, Camille Bron, Jean-Laurent Casanova, Colas Tcehrakian, Emilie Catherinot, Emilie Cardot, Eric Farfour, Dominique Valeyre, Pierre Cahen, Stéphanie Boisson-Dupuis, Louis-Jean Couderc, Jacinta Bustamante, Gilles Bonan, and Jérémie Rosain
Subjects: Non tuberculous mycobacterial, medicine.medical_specialty, business.industry, Internal medicine, Cohort, Medicine, In patient, business
Published: 2021

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

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

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

Author: Rui Yang, Rubén Martínez-Barricarte, Janet Markle, Franck Rapaport, Stuart G. Tangye, Mathieu Bourgey, David Langlais, Anne Puel, Aziz Belkadi, Masato Ogishi, Simon J. Pelham, Jean-Laurent Casanova, Bertrand Boisson, Cindy S. Ma, Vivien Béziat, Eman Abou Moussa, Jérémie Rosain, Laurent Abel, Tomi Lazarov, Serkan Belkaya, Fatima Ailal, Ibtihal Benhsaien, Coralie Briand, Alessandro Plebani, Romain Lévy, Frederic Geissmann, Caroline Deswarte, Andrea Guennoun, Luis R. Saraiva, Tanwir Habib, Mehdi Emam, Vassilios Lougaris, Philippe Gros, Yu Jerry Zhou, Ahmed Aziz Bousfiha, Geetha Rao, Kathryn Payne, Sylvain Breton, Ai Ing Lim, Kang Liu, Kunihiko Moriya, Danielle T. Avery, Bénédicte Neven, Nico Marr, Jacinta Bustamante, Mélanie Migaud, and James P. Di Santo
Subjects: Myeloid, Primary Immunodeficiency Diseases, Naive B cell, Adaptive Immunity, Biology, Lymphocyte Activation, Consanguinity, Immunity, medicine, Humans, Protein Isoforms, Myeloid Cells, Lymphocytes, Child, B cell, CD86, Host Microbial Interactions, Homozygote, Hematopoietic Stem Cell Transplantation, General Medicine, Acquired immune system, Immunity, Innate, Proto-Oncogene Proteins c-rel, medicine.anatomical_structure, Mutation, Immunology, Female, Genes, rel, REL, CD8, Research Article
Abstract: We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8(+) T cells, memory CD4(+) T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4(+) T cells. In naive CD4(+) T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient’s naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.
Published: 2021

24. 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

25. High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency

Author: Ibtihal Benhsaien, Bernhard Fleckenstein, Carys A. Croft, Stuart G. Tangye, Karim Dorgham, Rui Yang, Aziz Bousfiha, Laurent Abel, Laurie H. Glimcher, Jérémie Rosain, Guy Gorochov, Jing Han, Marc Weisshaar, Jean-Laurent Casanova, Paul Bastard, Federico Mele, James P. Di Santo, Federica Sallusto, Cindy S. Ma, Jacinta Bustamante, Samuele Notarbartolo, and Anne Puel
Subjects: 0301 basic medicine, Male, medicine.medical_treatment, Receptors, Antigen, T-Cell, alpha-beta, Immunology, Mutant, Stimulation, Autoimmunity, Th2 cytokines, Article, Epigenesis, Genetic, 03 medical and health sciences, Epitopes, 0302 clinical medicine, Th2 Cells, Antigen, medicine, Respiratory Hypersensitivity, Immunology and Allergy, Eosinophilia, Immunodeficiency, Animals, Humans, Interleukin 5, business.industry, Sequence Analysis, RNA, Pneumonia, respiratory system, Phenotype, 3. Good health, Pedigree, Mice, Inbred C57BL, 030104 developmental biology, Cytokine, 030220 oncology & carcinogenesis, Mutation, Cytokines, Female, medicine.symptom, Single-Cell Analysis, business, T-Box Domain Proteins, Immunologic Memory, Human Disease Genetics
Abstract: This study describes the multiple facets and molecular basis of excessive Th2 cytokine production by CD4+ αβ T lymphocytes as a possible mechanism underlying persistent upper airway inflammation and blood eosinophilia in a patient with inherited complete T-bet deficiency., We have described a child suffering from Mendelian susceptibility to mycobacterial disease (MSMD) due to autosomal recessive, complete T-bet deficiency, which impairs IFN-γ production by innate and innate-like adaptive, but not mycobacterial-reactive purely adaptive, lymphocytes. Here, we explore the persistent upper airway inflammation (UAI) and blood eosinophilia of this patient. Unlike wild-type (WT) T-bet, the mutant form of T-bet from this patient did not inhibit the production of Th2 cytokines, including IL-4, IL-5, IL-9, and IL-13, when overexpressed in T helper 2 (Th2) cells. Moreover, Herpesvirus saimiri–immortalized T cells from the patient produced abnormally large amounts of Th2 cytokines, and the patient had markedly high plasma IL-5 and IL-13 concentrations. Finally, the patient’s CD4+ αβ T cells produced most of the Th2 cytokines in response to chronic stimulation, regardless of their antigen specificities, a phenotype reversed by the expression of WT T-bet. T-bet deficiency thus underlies the excessive production of Th2 cytokines, particularly IL-5 and IL-13, by CD4+ αβ T cells, causing blood eosinophilia and UAI. The MSMD of this patient results from defective IFN-γ production by innate and innate-like adaptive lymphocytes, whereas the UAI and eosinophilia result from excessive Th2 cytokine production by adaptive CD4+ αβ T lymphocytes., Graphical Abstract
Published: 2021

26. LINE-1-Mediated AluYa5 Insertion Underlying Complete Autosomal Recessive IFN-γR1 Deficiency

Author: Maud Tusseau, Carmen Oleaga-Quintas, Gonca Hancioglu, Jérémie Rosain, Caroline Deswarte, Laurie Toullec, Jacinta Bustamante, Şeyhan Kutluğ, Alisan Yildiran, Isinsu Kuzu, Jean-Laurent Casanova, Ibrahim Kartal, and Ondokuz Mayıs Üniversitesi
Subjects: Male, Base Sequence, Extramural, Homozygote, Immunology, Long Interspersed Nucleotide Elements, Genes, Recessive, Exons, Biology, Molecular biology, Article, Pedigree, Exon, Alu Elements, DNA Transposable Elements, Humans, Immunology and Allergy, Female, Base sequence, Receptor, Gene, Receptors, Interferon
Abstract: KUZU, ISINSU/0000-0001-5519-1009 WOS: 000487139400010 PubMed: 31377971 … National Institute of Allergy and Infectious DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [5R37AI095983]; Rockefeller University; St. Giles Foundation; French National Institute of Health and Medical Research (INSERM), Paris Descartes University; Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]; French National Research Agency under the "Investments for the future" programFrench National Research Agency (ANR) [ANR-10-IAHU-01]; ANR-GENMSMDFrench National Research Agency (ANR) [ANR-16-CE17-0005-01]; SRC2017; INSERMInstitut National de la Sante et de la Recherche Medicale (Inserm); [ANR-14-CE15-006-01] The Laboratory of Human Genetics of Infectious Diseases is supported by the National Institute of Allergy and Infectious Diseases grant number 5R37AI095983, the Rockefeller University, the St. Giles Foundation, the French National Institute of Health and Medical Research (INSERM), Paris Descartes University, the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID) and the French National Research Agency under the "Investments for the future" program (grant number ANR-10-IAHU-01), ANR-GENMSMD (grant number ANR-16-CE17-0005-01 for JB) and SRC2017 (for JB). COQ is financially supported by ANR-14-CE15-006-01. JR is financially supported by the INSERM PhD program for medical and pharmaceutical doctors (" poste d'accueil INSERM").
Published: 2019

27. Pediatric Evans syndrome is associated with a high frequency of potentially damaging variants in immune genes

Author: Helder Fernandes, Guy Leverger, Vincent Barlogis, Yves Bertrand, Mohammed Zarhrate, Corinne Pondarré, E. Dore, Nathalie Cheikh, Elodie Colomb Bottollier, Caroline Thomas, Eric Jeziorski, Frédéric Rieux-Laucat, Fabienne Mazerolles, Y Perel, Capucine Picard, Pascale Blouin, Cécile Fourrage, Nicolas Garcelon, Aude Magerus-Chatinet, Marlène Pasquet, Sylvain Hanein, Benedicte Neven, Dominique Plantaz, Nathalie Aladjidi, Fanny Fouyssac, Thierry Leblanc, Jérémie Rosain, Alain Fischer, Marie-Claude Stolzenberg, Stéphane Ducassou, Sidonie Jacques, Frédéric Millot, Jérôme Hadjadj, Wadih Abou Chahla, Isabelle Pellier, Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Bordeaux, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence National des Cytopénies Auto-immunes de l'Enfant (CEREVANCE), Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-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), The Clinical Bioinformatics laboratory (Equipe Inserm U1163), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Amélioration génétique et adaptation des plantes méditerranéennes et tropicales (UMR AGAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Hospices Civils de Lyon, Departement de Neurologie (HCL), Service d'Immuno-Hémato-Oncologie Pédiatrique, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Clermont-Ferrand, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Universitaire [Grenoble] (CHU), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Rieux-Laucat, Frédéric, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Collège de France - Chaire Médecine expérimentale (A. Fischer), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Hôpital des Enfants, Institut National de la Recherche Agronomique (INRA)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), École Pratique des Hautes Études (EPHE), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Hôpital Arnaud de Villeneuve, École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Collège de France (CDF), and Collège de France (CdF)
Subjects: Adult, Male, Evans syndrome, Adolescent, [SDV.IMM] Life Sciences [q-bio]/Immunology, [SDV]Life Sciences [q-bio], Immunology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease_cause, Biochemistry, Genetic determinism, LRBA, Cohort Studies, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Humans, Medicine, Child, 030304 developmental biology, Genetic testing, Autoimmune disease, 0303 health sciences, Mutation, medicine.diagnostic_test, business.industry, Infant, Cell Biology, Hematology, medicine.disease, Thrombocytopenia, 3. Good health, [SDV] Life Sciences [q-bio], [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Child, Preschool, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Anemia, Hemolytic, Autoimmune, Autoimmune hemolytic anemia, business
Abstract: Evans syndrome (ES) is a rare severe autoimmune disorder characterized by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. In most cases, the underlying cause is unknown. We sought to identify genetic defects in pediatric ES (pES), based on a hypothesis of strong genetic determinism. In a national, prospective cohort of 203 patients with early-onset ES (median [range] age at last follow-up: 16.3 years ([1.2-41.0 years]) initiated in 2004, 80 nonselected consecutive individuals underwent genetic testing. The clinical data were analyzed as a function of the genetic findings. Fifty-two patients (65%) received a genetic diagnosis (the M+ group): 49 carried germline mutations and 3 carried somatic variants. Thirty-two (40%) had pathogenic mutations in 1 of 9 genes known to be involved in primary immunodeficiencies (TNFRSF6, CTLA4, STAT3, PIK3CD, CBL, ADAR1, LRBA, RAG1, and KRAS), whereas 20 patients (25%) carried probable pathogenic variants in 16 genes that had not previously been reported in the context of autoimmune disease. Lastly, no genetic abnormalities were found in the remaining 28 patients (35%, the M− group). The M+ group displayed more severe disease than the M− group, with a greater frequency of additional immunopathologic manifestations and a greater median number of lines of treatment. Six patients (all from the M+ group) died during the study. In conclusion, pES was potentially genetically determined in at least 65% of cases. Systematic, wide-ranging genetic screening should be offered in pES; the genetic findings have prognostic significance and may guide the choice of a targeted treatment.
Published: 2019

28. Successful in utero stem cell transplantation in X-linked severe combined immunodeficiency

Author: Aurélie Gabrion, Elisabeth A. Macintyre, Emmanuel Clave, Anne-Marie Darras, Alessandra Magnani, Stéphane Blanche, Brigitte Ternaux, Antoine Toubert, Capucine Picard, Marina Cavazzana, Cécile Roudaut, Laure Caccavelli, Jérémie Rosain, Elisa Magrin, Nizar Mahlaoui, Jennifer Nisoy, Fabien Touzot, Marion Alcantara, Isabelle Radford-Weiss, Jean-Marie Jouannic, Sven Kracker, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre pluridisciplinaire de diagnostic prénatal [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], CHU Necker - Enfants Malades [AP-HP], 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], 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), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: Transplantation Conditioning, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Hematopoietic stem cell transplantation, X-Linked Combined Immunodeficiency Diseases, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, X-linked severe combined immunodeficiency, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Severe combined immunodeficiency, business.industry, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Stimulus Report, 3. Good health, Transplantation, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, In utero, Child, Preschool, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Bone marrow, Stem cell, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Key Points IUT enables rapid immune reconstitution and avoids many clinical and economic problems; however, the indication is still limited. IUT may be a treatment option in select cases, eg, fetuses exposed to a significant infectious risk, where a matched sibling donor exists.
Published: 2019

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

Author: Jacinta Bustamante, Mélanie Migaud, Carla Nasca, Jérémie Rosain, Jean-Laurent Casanova, Laurent Abel, Gaspard Kerner, Aurélie Cobat, Bertrand Boisson, Yoann Seeleuthner, Benedetta Bigio, and Anne Puel
Subjects: AcademicSubjects/SCI01140, 0303 health sciences, AcademicSubjects/SCI01060, Computer science, AcademicSubjects/SCI00030, Computational biology, AcademicSubjects/SCI01180, 3. Good health, Euclidean distance, 03 medical and health sciences, Exon, 0302 clinical medicine, Simulated data, Sliding window protocol, Methods Article, Control set, AcademicSubjects/SCI00980, Copy-number variation, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
Abstract: The detection of copy number variations (CNVs) in whole-exome sequencing (WES) data is important, as CNVs may underlie a number of human genetic disorders. The recently developed HMZDelFinder algorithm can detect rare homozygous and hemizygous (HMZ) deletions in WES data more effectively than other widely used tools. Here, we present HMZDelFinder_opt, an approach that outperforms HMZDelFinder for the detection of HMZ deletions, including partial exon deletions in particular, in WES data from laboratory patient collections that were generated over time in different experimental conditions. We show that using an optimized reference control set of WES data, based on a PCA-derived Euclidean distance for coverage, strongly improves the detection of HMZ complete exon deletions both in real patients carrying validated disease-causing deletions and in simulated data. Furthermore, we develop a sliding window approach enabling HMZDelFinder_opt to identify HMZ partial deletions of exons that are undiscovered by HMZDelFinder. HMZDelFinder_opt is a timely and powerful approach for detecting HMZ deletions, particularly partial exon deletions, in WES data from inherently heterogeneous laboratory patient collections.
Published: 2021

30. Negative selection on human genes underlying inborn errors depends on disease outcome and both the mode and mechanism of inheritance

Author: Lluis Quintana-Murci, Etienne Patin, Jean-Laurent Casanova, Laurent Abel, Anne Puel, Jérémie Rosain, Shen-Ying Zhang, Vivien Béziat, Joseph G. Gleeson, Anne Gregor, Emmanuelle Jouanguy, Franck Rapaport, Stéphanie Boisson-Dupuis, Qian Zhang, Bertrand Boisson, Jacinta Bustamante, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for the Study of Primary Immunodeficiencies [Paris], Université Paris Descartes - Paris 5 (UPD5)-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 [La Jolla, CA, USA], Rady Children’s Institute of Genomic Medicine [La Jolla, CA, USA], University of California, Laboratory for Pediatric Brain Disease, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Collège de France (CdF (institution)), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU), This work was supported in part by the Rockefeller University, the St. Giles Foundation, Institut National de la Santé et de la Recherche Médicale, Paris Descartes University, the National Center for Research Resources and the National Center for Advancing Sciences, NIH Clinical and Translational Science Award program (Grant UL1TR001866), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (Grant ANR-10-LABX-62-IBEID), and the French National Research Agency (ANR) (Grants ANR-10-IAHU-01, ANR-15-CE17-0014). The laboratory of L.Q.-M. and E.P. is supported by the Institut Pasteur, the Collège de France, the Investissement d’Avenir program, Laboratoires d’Excellence 'Milieu Intérieur' (Grant ANR-10-LABX-69-01), Fondation pour la Recherche Médicale (Grant FRM DEQ20180339214), Fondation Allianz–Institut de France, and Fondation de France., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-15-CE17-0014,ProgLegio,Biomarqueurs bactériens et humains d'intérêt pronostic pour les légionelloses sévères(2015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of California (UC), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Collège de France - Chaire Génomique humaine et évolution, 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), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Candidate gene, Population, Genes, Recessive, Biology, 03 medical and health sciences, Negative selection, 0302 clinical medicine, Humans, Selection, Genetic, education, Selection (genetic algorithm), Loss function, Genes, Dominant, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Multidisciplinary, Mechanism (biology), Immunity, Inheritance (genetic algorithm), Genetic Variation, Biological Sciences, Penetrance, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Metabolism, Inborn Errors, 030217 neurology & neurosurgery
Abstract: International audience; Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.
Published: 2021

31. 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

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

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

33. 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

34. Pre-existing Autoantibodies Neutralizing High Concentrations of Type I Interferons in Almost 10% of COVID-19 Patients Admitted to Intensive Care in Barcelona

Author: Sergio Navarro, Enric Boza-Hernandez, Guillermo Suarez-Cuartin, Victor-David Gumucio, Quentin Philippot, Joan Sabater-Riera, Laura Calatayud, Xavier Solanich, Gemma Rocamora-Blanch, Francisco Morandeira, Xose-Luís Pérez-Fernández, Maria-Paz Fuset-Cabanes, Antoni Riera-Mestre, Paul Bastard, Xavier Corbella, Roger Colobran, Raül Rigo-Bonnin, Mario Framil, Alba Parra-Martínez, Miguel-Ángel Gordillo-Benitez, Jérémie Rosain, Arnau Antolí, Jean-Laurent Casanova, Université Paris Cité, Equipe HAL, Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), 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], Vall d’Hebron Research Institute (VHIR), Vall d'Hebron University Hospital [Barcelona], Universitat Internacional de Catalunya [Barcelona] (UIC), Howard Hughes Medical Institute (HHMI), and ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010)
Subjects: Male, medicine.medical_specialty, Immunology, 030204 cardiovascular system & hematology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Medical microbiology, law, Intensive care, Internal medicine, auto-antibodies, medicine, Humans, Immunology and Allergy, Leukocytosis, Aged, Autoantibodies, Retrospective Studies, 030304 developmental biology, 0303 health sciences, Thrombocytosis, business.industry, SARS-CoV-2, Acute kidney injury, COVID-19, Middle Aged, medicine.disease, Antibodies, Neutralizing, Intensive care unit, Neutrophilia, 3. Good health, Intensive Care Units, Pneumonia, acute kidney injury, type I interferons, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Interferon Type I, Female, Original Article, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, business
Abstract: Background It is important to predict which patients infected by SARS-CoV-2 are at higher risk of life-threatening COVID-19. Several studies suggest that neutralizing auto-antibodies (auto-Abs) against type I interferons (IFNs) are predictive of critical COVID-19 pneumonia. Objectives We aimed to test for auto-Abs to type I IFN and describe the main characteristics of COVID-19 patients admitted to intensive care depending on whether or not these auto-Abs are present. Methods Retrospective analysis of all COVID-19 patients admitted to an intensive care unit (ICU) in whom samples were available, from March 2020 to March 2021, in Barcelona, Spain. Results A total of 275 (70.5%) out of 390 patients admitted to ICU were tested for type I IFNs auto-antibodies (α2 and/or ω) by ELISA, being positive in 49 (17.8%) of them. Blocking activity of plasma diluted 1/10 for high concentrations (10 ng/mL) of IFNs was proven in 26 (9.5%) patients. Almost all the patients with neutralizing auto-Abs were men (92.3%). ICU patients with positive results for neutralizing IFNs auto-Abs did not show relevant differences in demographic, comorbidities, clinical features, and mortality, when compared with those with negative results. Nevertheless, some laboratory tests (leukocytosis, neutrophilia, thrombocytosis) related with COVID-19 severity, as well as acute kidney injury (17 [65.4%] vs. 100 [40.2%]; p = 0.013) were significantly higher in patients with auto-Abs. Conclusion Auto-Abs neutralizing high concentrations of type I IFNs were found in 9.5% of patients admitted to the ICU for COVID-19 pneumonia in a hospital in Barcelona. These auto-Abs should be tested early upon diagnosis of SARS-CoV-2 infection, as they account for a significant proportion of life-threatening cases. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01136-x.
Published: 2021

35. Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria

Author: Laurent Abel, Laurie H. Glimcher, Lluis Quintana-Murci, Nico Marr, Fatima Al Ali, Jean Marc Doisne, David Langlais, Jacinta Bustamante, Marc Weisshaar, Jing Han, Jamila El Baghdadi, Frédéric Batteux, Manon Roynard, Yichao Shen, Mathieu Bourgey, Flore Rozenberg, Federica Sallusto, Peng Zhang, David Jarrossay, Carmen Oleaga-Quintas, Jean-Laurent Casanova, Daniela Latorre, Gaspard Kerner, Mahbuba Rahman, Houda Elarabi, Federico Mele, Yoann Seeleuthner, James P. Di Santo, Stuart G. Tangye, Michael S. Kobor, Janet Markle, Dusan Bogunovic, Stéphanie Boisson-Dupuis, Julia L. Maclsaac, Lucas T. Husquin, Lisa Worley, Conor Gruber, Cindy S. Ma, Jérémie Rosain, Taushif Khan, Thomas L. Carroll, Mohamed Jeljeli, Abderrahmane Errami, Anne Puel, Qiang Pan-Hammarström, Philippe Gros, Ibithal Benhsaien, Aziz Bousfiha, Fatima Ailal, Carys A. Croft, Rui Yang, Masato Ogishi, Rockefeller University [New York], Università della Svizzera italiana = University of Italian Switzerland (USI), Garvan Institute of medical research, McGill University = Université McGill [Montréal, Canada], 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 (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Hassan II [Casablanca] (UH2MC), Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité (UPCité), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Icahn School of Medicine at Mount Sinai [New York] (MSSM), We thank the patients and families, members of the laboratory, Cecilia Lindestam Arlehamn and Alessandro Sette, NIH Tetramer Core Facility (NTCF), James McCluskey, Jamie Rossjohn, and David Fairlie, the Genomics and the Flow Cytometry Resource Center of Rockefeller University, National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001866 to Rockefeller University), Steven Elledge, National Institute of Allergy and Infectious Diseases (R37AI095983 to J.L.C. and U19AI118626 to F.S.), Sackler Center for Biomedicine and Nutrition at the Center for Clinical and Translational Science (CCTS), Shapiro-Silverberg Fund for the Advancement of Translational Research at CCTS, Rockefeller University (to R.Y.), Research Grant Program of the Immune Deficiency Foundation (to R.Y.), Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), French National Research Agency under the 'Investments for the future' program (ANR-10-IAHU-01), ANR-GENMSMD (ANR-16-CE17-0005-01 to J.B.), ANR-LTh-MSMD-CMCD (ANR-18-CE93-0008-01 to A.P and F.S.), Fonds de Recherche en Santé Respiratoire (SRC2017 to J.B.), French Foundation for Medical Research (FRM) (EQU201903007798), the SCOR Corporate Foundation for Science, ECOS Nord (C19S01-63407 to J.B.), Swiss National Science Foundation (310030L_182728 to F.S.), French Foundation for Medical Research (FRM) (EQU201903007798), Helmut Horten Foundation, Canadian Center for Computational Genomics (C3G), Genomics Technology Platform (GTP), and Genome Canada. J. R. was supported by INSERM Poste d’accueil and and Imagine Institute, T.K. by Qatar National Research Fund (PPM1-1220-150017). S.G.T. by Program grant (1113904), Principal Research Fellowship (1042925), and Leadership 3 Investigator grant (1176665) from the National Health and Medical Research Council of Australia, C.S.M. by an Early/Mid-Career Development Research Fellowship, Ministry of Health, NSW Government, R.Y. by Stony Wold-Herbert Fund., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-18-CE93-0008,LTh-MSMD-CMCD,Différenciation des lymphocytes T-helper (Th) dans les défauts génétiques de l'immunité contre Mycobacterium et/ou Candida species.(2018), Garvan Institute of Medical Research [Darlinghurst, Australia], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Paris (UP)
Subjects: Male, inborn errors of immunity, [SDV]Life Sciences [q-bio], Mendelian susceptibility to mycobacterial disease, MESH: Amino Acid Sequence, Adaptive Immunity, MESH: Base Sequence, Epigenesis, Genetic, mycobacterium, MESH: INDEL Mutation, 0302 clinical medicine, MESH: DNA Methylation, INDEL Mutation, Loss of Function Mutation, Interferon gamma, MESH: Epigenesis, Genetic, MESH: CpG Islands, IFN-γ, Immunodeficiency, 0303 health sciences, biology, MESH: Dendritic Cells, Homozygote, T-Lymphocytes, Helper-Inducer, MESH: Infant, Chromatin, Pedigree, 3. Good health, Killer Cells, Natural, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Immunity, Innate, medicine.drug, MESH: Homozygote, MESH: Killer Cells, Natural, MESH: Pedigree, MESH: T-Box Domain Proteins, MESH: Interferon-gamma, T-bet, Article, General Biochemistry, Genetics and Molecular Biology, MESH: Chromatin, Interferon-gamma, 03 medical and health sciences, Immunity, medicine, MESH: Mycobacterium, Humans, Cell Lineage, Amino Acid Sequence, MESH: Mycobacterium Infections, MESH: T-Lymphocytes, Helper-Inducer, Transcription factor, 030304 developmental biology, Mycobacterium Infections, MESH: Humans, Base Sequence, MESH: Transcriptome, MESH: Child, Preschool, Infant, MESH: Loss of Function Mutation, Dendritic Cells, DNA Methylation, Mycobacterial disease, MESH: Cell Lineage, medicine.disease, biology.organism_classification, Immunity, Innate, MESH: Male, innate-like adaptive lymphocyte, Mycobacterial antigen, Immunology, CpG Islands, innate lymphocyte, T-Box Domain Proteins, Transcriptome, immunodeficiency, MESH: Female, 030217 neurology & neurosurgery, CD8, MESH: Adaptive Immunity, Mycobacterium
Abstract: International audience; Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αβ T and non-classic CD4+ αβ TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αβ T, and CD4+ αβ TH1∗ cells unable to compensate for this deficit.
Published: 2020

36. 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

37. Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child

Author: Phillip Wong, Peng Zhang, Geetha Rao, Gaspard Kerner, Bertrand Boisson, Figen Dogu, Matthew Adamow, Taushif Khan, Ilhan Tezcan, Simon J. Pelham, Samuel C. Williams, Cindy S. Ma, Caner Aytekin, Deniz Cagdas, Mahbuba Rahman, Tasuku Honjo, Masato Ogishi, Jean-François Emile, Franck Rapaport, Jérémie Rosain, Conor Gruber, Leena Kainulainen, Nico Marr, Garrett Allington, Ferda O. Hosnut, Scott Drutman, Jedd D. Wolchok, David Langlais, Yuka Nakajima, Matthew D. Hellmann, Laurent Abel, Mathieu Bourgey, Aydan Ikinciogullari, Philippe Gros, Jacinta Bustamante, Wei-Te Lei, Stuart G. Tangye, Jean-Laurent Casanova, Flore Rozenberg, Richard P. Lifton, Fatima Al Ali, Michael S. Glickman, Maya Chrabieh, Stéphanie Boisson-Dupuis, Luigi D. Notarangelo, V. Koneti Rao, Ottavia M. Delmonte, Margaret K. Callahan, Vivien Béziat, Silvia Vilarinho, Dusan Bogunovic, András N Spaan, Tomonori Yaguchi, Kenji Chamoto, and Rui Yang
Subjects: 0301 basic medicine, CD4-Positive T-Lymphocytes, Male, STAT3 Transcription Factor, Tuberculosis, Programmed Cell Death 1 Receptor, Hepatosplenomegaly, Autoimmunity, CD8-Positive T-Lymphocytes, medicine.disease_cause, Interleukin-23, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Immune system, Immunity, RAR-related orphan receptor gamma, Interferon, Neoplasms, Medicine, Humans, Child, Immune Checkpoint Inhibitors, Intraepithelial Lymphocytes, business.industry, Interleukin-6, Interleukin, General Medicine, Mycobacterium tuberculosis, Nuclear Receptor Subfamily 1, Group F, Member 3, medicine.disease, CD56 Antigen, 030104 developmental biology, 030220 oncology & carcinogenesis, Immunology, Immunotherapy, medicine.symptom, business, medicine.drug
Abstract: The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient’s leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient’s lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2+ γδ T, mucosal-associated invariant T and CD56bright natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT+ CD4−CD8− double-negative αβ T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade. Dysregulated immune features in a patient with a homozygous loss-of-function mutation in PDCD1 suggest that IL-6, IL-23, STAT3 and RORγT might be potential targets for treatment of PD-1 blockade-induced autoimmunity.
Published: 2020

38. Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria

Author: Qiang Pan-Hammarström, Mathieu Bourgey, Conor Gruber, Fatima Al Ali, Lluis Quintana-Murci, Federico Mele, James P. Di Santo, Jean-Marc Doisne, Carmen Oleaga-Quintas, Flore Rozenberg, Carys A. Croft, Taushif Khan, Aziz Bousfiha, Daniela Latorre, Fatima Ailal, Houda Elarabi, Cindy S. Ma, Yoann Seeleuthner, Jing Han, Lucas T. Husquin, Stéphanie Boisson-Dupuis, David Jarrossay, Thomas L. Carroll, Janet Markle, Jean-Laurent Casanova, Anne Puel, Peng Zhang, David Langlais, Mohamed Jeljeli, Dusan Bogunovic, Jérémie Rosain, Laurent Abel, Gaspard Kerner, Lisa Worley, Laurie H. Glimcher, Michael S. Kobor, Nico Marr, Rui Yang, Frédéric Batteux, Julia L. Maclsaac, Yichao Shen, Stuart G. Tangye, Jacinta Bustamante, Marc Weisshaar, Federica Sallusto, Mahbuba Rahman, Manon Roynard, Philippe Gros, Ibithal Benhsaien, and Jamila El Baghdadi
Subjects: Immunity, DNA methylation, Immunology, Stimulation, Biology, Mycobacterial disease, Gene, Transcription factor, Lymphocyte subsets, Chromatin
Abstract: SummaryInborn errors of human IFN-γ immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to an inherited deficiency of the transcription factor T-bet. This deficiency abolishes the expression of T-bet target genes, including IFNG, by altering chromatin accessibility and DNA methylation in CD4+ T cells. The patient has profoundly diminished counts of mycobacterial-reactive circulating NK, invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of non-mycobacterial-reactive classic TH1 lymphocytes, the remainders of which also produce abnormally low amounts of IFN-γ. Other IFN-γ-producing lymphocyte subsets however develop normally, but with low levels of IFN-γ production, with exception of Vδ2− γδ T lymphocytes, which produce normal amounts of IFN-γ in response to non-mycobacterial stimulation, and non-classic TH1 (TH1*) lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of, and IFN-γ production by, innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells), with mycobacterial-specific, IFN-γ-producing, purely adaptive αβ TH1* cells unable to compensate for this deficit.
Published: 2020

39. Multibatch Cytometry Data Integration for Optimal Immunophenotyping

Author: Ji Eun Han, Jacinta Bustamante, Masato Ogishi, Rui Yang, Bertrand Boisson, Marwa Chbihi, Jérémie Rosain, Dusan Bogunovic, Simon J. Pelham, Peng Zhang, Stéphanie Boisson-Dupuis, V. Koneti Rao, András N Spaan, Conor Gruber, Jean-Laurent Casanova, and Leena Kainulainen
Subjects: Computer science, Immunology, Spectral flow, Computational Biology, computer.software_genre, Flow Cytometry, Article, Immunophenotyping, 03 medical and health sciences, Identification (information), R package, 0302 clinical medicine, Leukocytes, Mononuclear, Immunology and Allergy, Humans, Mass cytometry, In patient, Data mining, computer, Cytometry, Algorithms, Software, 030215 immunology, Data integration
Abstract: High-dimensional cytometry is a powerful technique for deciphering the immunopathological factors common to multiple individuals. However, rational comparisons of multiple batches of experiments performed on different occasions or at different sites are challenging because of batch effects. In this study, we describe the integration of multibatch cytometry datasets (iMUBAC), a flexible, scalable, and robust computational framework for unsupervised cell-type identification across multiple batches of high-dimensional cytometry datasets, even without technical replicates. After overlaying cells from multiple healthy controls across batches, iMUBAC learns batch-specific cell-type classification boundaries and identifies aberrant immunophenotypes in patient samples from multiple batches in a unified manner. We illustrate unbiased and streamlined immunophenotyping using both public and in-house mass cytometry and spectral flow cytometry datasets. The method is available as the R package iMUBAC (https://github.com/casanova-lab/iMUBAC).
Published: 2020

40. Multi-batch cytometry data integration for optimal immunophenotyping

Author: V. Koneti Rao, Rui Yang, Leena Kainulainen, András N Spaan, Ji Eun Han, Dusan Bogunovic, Conor Gruber, Masato Ogishi, Bertrand Boisson, Jean-Laurent Casanova, Jérémie Rosain, Jacinta Bustamante, Stéphanie Boisson-Dupuis, Marwa Chbihi, and Simon J. Pelham
Subjects: Identification (information), Immunophenotyping, medicine.diagnostic_test, Computer science, medicine, In patient, Data mining, computer.software_genre, computer, Cytometry, Flow cytometry, Data integration
Abstract: We describe the integration of multi-batch cytometry datasets (iMUBAC), a flexible, robust, and scalable computational framework for unsupervised cell-type identification across multiple batches of high-dimensional cytometry datasets. After overlaying cells from healthy controls across multiple batches, iMUBAC learns batch-specific cell-type classification boundaries and identifies aberrant immunophenotypes in patient samples. We illustrate unbiased and streamlined immunophenotyping, using both in-house and public mass and flow cytometry datasets.
Published: 2020

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

Author: Vivien, Béziat, Simon J, Tavernier, Yin-Huai, Chen, Cindy S, Ma, Marie, Materna, Arian, Laurence, Jens, Staal, Dominik, Aschenbrenner, Lisa, Roels, Lisa, Worley, Kathleen, Claes, Lisa, Gartner, Lisa A, Kohn, Marieke, De Bruyne, Klaus, Schmitz-Abe, Louis-Marie, Charbonnier, Sevgi, Keles, Justine, Nammour, Natasha, Vladikine, Majistor Raj Luxman, Maglorius Renkilaraj, Yoann, Seeleuthner, Mélanie, Migaud, Jérémie, Rosain, Mohamed, Jeljeli, Bertrand, Boisson, Eva, Van Braeckel, Jill A, Rosenfeld, Hongzheng, Dai, Lindsay C, Burrage, David R, Murdock, Bart N, Lambrecht, Véronique, Avettand-Fenoel, Tiphanie P, Vogel, Charles R, Esther, Sule, Haskologlu, Figen, Dogu, Peter, Ciznar, David, Boutboul, Marie, Ouachée-Chardin, Jean, Amourette, Marie-Noëlle, Lebras, Clément, Gauvain, Colas, Tcherakian, Aydan, Ikinciogullari, Rudi, Beyaert, Laurent, Abel, Joshua D, Milner, Bodo, Grimbacher, Louis-Jean, Couderc, Manish J, Butte, Alexandra F, Freeman, Émilie, Catherinot, Claire, Fieschi, Talal A, Chatila, Stuart G, Tangye, Holm H, Uhlig, Filomeen, Haerynck, Jean-Laurent, Casanova, Anne, Puel, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Laboratory of Human Genetics of Infectious Diseases (Necker Branch - INSERM U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Ghent University Hospital, VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Center for Medical Genetics [Ghent], John Radcliffe Hospital [Oxford University Hospital], University of Oxford [Oxford], Garvan Institute of Medical Research [Darlinghurst, Australia], St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales [Sydney] (UNSW), University of California, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Necmettin Erbakan University [Konya, Turquie], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Baylor College of Medicine (BCM), Baylor University, Laboratoire de Virologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Ankara University School of Medicine [Turkey], Comenius University in Bratislava, Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Groupe Hospitalier Artois-Ternois Centre Hospitalier d’Arras, Service de pneumologie [Hôpital Foch], Hôpital Foch [Suresnes], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Columbia University Irving Medical Center (CUIMC), Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Centre for Integrative Biological Signaling Studies [Freiburg, Germany], University of Freiburg [Freiburg], Hanover Medical School, Laboratoire de recherche sur les mécanismes moléculaires et pharmacologiques de l’obstruction bronchique (LOBIP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], and University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW)
Subjects: Male, Adolescent, Models, Biological, Young Adult, Th2 Cells, Loss of Function Mutation, Cytokine Receptor gp130, Humans, Immunodeficiency, Child, Alleles, Cells, Cultured, Genes, Dominant, Human disease genetics, Cell Membrane, Correction, Fibroblasts, Middle Aged, Pedigree, Up-Regulation, Kinetics, C-Reactive Protein, Genetics, Population, HEK293 Cells, Phenotype, Mutation, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Job Syndrome
Abstract: International audience; Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.
Published: 2020

42. Improving the diagnostic efficiency of primary immunodeficiencies with targeted next-generation sequencing

Author: Brigitte Bader-Meunier, Thibault Comont, Felipe Suarez, Alain Fischer, Vincent Barlogis, David Boutboul, Claire Fieschi, Guillaume Vogt, Marlène Pasquet, Frédéric Rieux-Laucat, Jérémie Rosain, Marine Gil, Lionel Galicier, Etienne Merlin, Cécile Fourrage, Christine Bole, Nicholas Renaud, Wadih Abou Chahla, Capucine Picard, Sylvain Hanein, Stéphane Blanche, Patrick Nitschké, Despina Moshous, Benedicte Neven, Isabelle André, Virginie Grandin, Alexandre Alcaïs, Sylvain Latour, Jean-Pierre de Villartay, Chantal Lagresle-Peyrou, Jean-Sebastien Diana, Eric Oksenhendler, Marion Malphettes, Samuel Chevalier, Elisabeth Hulier-Ammar, Olivier Hermine, Mathieu Fusaro, Jacinta Bustamante, Nathalie Lambert, Vivien Béziat, Geneviève de Saint Basile, Nizar Mahlaoui, Martin Castelle, Sven Kracker, Alain Lefevre-Utile, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)
Subjects: 0301 basic medicine, Adult, Male, Adolescent, Primary Immunodeficiency Diseases, health care facilities, manpower, and services, [SDV]Life Sciences [q-bio], Immunology, education, MEDLINE, Immunoglobulins, Bioinformatics, DNA sequencing, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Immunology and Allergy, Medicine, Guanine Nucleotide Exchange Factors, Humans, Child, health care economics and organizations, Aged, Primary (chemistry), business.industry, Infant, Newborn, High-Throughput Nucleotide Sequencing, Infant, Middle Aged, medicine.disease, 3. Good health, I-kappa B Kinase, 030104 developmental biology, Child, Preschool, Cohort, Mutation, Etiology, Primary immunodeficiency, Female, business, 030215 immunology
Abstract: This study aims to validate a targeted next-generation sequencing panel of 300 genes to diagnose a cohort of 129 patients with primary immunodeficiency with no prior molecular etiology.
Published: 2020

43. Negative selection on human genes causing severe inborn errors depends on disease outcome and both the mode and mechanism of inheritance

Author: Bertrand Boisson, Lluis Quintana-Murci, Jacinta Bustamante, Anne Gregor, Emmanuelle Jouanguy, Stéphanie Boisson-Dupuis, Anne Puel, Franck Rapaport, Jérémie Rosain, Vivien Béziat, Joseph G. Gleeson, Shen-Ying Zhang, Qian Zhang, Jean-Laurent Casanova, Etienne Patin, and Laurent Abel
Subjects: Genetics, 0303 health sciences, education.field_of_study, Candidate gene, Mechanism (biology), Population, Inheritance (genetic algorithm), Biology, Penetrance, 03 medical and health sciences, Negative selection, 0302 clinical medicine, education, Haploinsufficiency, 030217 neurology & neurosurgery, Selection (genetic algorithm), 030304 developmental biology
Abstract: BackgroundGenetic variants underlying severe diseases are less likely to be transmitted to the next generation, and are thus gradually and selectively eliminated from the population through negative selection. Here, we study the determinants of this evolutionary process in genes underlying severe diseases in humans.ResultsWe propose a novel approach, CoNeS, integrating known negative selection scores through principal component projection. We compare evidence for negative selection at 319 genes underlying inborn errors of immunity (IEI), which are life-threatening monogenic disorders. We find that genes underlying autosomal dominant (AD) or X-linked IEI are under stronger negative selection than those underlying autosomal recessive (AR) IEI, which are under no stronger selection than genes not known to be disease-causing. However, we find that genes with mutations causing AR IEI that are lethal before reproductive maturity and that display complete penetrance are under stronger negative selection than other genes underlying AR IEI. We also find that genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. Finally, we replicate these results in a study of 1,140 genes causing inborn errors of neurodevelopment.ConclusionsThese findings collectively show that the clinical outcomes of inborn errors, together with the mode and mechanism of inheritance of these errors, determine the strength of negative selection acting on severe disease-causing genes. These findings suggest that estimating the intensity of negative selection with CoNeS may facilitate the selection of candidate genes in patients suspected to carry an inborn error.
Published: 2020
Full Text: View/download PDF

44. Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

Author: Jérémie Rosain, Sofija Buta, Jennie B. Altman, Dusan Bogunovic, Aziz Bousfiha, Fatima Ailal, Marta Martín-Fernández, Justin Taft, Xueer Qiu, Jacinta Bustamante, Conor Gruber, and Jean-Laurent Casanova
Subjects: Genetics, 0303 health sciences, Protein subunit, Biology, ISG15, 03 medical and health sciences, 0302 clinical medicine, Interferon, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), medicine, biology.protein, Gain of function mutation, Missense mutation, STAT2, Receptor, 030304 developmental biology, medicine.drug
Abstract: Type I interferonopathies are monogenic disorders characterized by enhanced Type I interferon (IFN-I) activity. Inherited ISG15 and USP18 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, ISG15/USP18 are induced by IFN-I and sterically hinder JAK1 from binding to the IFNAR2 subunit of IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is gain-of-function (GOF) for ISGF3-dependent induction of late but not early response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic transcriptional activity of ISGF3. Rather, the STAT2 R148Q variant is GOF because it fails to appropriately interact with and traffic USP18 to IFNAR2, preventing USP18 from negatively regulating responses to IFN-I. Overall, a STAT2 missense mutation that fails to facilitate USP18-mediated signal termination in the homozygous state underlies a novel genetic etiology of type I interferonopathy.
Published: 2019
Full Text: View/download PDF

45. Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

Author: Jean-Laurent Casanova, Justin Taft, Xueer Qiu, Jennie B. Altman, Dusan Bogunovic, Aziz Bousfiha, Marta Martín-Fernández, Fatima Ailal, Conor Gruber, Sofija Buta, Jérémie Rosain, and Jacinta Bustamante
Subjects: Male, Immunology, Innate Immunity and Inflammation, Biology, medicine.disease_cause, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, Exome Sequencing, medicine, Immunology and Allergy, Missense mutation, Humans, Immunodeficiency, Amino Acid Sequence, STAT2, 030304 developmental biology, Genetics, Phenocopy, Regulation of gene expression, 0303 health sciences, Mutation, Base Sequence, Homozygote, Infant, Newborn, Brief Definitive Report, STAT2 Transcription Factor, Phenotype, ISG15, Pedigree, Gene Expression Regulation, 030220 oncology & carcinogenesis, Gain of Function Mutation, Interferon Type I, biology.protein, Female, Ubiquitin Thiolesterase, Interferon type I, Human Disease Genetics, medicine.drug
Abstract: Gruber et al. describe a gain-of-function mutation in STAT2 that leads to a lethal autoinflammatory disease with autosomal recessive inheritance. This syndrome defines a novel form of type I interferonopathy characterized by impaired regulation of the type I IFN response., Type I interferonopathies are monogenic disorders characterized by enhanced type I interferon (IFN-I) cytokine activity. Inherited USP18 and ISG15 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, USP18, being stabilized by ISG15, sterically hinders JAK1 from binding to the IFNAR2 subunit of the IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is a gain of function (GOF) for induction of the late, but not early, response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic activity of the STAT2-containing transcriptional complex responsible for IFN-I–stimulated gene induction. Rather, the STAT2 R148Q variant is a GOF because it fails to appropriately traffic USP18 to IFNAR2, thereby preventing USP18 from negatively regulating responses to IFN-I. Homozygosity for STAT2 R148Q represents a novel molecular and clinical phenocopy of inherited USP18 deficiency, which, together with inherited ISG15 deficiency, defines a group of type I interferonopathies characterized by an impaired regulation of late cellular responses to IFN-I., Graphical Abstract
Published: 2019

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

Author: Yuriy Stepanovskiy, Liudmyla Chernyshova, Elfride De Baere, Davood Mansouri, Nima Parvaneh, Mahboubeh Mansouri, María Teresa Herrera, S. Alireza Mahdaviani, Fabienne Jabot-Hanin, Jacinta Bustamante, Mélanie Migaud, Laurent Abel, Anne Puel, Jérémie Rosain, Alejandro Nieto-Patlán, Frédéric Tores, Mehrnaz Mesdaghi, Emilie Corvilain, Gaspard Kerner, Virginie Grandin, Edna Venegas-Montoya, Capucine Picard, Stéphanie Boisson-Dupuis, Patrick Nitschke, Sigifredo Pedraza-Sánchez, Carmen Oleaga-Quintas, Stéphane Marot, Caroline Deswarte, Jean-Laurent Casanova, Christine Bole-Feysot, Hannah Verdin, Anastasia Bondarenko, Garyfallia Syridou, Maria Tsolia, Sara Elva Espinosa-Padilla, Nathalie Lambert, Corinne Jacques, Lizbeth Blancas-Galicia, and Marco Antonio Yamazaki-Nakashimada
Subjects: Male, 0301 basic medicine, DNA Copy Number Variations, Immunology, Gene Expression, Alu element, Locus (genetics), Biology, Genome, Article, Interferon-gamma, 03 medical and health sciences, symbols.namesake, Alu Elements, Gene duplication, Interleukin-12 Receptor beta 1 Subunit, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Copy-number variation, Indel, Interleukin 12 receptor, beta 1 subunit, Alleles, Genetic Association Studies, Genetics, Mycobacterium Infections, Base Sequence, Chromosome Mapping, Pedigree, Phenotype, 030104 developmental biology, Mutation, Mendelian inheritance, symbols, Female
Abstract: PURPOSE: Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Autosomal recessive complete IL-12Rβ1 deficiency is the most frequent genetic etiology of MSMD. Only two of the 84 known mutations are copy number variations (CNVs), identified in two of the 213 IL-12Rβ1-deficient patients and two of the 164 kindreds reported. These two CNVs are large deletions found in the heterozygous or homozygous state. We searched for novel families with IL-12Rβ1 deficiency due to CNVs. METHODS: We studied six MSMD patients from five unrelated kindreds displaying adverse reactions to BCG vaccination. Three of the patients also presented systemic salmonellosis, two had mucocutaneous candidiasis, and one had disseminated histoplasmosis. We searched for CNVs and other variation by IL12RB1-targeted next-generation sequencing (NGS). RESULTS: We identified six new IL-12Rβ1-deficient patients with a complete loss of IL-12Rβ1 expression on PHA-activated T cells and/or EBV-transformed B cells. The cells of these patients did not respond to IL-12 and IL-23. Five different CNVs encompassing IL12RB1 (four deletions and one duplication) were identified in these patients by NGS coverage analysis, in either the homozygous state (n=1) or in trans (n=4) with a single nucleotide variation (n=3) or a small indel (n=1). Seven of the nine mutations are novel. Interestingly, four of the five CNVs were predicted to be driven by nearby Alu elements, as well as the two previously reported large deletions. The IL12RB1 locus is actually enriched in Alu elements (44.7%), when compared with the rest of the genome (10.5%). CONCLUSION: The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rβ1 deficiency.
Published: 2018

47. Hemolytic anemia, iron deficiency and personal history of deep vein thrombosis: consider paroxysmal nocturnal hemoglobinuria

Author: Régis Peffault de La Tour, Luc Darnige, Pascale Gaussem, Sidonie Dupeux, Jean-Benoît Arlet, Nicolas Gendron, Jérémie Rosain, and Isabelle Radford-Weiss
Subjects: Male, Hemolytic anemia, Anemia, Hemolytic, medicine.medical_specialty, Anemia, Urinary system, Deep vein, Hemoglobinuria, Paroxysmal, 01 natural sciences, Gastroenterology, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, medicine, Humans, 030212 general & internal medicine, 0101 mathematics, Aged, Venous Thrombosis, Anemia, Iron-Deficiency, business.industry, 010102 general mathematics, Hematopoietic stem cell, General Medicine, Hematology, Iron deficiency, medicine.disease, Thrombosis, Hemolysis, medicine.anatomical_structure, Paroxysmal nocturnal hemoglobinuria, business
Abstract: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematopoietic stem cell disorder that must be correctly diagnose because it is a chronic disease with a real impact on the quality of life and the survival of the patients. PNH screening of all patients with anemia or thrombosis is not recommended. We report the case of a 71-year-old male patient referred for chronic anemia. Anemia work-up revealed a misunderstood association of a hemolytic anemia with a negative direct antiglobulin test and iron deficiency. The patient exhibits biological signs of intravascular hemolysis, as well as a recent history of two episodes of deep vein thrombosis. Screening for PNH by flow cytometry shown a PNH clone with a size of approximately 33% of the granulocytes and 11% of the red blood cells. An interstitial deletion of the chromosome 13 was found in the medullar karyotype. PNH through chronic intravascular hemolysis induces an urinary iron loss. This is the only cause of hemolytic anemia inducing iron deficiency.
Published: 2018

48. Autoantibodies Against Type I IFNs in Patients with Ph-Negative Myeloproliferative Neoplasms

Author: Emanuela Sant’Antonio, Alessandro Borghesi, Ilaria Carola Casetti, Luca Malcovati, Paul Bastard, Virginia Valeria Ferretti, Adrian Gervais, Elisa Rumi, Jean-Laurent Casanova, Luca Arcaini, Daniele Vanni, Jérémie Rosain, Oscar Borsani, Chiara Trotti, and Daniela Pietra
Subjects: business.industry, Immunology, Ph Negative, Autoantibody, Medicine, In patient, Cell Biology, Hematology, business, Biochemistry, 631.Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational
Abstract: Background. The classic Ph-negative myeloproliferative neoplasms (MPN) are a group of clonal haematopoietic disorders, including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), whose shared and diverse phenotypic signatures are caused by a dysregulated JAK/STAT signal transduction because of acquired somatic mutations. It has been demonstrated that autoimmune diseases and MPN can be associated (Kristinsson et al., Haematologica. 2010 Jul;95(7):1216-20.), suggesting a common background of immune dysregulation (Barosi, Curr Hematol Malig Rep. 2014 Dec;9(4):331-9). SARS-CoV-2 infection displays extreme inter-individual clinical variability, ranging from silent infection to lethal disease. It has been described that at least 10% of patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia have neutralizing autoantibodies (AAbs) against type I IFNs, that precede SARS-CoV-2 infection (Bastard et al., Science. 2020 Oct 23;370(6515):eabd4585). In this study we searched for AAbs against type I IFNs in a cohort of MPN patients to evaluate the prevalence of these AAbs in the MPN population and to check for clinical correlations, including severity of COVID-19. Methods. Plasma samples from consecutively referred MPN patients were prospectively collected between November 2020 and June 2021 and frozen at -30°C immediately after collection. Levels of AAbs against type I IFN subtypes including IFNs alpha, beta and omega were measured using the enzyme-linked immunosorbent assay (ELISA) and a neutralization assay, as previously reported (Bastard et al., Science. 2020 Oct 23;370(6515):eabd4585; Moreews et al., Sci Immunol. 2021 May 25;6(59):eabh1516). Results. We included a total of 219 MPN patients (101 ET, 76 PV, 36 MF and 6 MPN unclassificable). Neutralizing AAbs to type I IFNs were detected in 29 patients (13.2%, 95%CI: 9.1% - 18.5%). Comparing patients with and without AAbs we observed a significant difference in terms of distribution of MPN diagnosis (P = 0.029) and driver mutations (P = 0.019), while we did not observe a difference in terms of age, sex, and treatment (Table 1). Overall, 29 patients (13%) got SARS-CoV-2 infection and 8 of them (28%) required hospitalization due to severe COVID-19. AAbs against type I IFNs were detected in 4 of the 29 SARS-CoV-2 infected patients. A higher rate of hospitalization for severe COVID-19 was observed in patients with AAbs to type I IFNs (2 of 4 patients, 50%) compared to those without these AAbs (6 of 25 patients, 24%), although the difference did not reach a statistical significance (P = 0.300). Conclusions. In this study, we detected a prevalence of AAbs against type I IFNs which is much higher in our MPN cohort (13%) than in the general population (2-3%). We also found a correlation between the presence of AAbs to type I IFNs and both the hematological diagnosis and the driver mutation. Despite a comparable prevalence of SARS-CoV-2 infection between MPN patients with or without AAbs to type I IFNs, we observed a different rate of hospitalization due to severe COVID-19 which is almost twice in those with AAbs against type I IFNs compared to those without these AAbs. However, this difference did not reach a statistical significance, probably because of the low number of SARS-CoV-2 infection in the subgroup of patients with AAbs against type I IFNs. Thus, further studies to analyse the prevalence of AAbs against type I IFNs in patients with MPN, their association with other forms of auto-immunity and severe COVID-19 are warranted. Figure 1 Figure 1. Disclosures Arcaini: Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses; Celgene: Speakers Bureau. Rumi: Novartis, Abbvie: Consultancy.
Published: 2021

49. Auto-anticorps anti-interférons de type I et COVID-19 sévère

Author: Pierre Tiberghien, Quentin Philippot, Adrian Gervais, Tom Le Voyer, Jérémie Rosain, Paul Bastard, Emmanuelle Jouanguy, Qian Zhang, Jean-Laurent Casanova, and Anne Puel
Subjects: R-76, Biochemistry (medical), Clinical Biochemistry, Hematology
Abstract: L’infection à SARS-CoV-2 conduit à une variabilité inter-individuelle importante. Nous avons identifié que des défauts génétiques de l’immunité lié aux interférons de type 1, TLR3 et IRF7-dépendants, peuvent être la cause de formes sévères de pneumopathie à COVID-19. Les patients déficients en AIRE, souffrent d’APS-1 et produisent de nombreux autoanticorps (auto-Ac), notamment les anti-IFNs de type I. Étonnamment, chez les patients avec des formes sévères de pneumopathie à COVID-19, nous avons trouvé qu’au moins 10 % d’entre eux avaient des auto-Ac IgG neutralisants 10 ng/mL d’IFN-w, d’IFN-a2. Ces auto-Ac neutralisent la capacité des IFNs de type I de bloquer l’infection à SARS-CoV-2 in vitro, et ont été retrouvé dans des plasmas de donneurs convalescents. Nous avons également trouvé des auto-Ac neutralisants des doses 100 fois moindres, donc plus physiologiques chez au moins 15 % des patients avec des formes sévères de pneumopathie à COVID-19, notamment chez 21 % des patients de plus de 80 ans. Enfin, dans un échantillon de 33 352 individus non infectés de la population générale, notamment des donneurs de sang de l’EFS, la prévalence des auto-Ac neutralisants les doses fortes d’IFNs de type I augmente avec l’âge. La proportion d’individus porteurs d’auto-Ac neutralisants des concentrations d’IFN 100 fois plus faibles étaient encore plus élevée. Le dépistage des donneurs de sang et de plasma convalescent pourrait avoir un impact thérapeutique. Les auto-Ac anti-IFNs de type I précèdent l’infection à SARS-CoV-2, augmentent de façon importante après 70 ans, et expliquent au moins 20 % des formes fatales et des formes sévères de COVID-19 chez les individus de plus de 80 ans.
Published: 2021

50. Strains Responsible for Invasive Meningococcal Disease in Patients With Terminal Complement Pathway Deficiencies

Author: Loïc de Pontual, Carine El Sissy, Felipe Suarez, Jérémie Rosain, Capucine Picard, Véronique Frémeaux-Bacchi, Paula Vieira Martins, Claire Fieschi, Muhamed-Kheir Taha, David Launay, Despina Moshous, Caroline Thomas, Eva Hong, Marie Ouachee, Ala-Eddine Deghmane, Service d'immunologie [HEGP, Paris], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre National de Référence des Méningocoques et Haemophilus influenzae - National Reference Center Meningococci and Haemophilus influenzae (CNR), Institut Pasteur [Paris] (IP), Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpitaux Universitaires de Paris Seine-Saint-Denis, Université Paris Descartes - Paris 5 (UPD5), Immunologie clinique [CHU St-Louis], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Différenciation et progression tumorale des lymphocytes, École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Hématologie et oncologie pédiatrique, Centre hospitalier universitaire de Nantes (CHU Nantes), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT), 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), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), This work was supported by Agence Régionale de Santé Ile-de-France ('Année Recherche' fellowship to J. R.), Institut Pasteur [Paris], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), École pratique des hautes études (EPHE), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre National de Référence des Méningocoques-Infections Bactériennes Invasives (CNR), Lille Inflammation Research International Center (LIRIC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), École pratique des hautes études (EPHE)-Institut Universitaire d'Hématologie (IUH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: Male, 0301 basic medicine, Complement Membrane Attack Complex, Neisseria meningitidis, MESH: Virulence, MESH: Meningococcal Infections, medicine.disease_cause, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Immunology and Allergy, complement, terminal complement pathway, Child, Complement Activation, Virulence, MESH: Genetic Testing, MESH: Paris, 3. Good health, Infectious Diseases, Female, Terminal complement pathway deficiency, Paris, Adolescent, MESH: Complement Activation, membrane attack complex, Biology, primary immunodeficiency, MESH: Neisseria meningitidis, 03 medical and health sciences, MESH: Complement Membrane Attack Complex, medicine, Humans, Genetic Testing, Gene, Retrospective Studies, MESH: Adolescent, MESH: Humans, MESH: Retrospective Studies, medicine.disease, Virology, MESH: Male, Complement system, Meningococcal Infections, 030104 developmental biology, Carriage, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Primary immunodeficiency, Complement membrane attack complex, MESH: Female
Abstract: International audience; Background:Patients with terminal complement pathway deficiency (TPD) are susceptible to recurrent invasive meningococcal disease (IMD). Neisseria meningitidis (Nm) strains infecting these patients are poorly documented in the literature.Methods:We identified patients with TPD and available Nm strains isolated during IMD. We investigated the genetic basis of the different TPDs and the characteristics of the Nm strains.Results:We included 56 patients with C5 (n = 8), C6 (n = 20), C7 (n = 18), C8 (n = 9), or C9 (n = 1) deficiency. Genetic study was performed in 47 patients and 30 pathogenic variants were identified in the genes coding for C5 (n = 4), C6 (n = 5), C7 (n = 12), C8 (n = 7), and C9 (n = 2). We characterized 61 Nm strains responsible for IMD in the 56 patients with TPD. The most frequent strains belonged to groups Y (n = 27 [44%]), B (n = 18 [30%]), and W (n = 8 [13%]). Hyperinvasive clonal complexes (CC11, CC32, CC41/44, and CC269) were responsible for 21% of IMD cases. The CC23 predominates and represented 26% of all invasive isolates. Eleven of the 15 clonal complexes identified fit to 12 different clonal complexes belonging to carriage strains.Conclusions:Unusual meningococcal strains with low level of virulence similar to carriage strains are most frequently responsible for IMD in patients with TPD.
Published: 2017

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

70 results on '"Jérémie Rosain"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources