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51. [Some lessons from 18 months of COVID vaccination]

Author: Alain, Fischer
Subjects: SARS-CoV-2, Vaccination, COVID-19, Humans
Published: 2022

52. Clonal hematopoiesis is not significantly associated with COVID-19 disease severity

Author: Yifan Zhou, Ruba Shalhoub, Stephanie N. Rogers, Shiqin Yu, Muxin Gu, Margarete A. Fabre, Pedro M. Quiros, Tae-Hoon Shin, Arch Diangson, Wenhan Deng, Shubha Anand, Wenhua Lu, Matthew Cullen, Anna L. Godfrey, Jacobus Preller, Jerome Hadjadj, Emmanuelle Jouanguy, Aurélie Cobat, Laurent Abel, Frederic Rieux-Laucat, Benjamin Terrier, Alain Fischer, Lara Novik, Ingelise J. Gordon, Larisa Strom, Martin R. Gaudinski, Andrea Lisco, Irini Sereti, Thomas J. Gniadek, Andrea Biondi, Paolo Bonfanti, Luisa Imberti, Clifton L. Dalgard, Yu Zhang, Kerry Dobbs, Helen C. Su, Luigi D. Notarangelo, Colin O. Wu, Peter J.M. Openshaw, Malcolm G. Semple, Ziad Mallat, Kenneth Baillie, Cynthia E. Dunbar, George S. Vassiliou, Zhou, Yifan [0000-0002-3538-621X], Rogers, Stephanie N [0000-0002-4563-1899], Gu, Muxin [0000-0003-4376-795X], Fabre, Margarete A [0000-0001-7794-610X], Quiros, Pedro M [0000-0002-7793-6291], Shin, Tae-Hoon [0000-0002-9619-8554], Preller, Jacobus [0000-0001-5706-816X], Cobat, Aurélie [0000-0001-7209-6257], Rieux-Laucat, Frederic [0000-0001-7858-7866], Gaudinski, Martin R [0000-0002-3743-5281], Biondi, Andrea [0000-0002-6757-6173], Bonfanti, Paolo [0000-0001-7289-8823], Imberti, Luisa [0000-0002-2075-8391], Dobbs, Kerry [0000-0002-3432-3137], Notarangelo, Luigi D [0000-0002-8335-0262], Openshaw, Peter JM [0000-0002-7220-2555], Semple, Malcolm G [0000-0001-9700-0418], Mallat, Ziad [0000-0003-0443-7878], Baillie, Kenneth [0000-0001-5258-793X], Dunbar, Cynthia E [0000-0002-7645-838X], Vassiliou, George S [0000-0003-4337-8022], Apollo - University of Cambridge Repository, Zhou, Y, Shalhoub, R, Rogers, S, Yu, S, Gu, M, Fabre, M, Quiros, P, Diangson, A, Deng, W, Anand, S, Lu, W, Cullen, M, Godfrey, A, Preller, J, Hadjadj, J, Jouanguy, E, Cobat, A, Abel, L, Rieux-Laucat, F, Terrier, B, Fischer, A, Novik, L, Gordon, I, Strom, L, Gaudinski, M, Lisco, A, Sereti, I, Gniadek, T, Biondi, A, Bonfanti, P, Imberti, L, Zhang, Y, Dalgard, C, Dobbs, K, Su, H, Notarangelo, L, Wu, C, Openshaw, P, Semple, M, Mallat, Z, Baillie, K, Dunbar, C, and Vassiliou, G
Subjects: Clonal Evolution, Immunology, Mutation, COVID-19, Humans, Cell Biology, Hematology, Clonal Hematopoiesis, Biochemistry, Severity of Illness Index, Hematopoiesis
Abstract: Clonal hematopoiesis (CH) describes the disproportionate expansion of a hematopoietic stemcell (HSC) and its progeny, in association with leukemia-associated somatic mutations, mostcommonly affecting the genes for epigenetic regulators DNMT3A, TET2 and ASXL1.The prevalence and size of such clones rise with age, in association with changes in the driver gene landscape.10 CH is associated with an increased risk of hematologic malignancies, but also of cardiovascular disease (CVD), independently of other known CVD risk factors.11,12 The basis forthis increased CVD risk has been linked to hyperinflammatory positive feedback loops driven by increased cytokine release from clonal myeloid cells, particularly interleukin IL-6 and IL-1β.
Published: 2022
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53. SARS-CoV-2 vaccines, where do we stand?

Author: Alain Fischer
Subjects: 0106 biological sciences, 0301 basic medicine, COVID-19 Vaccines, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), media_common.quotation_subject, Population, Disease, 01 natural sciences, 03 medical and health sciences, Pandemic, Humans, Infection control, Quality (business), education, Pandemics, media_common, Vaccines, education.field_of_study, SARS-CoV-2, COVID-19, General Medicine, Vaccination, 030104 developmental biology, Risk analysis (engineering), Business, 010606 plant biology & botany
Abstract: Vaccination against the SARS-CoV-2, the virus responsible for the Covid-19 pandemic, represents a major infection control strategy in the absence of effective treatment of the disease to date. Unprecedented mobilization has led to the development of a large number of projects, some of which have already been in test in humans for several months. The first efficacy and safety data are expected in the coming weeks. New vaccine technologies are being evaluated (RNA, replicating or non-replicating viral vectors), further increasing the chances of success. The criteria for evaluating vaccines-despite the exceptional speed of their development-must remain rigorous enough to ensure their acceptance by the population. Beyond their development, mass production and equitable distribution raise many questions. Finally, vaccination can only be successfully implemented if health professionals and the population are convinced of its validity, which implies particular attention to the quality of the information given and the methods of communication.La vaccination contre le SARS-CoV-2, virus responsable de la pandémie de Covid-19 représente une stratégie majeure de contrôle de l’infection en l’absence à ce jour de traitement efficace de la maladie. Une mobilisation sans précédent a conduit au développement de très nombreux projets dont certains sont en test chez l’homme depuis déjà quelques mois. Les premières données d’efficacité et de sécurité d’emploi sont attendues dans les prochaines semaines. De nouvelles technologies de vaccin sont évaluées (ARN, vecteurs viraux réplicatifs ou non), élargissant d’autant les chances de succès. Les critères d’évaluation des vaccins — malgré la rapidité exceptionnelle de leurs développements — doivent garder la rigueur nécessaire à leur acceptation par la population. Au-delà de leur mise au point, la production massive et leur distribution équitable soulèvent de nombreuses questions. Cette vaccination enfin, ne pourra être mise en œuvre avec succès que si les professionnels de santé et la population sont convaincus de son bien-fondé, ce qui implique une attention particulière apportée à la qualité de l’information donnée et aux modalités de communication.
Published: 2021
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54. Retrieval of vector integration sites from cell-free DNA

Author: Alessio Cantore, Serena Acquati, Francesca Fumagalli, Fabrizio Benedicenti, Valeria Calbi, Marina Cavazzana, Eugenio Montini, Alessandro Aiuti, Frederic D. Bushman, Pierangela Gallina, Alessandra Magnani, Andrea Calabria, Laura Rudilosso, Maximilian Witzel, Luigi Naldini, Giulio Spinozzi, Christoph Klein, Pietro Genovese, Emmanuelle Six, Alain Fischer, Giulia Schiroli, Daniela Cesana, Cesana, D., Calabria, A., Rudilosso, L., Gallina, P., Benedicenti, F., Spinozzi, G., Schiroli, G., Magnani, A., Acquati, S., Fumagalli, F., Calbi, V., Witzel, M., Bushman, F. D., Cantore, A., Genovese, P., Klein, C., Fischer, A., Cavazzana, M., Six, E., Aiuti, A., Naldini, L., and Montini, E.
Subjects: 0301 basic medicine, Lymphoma, Genetic enhancement, Genetic Vectors, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, law.invention, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, law, In vivo, medicine, Humans, Liquid biopsy, Polymerase chain reaction, Leukemia, Hematopoietic stem cell, Genetic Therapy, Leukodystrophy, Metachromatic, General Medicine, Genetically modified organism, 030104 developmental biology, medicine.anatomical_structure, Cell-free fetal DNA, chemistry, 030220 oncology & carcinogenesis, Cell-Free Nucleic Acids, DNA
Abstract: Gene therapy (GT) has rapidly attracted renewed interest as a treatment for otherwise incurable diseases, with several GT products already on the market and many more entering clinical testing for selected indications. Clonal tracking techniques based on vector integration enable monitoring of the fate of engineered cells in the blood of patients receiving GT and allow assessment of the safety and efficacy of these procedures. However, owing to the limited number of cells that can be tested and the impracticality of studying cells residing in peripheral organs without performing invasive biopsies, this approach provides only a partial snapshot of the clonal repertoire and dynamics of genetically modified cells and reduces the predictive power as a safety readout. In this study, we developed liquid biopsy integration site sequencing, or LiBIS-seq, a polymerase chain reaction technique optimized to quantitatively retrieve vector integration sites from cell-free DNA released into the bloodstream by dying cells residing in several tissues. This approach enabled longitudinal monitoring of in vivo liver-directed GT and clonal tracking in patients receiving hematopoietic stem cell GT, improving our understanding of the clonal composition and turnover of genetically modified cells in solid tissues and, in contrast to conventional analyses based only on circulating blood cells, enabling earlier detection of vector-marked clones that are aberrantly expanding in peripheral tissues.
Published: 2021
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55. Current Spectrum of Infections in Patients with X-Linked Agammaglobulinemia

Author: Olivier Hermine, Felipe Suarez, Bénédicte Neven, Olivier Lortholary, Capucine Picard, Olivier Paccoud, Alain Fischer, Stéphane Blanche, Marc Lecuit, Claire Aguilar, Nizar Mahlaoui, Despina Moshous, and Fanny Lanternier
Subjects: Current spectrum, medicine.medical_specialty, biology, business.industry, Immunology, X-linked agammaglobulinemia, medicine.disease, Medical microbiology, hemic and lymphatic diseases, Internal medicine, medicine, biology.protein, Immunology and Allergy, Trough level, In patient, Antibody, Antibiotic prophylaxis, business, Image-guided radiation therapy
Abstract: Outcome of patients with X-linked agammaglobulinemia (XLA) has improved with the widespread use of immunoglobulin replacement therapy (IgRT). There are few data on the spectrum of infections experienced by patients undergoing IgRT. We carried out a retrospective cross-sectional analysis of the records of XLA patients seen at Necker-Enfants Malades Hospital, Paris. For each infection, we evaluated infection site, microbial etiology, antibiotic prophylaxis, immunosuppressive treatment, IgRT route, and last known IgG trough level. Sixty patients were included, who cumulated a follow-up of 1470 patient-years. We recorded 188 infections, including 97 after initiation of IgRT. The rate of infection was highest before IgRT (0.66 vs. 0.06 per person-year (ppy), p 8 g/L, and 16/97 (16.7%) in patients with trough levels > 10 g/L. Infection remains a significant issue in patients with XLA undergoing IgRT despite adequate IgG trough levels. Chronic inflammatory manifestations of X-linked agammaglobulinemia and immunosuppressive therapies may be significant drivers of infection during adulthood.
Published: 2021
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56. Wiskott-Aldrich syndrome

Author: Charline Miot, Alain Fischer, Nizar Mahlaoui, and Isabelle Pellier
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, business.industry, Immunosuppressive regimen, macromolecular substances, Hematology, Surgery, Transplantation, Methylprednisolone, hemic and lymphatic diseases, medicine, In patient, Cadaveric spasm, business, medicine.drug
Abstract: Two cases of successful cadaveric renal transplantation in patients with the Wiskott-Aldrich syndrome have previously been reported in the literature [1,2]. The first patient [1] had an almost uneventful outcome, while the second one [2] had to be treated with highdose methylprednisolone for biopsy-proven cellular rejection. The optimal immunosuppressive regimen in patients with Wiskott-Aldrich syndrome remains unknown. We report here the case of a Wiskott-Aldrich patient who underwent living-related renal transplantation. This patient however developed a number of infectious and non-infectious complications which led to his death 3 months after transplantation.
Published: 2021
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57. L’innovation thérapeutique au service du bien commun

Author: Michel Goldman, Mathias Dewatripont, and Alain Fischer
Subjects: General Medicine, General Biochemistry, Genetics and Molecular Biology
Published: 2022
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58. Allogeneic stem cell transplantation compared to conservative management in adults with inborn errors of immunity

Author: Morgane Cheminant, Thomas A. Fox, Mickael Alligon, Olivier Bouaziz, Bénédicte Neven, Despina Moshous, Stéphane Blanche, Aurélien Guffroy, Claire Fieschi, Marion Malphettes, Nicolas Schleinitz, Antoinette Perlat, Jean-François Viallard, Nathalie Dhedin, Françoise Sarrot-Reynauld, Isabelle Durieu, Sébastien Humbert, Fanny Fouyssac, Vincent Barlogis, Benjamin Carpenter, Rachael Hough, Arian Laurence, Ambroise Marçais, Ronjon Chakraverty, Olivier Hermine, Alain Fischer, Siobhan O. Burns, Nizar Mahlaoui, Emma C. Morris, and Felipe Suarez
Subjects: Adult, Transplantation Conditioning, Immunology, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Cell Biology, Hematology, Granulomatous Disease, Chronic, Conservative Treatment, Biochemistry, Young Adult, Humans, Transplantation, Homologous, Retrospective Studies, Stem Cell Transplantation
Abstract: Allogeneic hematopoietic stem cell transplantation (alloSCT) is curative for severe inborn errors of immunity (IEIs), with recent data suggesting alloSCT in adulthood is safe and effective in selected patients. However, questions remain regarding the indications for and optimal timing of transplant. We retrospectively compared outcomes of transplanted vs matched nontransplanted adults with severe IEIs. Seventy-nine patients (aged ≥ 15 years) underwent alloSCT between 2008 and 2018 for IEIs such as chronic granulomatous disease (n = 20) and various combined immune deficiencies (n = 59). A cohort of nontransplanted patients from the French Centre de Référence Déficits Immunitaires Héréditaires registry was identified blindly for case-control analysis, with ≤3 matched controls per index patient, without replacement. The nontransplanted patients were matched for birth decade, age at last review greater than index patient age at alloSCT, chronic granulomatous disease or combined immune deficiencies, and autoimmune/lymphoproliferative complications. A total of 281 patients were included (79 transplanted, 202 nontransplanted). Median age at transplant was 21 years. Transplant indications were mainly lymphoproliferative disease (n = 23) or colitis (n = 15). Median follow-up was 4.8 years (interquartile range, 2.5-7.2). One-year transplant-related mortality rate was 13%. Estimated disease-free survival at 5 years was higher in transplanted patients (58% vs 33%; P = .007). Nontransplanted patients had an ongoing risk of severe events, with an increased mean cumulative number of recurrent events compared with transplanted patients. Sensitivity analyses removing patients with common variable immune deficiency and their matched transplanted patients confirm these results. AlloSCT prevents progressive morbidity associated with IEIs in adults, which may outweigh the negative impact of transplant-related mortality.
Published: 2022

59. Life-Saving, Dose-Adjusted, Targeted Therapy in a Patient with a STAT3 Gain-of-Function Mutation

Author: Capucine Picard, Marie-Louise Frémond, Frédéric Rieux-Laucat, Laureline Berteloot, Bénédicte Neven, Alain Fischer, Marion Grimaud, Claire Pressiat, Eytan Sarfati, Cécile Godot, Jérôme Hadjadj, Mathieu Fusaro, Thierry Jo Molina, Sylvain Renolleau, Stéphane Blanche, Marie-Claude Stolzenberg, Roman Klifa, and Alice Hadchouel
Subjects: medicine.medical_specialty, Medical microbiology, business.industry, medicine.medical_treatment, Immunology, MEDLINE, Immunology and Allergy, Medicine, Gain of function mutation, Life saving, business, Intensive care medicine, Targeted therapy
Published: 2021
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60. A 23-Year Follow-Up of a Patient with Gain-of-Function IkB-Alpha Mutation and Stable Full Chimerism After Hematopoietic Stem Cell Transplantation

Author: Alain Fischer, Francesca Conti, Caterina Cancrini, Rita Carsetti, and Jean-Laurent Casanova
Subjects: business.industry, medicine.medical_treatment, Immunology, Alpha (ethology), Epidermodysplasia verruciformis, Hematopoietic stem cell transplantation, medicine.disease, Settore MED/38, Gain of function, Mutation (genetic algorithm), Cancer research, Immunology and Allergy, Medicine, business
Published: 2020
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61. Chronic Granulomatous Disease with the McLeod Phenotype: a French National Retrospective Case Series

Author: Pierre-Simon Rohrlich, Souha Albinni, Wadih Abou-Chahla, Benedicte Neven, Jérôme Babinet, Christophe Marguet, Felipe Suarez, Olivier Hermine, Faustine Lhomme, Sébastien Héritier, Olivier Lortholary, Isabelle Durieu, Nizar Mahlaoui, Alain Fischer, Marie-Dominique Dumont, Stéphane Blanche, Despina Moshous, Denise Amiranoff, and Thierry Peyrard
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Duchenne muscular dystrophy, medicine.medical_treatment, Immunology, Disease, Hematopoietic stem cell transplantation, Granulomatous Disease, Chronic, Young Adult, Chronic granulomatous disease, Isoantibodies, Retinitis pigmentosa, Epidemiology, medicine, Humans, Immunology and Allergy, CYBB, Child, Retrospective Studies, business.industry, Infant, medicine.disease, Survival Analysis, Abetalipoproteinemia, Child, Preschool, NADPH Oxidase 2, Primary immunodeficiency, Female, France, business, Neuroacanthocytosis, Follow-Up Studies
Abstract: X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype. We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types. The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well. This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.
Published: 2020
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62. L’innovation thérapeutique, à quel prix ?

Author: Michel Goldman, Mathias Dewatripont, Alain Fischer, Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), and Université libre de Bruxelles (ULB)
Subjects: 0301 basic medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, [SDV]Life Sciences [q-bio], Political science, 030212 general & internal medicine, General Medicine, Sciences bio-médicales et agricoles, Biologie, Humanities, General Biochemistry, Genetics and Molecular Biology
Abstract: SCOPUS: no.j, info:eu-repo/semantics/published
Published: 2020
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63. Dealing with a mucosal viral pandemic: lessons from COVID-19 vaccines

Author: Violette Mouro and Alain Fischer
Subjects: COVID-19 Vaccines, SARS-CoV-2, Immunology, Immunology and Allergy, COVID-19, Humans, Viral Vaccines, Antibodies, Viral, Pandemics, Immunoglobulin A
Abstract: The development and deployment of vaccines against COVID-19 demonstrated major successes in providing immunity and preventing severe disease and death. Yet SARS-CoV-2 evolves and vaccine-induced protection wanes, meaning progress in vaccination strategies is of upmost importance. New vaccines directed at emerging viral strains are being developed while vaccination schemes with booster doses and combinations of different platform-based vaccines are being tested in trials and real-world settings. Despite these diverse approaches, COVID-19 vaccines are only delivered intramuscularly, whereas the nasal mucosa is the primary site of infection with SARS-CoV-2. Preclinical mucosal vaccines with intranasal or oral administration demonstrate promising results regarding mucosal IgA generation and tissue-resident lymphocyte responses against SARS-CoV-2. By mounting an improved local humoral and cell-mediated response, mucosal vaccination could be a safe and effective way to prevent infection, block transmission and contribute to reduce SARS-CoV-2 spread. However, questions and limitations remain: how effectively and reproducibly will vaccines penetrate mucosal barriers? Will vaccine-induced mucosal IgA responses provide sustained protection against infection?
Published: 2022

64. Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

Author: Akihiro Hoshino, David Boutboul, Yuan Zhang, Hye Sun Kuehn, Jerôme Hadjadj, Nihal Özdemir, Tiraje Celkan, Christoph Walz, Capucine Picard, Christelle Lenoir, Nizar Mahlaoui, Christoph Klein, Xiao Peng, Antoine Azar, Erin Reigh, Morgane Cheminant, Alain Fischer, Frédéric Rieux-Laucat, Isabelle Callebaut, Fabian Hauck, Joshua Milner, Sergio D. Rosenzweig, Sylvain Latour, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement [IRD] : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), ANR-18-CE15-0025,ImmunoBioCTPS1,Comprendre la biologie et la physiopathologie de CTPS1, une nouvelle cible pour le développement d'immunosuppresseurs.(2018), ANR-18-CE17-0001,ACTION,Cytopénies Auto-immunes: génétique et mécanismes physiopathologiques du syndrome d'Evans pédaitrique(2018), and ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018)
Subjects: [SDV]Life Sciences [q-bio], Immunology, General Medicine
Abstract: IKZF1/IKAROS is a key transcription factor of lymphocyte development expressed throughout hematopoiesis. Heterozygous germline IKZF1 haploinsufficient ( IKZF1 HI ) and dominant-negative ( IKZF1 DN ) variants in humans cause B cell immune deficiency and combined immunodeficiency. Here, we identified previously unidentified heterozygous IKZF1 variants (R183C/H) located in the DNA binding domain in eight individuals with inflammatory, autoimmune, allergic symptoms, and abnormal plasma cell (PC) proliferation. Leukocytes of patients exhibited specific defects including impaired IL-2 production by T cells, T helper (T H ) skewing toward T H 2, low numbers of regulatory T cells (T reg ), eosinophilia, and abnormal PC proliferation. In contrast to IKZF1 HI and IKZF1 DN , IKZF1 R183H/C proteins showed increased DNA binding associated with increased gene expression of T H 2 and PC differentiation, thus demonstrating that IKZF1 R183H/C behave as gain-of-function (GOF) alleles. In vitro treatment with lenalidomide, known to degrade IKZF1, corrected T H 2 and PC abnormalities caused by IKZF1 R183H/C . These data extend the spectrum of pathological mechanisms associated with IKZF1 deficiencies and highlight the role of IKZF1 in late lymphoid differentiation stages.
Published: 2022
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65. Gain-of-function

Author: Akihiro, Hoshino, David, Boutboul, Yuan, Zhang, Hye Sun, Kuehn, Jerôme, Hadjadj, Nihal, Özdemir, Tiraje, Celkan, Christoph, Walz, Capucine, Picard, Christelle, Lenoir, Nizar, Mahlaoui, Christoph, Klein, Xiao, Peng, Antoine, Azar, Erin, Reigh, Morgane, Cheminant, Alain, Fischer, Frédéric, Rieux-Laucat, Isabelle, Callebaut, Fabian, Hauck, Joshua, Milner, Sergio D, Rosenzweig, and Sylvain, Latour
Subjects: B-Lymphocytes, Ikaros Transcription Factor, Gain of Function Mutation, T-Lymphocytes, Humans, DNA, Haploinsufficiency, Hematopoiesis
Abstract: IKZF1/IKAROS is a key transcription factor of lymphocyte development expressed throughout hematopoiesis. Heterozygous germline
Published: 2022

66. Quelques leçons à tirer de dix-huit mois de vaccination contre le Covid

Author: Alain Fischer
Subjects: General Medicine, General Biochemistry, Genetics and Molecular Biology
Published: 2022
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67. Curative allogeneic hematopoietic stem cell transplantation following reduced toxicity conditioning in adults with primary immunodeficiency

Author: Ambroise Marçais, Nizar Mahlaoui, Bénédicte Neven, Fanny Lanternier, Émilie Catherinot, Hélène Salvator, Morgane Cheminant, Maxime Jeljeli, Vahid Asnafi, Peter van Endert, Louis-Jean Couderc, Olivier Lortholary, Capucine Picard, Despina Moshous, Olivier Hermine, Alain Fischer, and Felipe Suarez
Subjects: Adult, Transplantation, Young Adult, Transplantation Conditioning, Adolescent, Hematopoietic Stem Cell Transplantation, Graft vs Host Disease, Humans, Hematology, Child, Granulomatous Disease, Chronic, Busulfan
Abstract: Primary immunodeficiencies (PID) are heterogeneous inborn errors of the immune system. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative and safe at the pediatric age but remains underperformed in adults. We report our experience on 32 consecutive adult patients with various PID including 17 (53%) with a combined immune deficiency, six (19%) with a disease of immune dysregulation and nine (28%) with a chronic granulomatous disease (CGD) who underwent an allo-HSCT between 2011 and 2020. The median age at transplant was 27 years (17-41). All assessable patients engrafted. The majority of patients received a fludarabine-Busulfan (FB) based regimen (FB2-3 in 16, FB4 in 12). Overall survival (OS) was 80.4% (100% for CGD and 74% for other PID patients) at 9 months and beyond (median follow-up 51.6 months). Six patients died, all in the first-year post-transplant. Cumulative incidences of grade II-IV acute GVHD/chronic GVHD were 18%/22%. Stem cell source, GVHD prophylaxis and conditioning intensity had no impact on OS. All surviving patients had over 90% donor chimerism, immune reconstitution, no sign of active PID related complications and were clinically improved. Allo-HSCT is effective in young adults PID patients with an acceptable toxicity and should be discussed in case of life-threatening PID.
Published: 2022

68. Long-Term Follow-up Study after Lentiviral Hematopoietic Stem/Progenitor Cell Gene Therapy for Wiskott - Aldrich Syndrome

Author: Salima Hacein-Bey-Abina, Adeline Denis, Alexandre Kauskot, Elizabeth Macintyre, Jin Hua Xu-Bayford, Aurélie Gabrion, Guy Gorochov, Cécile Roudaut, Chantal Lagresle-Peyrou, Aoife M. Doto, Capucine Picard, Frédéric Adam, Felipe Suarez, Alessandra Magnani, Frederic D. Bushman, Alain Fischer, Rachel Petermann, Emma C. Morris, Sarah Abbas, Emmanuel Clave, Marianne Guisset, Chrystelle Abdo, Christine Rivat, Loïc Dupré, Amélie Trinquand, Reem Elfeky, Marina Cavazzana, Elisa Magrin, Despina Moshous, Claire Booth, Anne Galy, Emmanuelle Six, Antoine Toubert, Bobby Gaspar, Adrian J. Thrasher, Mélanie Guiot, Delphine Borgel, Michaela Semeraro, John K. Everett, Makoto Miyara, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Great Ormond Street Hospital for Children [London] (GOSH), Great Ormond Street Institute of Child Health (UCL), University College of London [London] (UCL), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Universitaire Ouest, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Hopital Saint-Louis [AP-HP] (AP-HP), Arthrites autoimmunes (AA), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Transfusion Sanguine [Paris] (INTS), Service d'immuno-hématologie pédiatrique [CHU Necker], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: business.industry, Wiskott–Aldrich syndrome, Long term follow up, Genetic enhancement, Immunology, Cell Biology, Hematology, medicine.disease, Biochemistry, Haematopoiesis, Cancer research, Medicine, Progenitor cell, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Wiskott Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency associated with thrombocytopenia, eczema, infectious, autoimmune complications, and lymphomas. Patients lacking an HLA-matched donor may benefit from an alternative therapeutic approach based on the infusion of autologous gene corrected CD34+ cells. We previously reported a non-randomised, open-label, phase 1/2 clinical study applying a lentiviral vector based gene therapy (GT) protocol in 7 paediatric patients with severe WAS (score ≥ 3/5) (S. Hacein-Bey Abina et al, JAMA 2015). One patient died 7 months after GT because of pre-existing severe opportunistic infections, as reported. Two additional patients have been treated since that initial report, with a follow-up of at least 4 years. We here present a comprehensive long-term study on 8 patients with a follow-up from 4 to 9 years (median 7.6). The safety and efficacy of the approach is thoroughly investigated, with a particular focus on the correction of thrombocytopenia and auto-immunity. A stable engraftment of genetically and functionally corrected lymphoid and myeloid cells was reached in all patients, with no serious treatment-associated adverse events or concerning clonal expansion. Corrected lymphoid cells displayed a selective advantage over time with increasing vector copy number (VCN) level. In turn, this led to (i) sustained expression of WAS protein (WASp) in the patients' cells and (ii) clinical resolution of severe eczema and susceptibility to recurrent infections. In line with these results, T-cell function was restored after GT, as shown by the recovery of immune synapse assembly and the normalization of naïve T cell numbers. The T-cell compartment was also reconstituted in the patient treated at the age of 30 years, suggesting that GT for WAS is a treatment option in adult patients. In parallel with the robustness of T-cell reconstitution a normalized B-cell compartment was observed after GT, as shown in particular by increasing levels of WASp + switched memory B cells over time and the age-matched levels of KRECs. Five patients out of 8 were able to discontinue Ig replacement therapy while achieving normal post-vaccination antibody titers. Autoimmune disorders and bleeding episodes were significantly less frequent, despite only partial correction of the platelet compartment. After GT, a few autoimmune manifestations were observed: the persistence of lower extremity vasculitis (P2, very severe prior to GT), the new occurrence of nephrotic syndrome (P9), and the presence of anti-platelet antibodies (P2, P4, P7). The levels of circulating autoantibodies detected before GT (including ANA and vasculitis-related autoantibodies) normalized after treatment. Following GT, platelets were found to express sub-normal levels of WASp and to only partially augment their size. Platelet function studies indicated a partial correction of the platelet compartment achieved by GT, which may be sufficient to prevent occurrence of the hemorrhagic symptoms typical of WAS. Our results suggest that lentiviral GT provides sustained clinical benefits for patients with WAS. Overall clinical remission was observed in our patients despite very severe disease scores before GT. More efficacious and more reliable transduction protocols and conditioning regimen are likely to further improve outcomes, particularly with regard to platelet recovery, where the advantages of intrinsic correction are less apparent. Disclosures Booth: Orchard Therapeutics: Consultancy, Honoraria; SOBI: Consultancy, Honoraria; Takeda: Honoraria; GSK: Honoraria; Rocket Pharmaceuticals, Inc.: Consultancy. Thrasher: Orchard Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Generation bio: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; 4Bio Capital: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavazzana: Smart Immune: Other: co-founder.
Published: 2021
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69. Actin dynamics regulation by TTC7A/PI4KIIIα axis limits DNA damage and cell death during leukocyte migration

Author: Mathieu Kurowska, Gregoire Le Lay, Mathilde Bernard, Claire Leveau, Marie Lô, Despina Moshous, Gaël Ménasché, Pablo Vargas, Tania Gajardo, Marie-Thérèse El-Daher, Alain Fischer, Geneviève de Saint Basile, Bénédicte Neven, and Fernando E. Sepulveda
Subjects: Leukocyte migration, medicine.anatomical_structure, RHOA, biology, Downregulation and upregulation, Cell, medicine, biology.protein, Cell migration, Actin cytoskeleton, Protein kinase B, PI3K/AKT/mTOR pathway, Cell biology
Abstract: The actin cytoskeleton has a crucial role in the maintenance of the immune homeostasis by controlling various cell processes, including cell migration. Mutations in the TTC7A gene have been described as the cause of a primary immunodeficiency associated to different degrees of gut involvement and alterations in the actin cytoskeleton dynamics. Although several cellular functions have been associated with TTC7A, the role of the protein in the maintenance of the immune homeostasis is still poorly understood. Here we leverage microfabricated devices to investigate the impact of TTC7A deficiency in leukocytes migration at the single cell level. We show that TTC7A-deficient leukocytes exhibit an altered cell migration and reduced capacity to deform through narrow gaps. Mechanistically, TTC7A-deficient phenotype resulted from impaired phosphoinositides signaling, leading to the downregulation of the PI3K/AKT/RHOA regulatory axis and imbalanced actin cytoskeleton dynamic. This resulted in impaired cell motility, accumulation of DNA damage and increased cell death during chemotaxis in dense 3D gels. Our results highlight a novel role of TTC7A as a critical regulator of leukocyte migration. Impairment of this cellular function is likely to contribute to pathophysiology underlying progressive immunodeficiency in patients.
Published: 2021
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70. A monocyte/dendritic cell molecular signature of SARS-CoV-2-related multisystem inflammatory syndrome in children with severe myocarditis

Author: Cécile Masson, Aurélien Corneau, Florence Moulin, Ghaith Abdessalem, Pedro Gonçalves, Marianne Leruez, James P. Di Santo, Mathie Lorrot, Julie Toubiana, Julien Haroche, Camille Bruneau, Isabelle Melki, Bruno Charbit, Zahra Belhadjer, Loïc de Pontual, Camille de Cevins, Brigitte Bader Meunier, Alain Fischer, Victor Garcia-Paredes, Brieuc P. Perot, Marine Luka, Damien Bonnet, Quentin Riller, Nikaïa Smith, Slimane Allali, Sonia Meynier, Aude Magérus, Christele Gras Leguen, Shen-Ying Zhang, Olivier Schwartz, Jean-Laurent Casanova, Frédéric Rieux-Laucat, Nicolas Cagnard, Francesco Carbone, Tinhinane Fali, Mélanie Parisot, Mickaël M. Ménager, Maxime Beretta, Mohammed Zarhrate, Christine Bole-Feysot, Vithura Pirabarakan, Ludivine Grzelak, Mehdi Oualha, Darragh Duffy, Laura Barnabei, Hugo Mouquet, Maxime Batignes, Alexandre Boullé, Boris Sorin, Marie-Claude Stolzenberg, Inflammatory Responses and Transcriptomic Networks in diseases (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), Sanofi Aventis R&D [Chilly-Mazarin], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Immunité Innée - Innate Immunity, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Rockefeller University [New York], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital universitaire Robert-Debré [Paris], Université Paris Cité (UPCité), CHU Trousseau [APHP], Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Jean Verdier [AP-HP], Université Paris 13 (UP13), Collège de France (CdF (institution)), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), ANR-17-EURE-0013,GENE,Génétique et Epigénétique Nouvelle Ecole(2017), ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), and Université Paris Cité (UPC)
Subjects: Adult, Vascular Endothelial Growth Factor A, Chemokine, Myocarditis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], MIS-C, Monocytes, chemistry.chemical_compound, Viewpoint, scRNA-seq, medicine, otorhinolaryngologic diseases, Humans, Kawasaki Disease, Child, Connective Tissue Diseases, biology, business.industry, SARS-CoV-2, Monocyte, NF-kappa B, COVID-19, General Medicine, Dendritic Cells, Gene signature, medicine.disease, Pathophysiology, Systemic Inflammatory Response Syndrome, Vascular endothelial growth factor, medicine.anatomical_structure, Cytokine, chemistry, TNF-α and NF-κB signaling, Immunology, biology.protein, Cytokines, Tumor necrosis factor alpha, lack of responses to type I and type II IFN secretion, Clinical and Translational Article, Chemokines, myocarditis, business, PIMS-TS
Abstract: Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is generally milder than in adults, but a proportion of cases result in hyperinflammatory conditions often including myocarditis. Methods To better understand these cases, we applied a multiparametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. Plasma cytokine and chemokine levels and blood cellular composition were measured, alongside gene expression at the bulk and single-cell levels. Findings The most severe forms of multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 that resulted in myocarditis were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomics analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis characterized by sustained nuclear factor κB (NF-κB) activity and tumor necrosis factor alpha (TNF-α) signaling and associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type I and type II interferons, hyperinflammation, and response to oxidative stress related to increased HIF-1α and Vascular endothelial growth factor (VEGF) signaling. Conclusions These results provide potential for a better understanding of disease pathophysiology. Funding Agence National de la Recherche (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01; Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010; Laboratoire d’Excellence ‘‘Milieu Intérieur,” grant ANR-10-LABX-69-01; ANR-flash Covid19 “AIROCovid” and “CoVarImm”), Institut National de la Santé et de la Recherche Médicale (INSERM), and the “URGENCE COVID-19” fundraising campaign of Institut Pasteur., Graphical abstract, Context and significance Children with SARS-CoV-2 infection were initially thought to have only mild COVID-19 symptoms. However, several weeks into the first wave of SARS-CoV-2 infections, there was a surge of a postacute pathology called multisystem inflammatory syndrome in children (MIS-C). The authors recruited a cohort of children with suspicion of SARS-CoV-2 infection and uncovered hyperinflammation, hypoxic conditions, exacerbation of TNF-α signaling via NF-κB, and absence of responses to type I and type II IFN secretion in the most severe forms of MIS-C with severe myocarditis. This work led the authors to identify in monocytes and validate in peripheral blood mononuclear cells a molecular signature of 25 genes that allows discrimination of the most severe forms of MIS-C with myocarditis., Multiparametric analysis identifies, in monocytes and dendritic cells, a molecular signature of the most severe forms of multisystem inflammatory syndrome in children caused by SARS-CoV-2 infection. Severe myocarditis is characterized by an excess of TNF-α signaling via NF-κB, hypoxic conditions, and hyperinflammation in the absence of type I and type II interferon responses.
Published: 2021
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71. Resistance of children to Covid-19. How?

Author: Alain Fischer
Subjects: 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), business.industry, Viral Epidemiology, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Immunology, medicine.disease, Virology, Pneumonia, Pandemic, Severity of illness, Immunology and Allergy, Medicine, business, Viral immunology
Published: 2020
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72. 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
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73. Survival and Functional Outcomes in Boys with Cerebral Adrenoleukodystrophy with and without Hematopoietic Stem Cell Transplantation

Author: Maria L. Escolar, Susan Paadre, Asif M. Paker, Jean Hugues Dalle, Joanne Kurtzberg, Vinod K. Prasad, Paul J. Orchard, John J Balser, Gerald V. Raymond, Alain Fischer, Weston P. Miller, Patrick Aubourg, André Baruchel, David Nascene, Troy C. Lund, Stéphane Blanche, and Gérard Michel
Subjects: Male, medicine.medical_specialty, Adolescent, medicine.medical_treatment, Graft vs Host Disease, Disease, Hematopoietic stem cell transplantation, Infections, Time-to-Treatment, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, Adrenoleukodystrophy, Child, Adverse effect, Retrospective Studies, Transplantation, business.industry, Mortality rate, Hematopoietic Stem Cell Transplantation, Hematology, Prognosis, Survival Analysis, Confidence interval, Natural history, surgical procedures, operative, Case-Control Studies, 030220 oncology & carcinogenesis, Cohort, Disease Progression, business, 030215 immunology
Abstract: Cerebral adrenoleukodystrophy (CALD) is a rapidly progressing, often fatal neurodegenerative disease caused by mutations in the ABCD1 gene, resulting in deficiency of ALD protein. Clinical benefit has been reported following allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a large multicenter retrospective chart review to characterize the natural history of CALD, to describe outcomes after HSCT, and to identify predictors of treatment outcomes. Major functional disabilities (MFDs) were identified as having the most significant impact on patients' abilities to function independently and were used to assess HSCT outcome. Neurologic function score (NFS) and Loes magnetic resonance imaging score were assessed. Data were collected on 72 patients with CALD who did not undergo HSCT (untreated cohort) and on 65 patients who underwent transplantation (HSCT cohort) at 5 clinical sites. Kaplan-Meier (KM) estimates of 5-year overall survival (OS) from the time of CALD diagnosis were 55% (95% confidence interval [CI], 42.2% to 65.7%) for the untreated cohort and 78% (95% CI, 64% to 86.6%) for the HSCT cohort overall (P = .01). KM estimates of 2-year MFD-free survival for patients with gadolinium-enhanced lesions (GdE+) were 29% (95% CI, 11.7% to 48.2%) for untreated patients (n = 21). For patients who underwent HSCT with GdE+ at baseline, with an NFS ≤1 and Loes score of 0.5 to ≤9 (n = 27), the 2-year MFD-free survival was 84% (95% CI, 62.3% to 93.6%). Mortality rates post-HSCT were 8% (5 of 65) at 100days and 18% (12 of 65) at 1 year, with disease progression (44%; 7 of 16) and infection (31%; 5 of 16) listed as the most common causes of death. Adverse events post-HSCT included infection (29%; 19 of 65), acute grade II-IV graft-versus-host disease (GVHD) (31%; 18 of 58), and chronic GVHD (7%; 4 of 58). Eighteen percent of the patients (12 of 65) experienced engraftment failure after their first HSCT. Positive predictors of OS in the HSCT cohort may include donor-recipient HLA matching and lack of GVHD, and early disease treatment was predictive of MFD-free survival. GdE+ status is a strong predictor of disease progression in untreated patients.‎ This study confirms HSCT as an effective treatment for CALD when performed early. We propose survival without MFDs as a relevant treatment goal, rather than solely assessing OS as an indicator of treatment success.
Published: 2019
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74. Alternative pathways for the development of lymphoid structures in humans

Author: Vincent Barlogis, Thierry Jo Molina, Véronique Secq, Nathalie Boddaert, Capucine Picard, Julie Bruneau, Alain Fischer, Bénédicte Neven, Claude Griscelli, Chrystelle Abdo, Laureline Berteloot, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Robert Debré, Université Paris Cité (UPCité), Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Collège de France (CdF (institution)), and NUNES, Jacques A
Subjects: Adult, Male, 0301 basic medicine, Adolescent, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Spleen, Thymus Gland, Biology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Transplantation, Homologous, lymphoid tissue, lymphoid organs, Severe combined immunodeficiency, Multidisciplinary, Innate lymphoid cell, T-Lymphocytes, Helper-Inducer, Biological Sciences, medicine.disease, Magnetic Resonance Imaging, Transplantation, immune system, 030104 developmental biology, medicine.anatomical_structure, Lymphatic system, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Severe Combined Immunodeficiency, Stem cell, 030215 immunology
Abstract: International audience; Lymphoid tissue inducer (LTi) cells are critical for inducing the differentiation of most secondary lymphoid organs (SLOs) in mice. In humans, JAK3 and γc deficiencies result in severe combined immunodeficiency (SCIDs) characterized by an absence of T cells, natural killer cells, innate lymphoid cells (ILCs), and presumably LTi cells. Some of these patients have undergone allogeneic stem cell transplantation (HSCT) in the absence of myeloablation, which leads to donor T cell engraftment, while other leukocyte subsets are of host origin. By using MRI to look for SLOs in nine of these patients 16 to 44 y after HSCT, we discovered that SLOs were exclusively found in the three areas of the abdomen that drain the intestinal tract. A postmortem examination of a child with γc-SCID who had died 3.5 mo after HSCT showed corticomedullary differentiation in the thymus, T cell zones in the spleen, and the appendix, but in neither lymph nodes nor Peyer patches. Tertiary lymphoid organs were observed in the lung. No RAR-related orphan receptor-positive LTi cells could be detected in the existing lymphoid structures. These results suggest that while LTi cells are required for the genesis of most SLOs in humans, SLO in the appendix and in gut-draining areas, as well as tertiary lymphoid organs, can be generated likely by LTi cell-independent mechanisms.
Published: 2021
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75. An appraisal of the frequency and severity of noninfectious manifestations in primary immunodeficiencies: A study of a national retrospective cohort of 1375 patients over 10 years

Author: Mickaël Alligon, Nizar Mahlaoui, Virginie Courteille, Laurence Costes, Veronica Afonso, Philippe Randrianomenjanahary, Nathalie de Vergnes, Anja Ranohavimparany, Duy Vo, Inès Hafsa, Perrine Bach, Vincent Benoit, Nicolas Garcelon, Alain Fischer, Wadih Abou-Chahla, Daniel Adoue, Nathalie Aladjidi, Corinne Armari-Alla, Vincent Barlogis, Sophie Bayart, Yves Bertrand, Stéphane Blanche, Damien Bodet, Bernard Bonnotte, Raphaël Borie, Patrick Boutard, David Boutboul, Claire Briandet, Jean-Paul Brion, Jacques Brouard, Liana Carausu, Martin Castelle, Pascal Cathebras, Emilie Catherinot, Nathalie Cheikh, Morgane Cheminant, Sarah Cohen-Beaussant, Thibault Comont, Louis-Jean Couderc, Pierre Cougoul, Gérard Couillault, Lionel Crevon, Elisa Demonchy, Anne Deville, Catherine Devoldere, Eric Dore, Fabienne Dulieu, Isabelle Durieu, Natacha Entz-Werle, Claire Fieschi, Fanny Fouyssac, Pierre Frange, Vincent Gajdos, Lionel Galicier, Virginie Gandemer, Martine Gardembas, Catherine Gaud, Bernard Grosbois, Aurélien Guffroy, Corinne Guitton, Gaëlle Guillerm, Eric Hachulla, Mohamed Hamidou, Sophie Haro, Yves Hatchuel, Olivier Hermine, Cyrille Hoarau, Arnaud Hot, Sébastien Humbert, Arnaud Jaccard, Jean-Philippe Jais, Sarah Jannier, Serge Jacquot, Roland Jaussaud, Pierre-Yves Jeandel, Eric Jeziorski, Kamila Kebaili, Anne-Sophie Korganow, Olivier Lambotte, Fanny Lanternier, Claire Larroche, David Launay, Emmanuelle Le Moigne, Alain Le Quellec, Vincent Le Moing, Yvon Lebranchu, Marc Lecuit, Guillaume Lefèvre, Jean-Daniel Lelièvre, Richard Lemal, Valérie Li-Thiao-Te, Olivier Lortholary, Luminita Luca, Coralie Mallebranche, Marion Malphettes, Aude Marie-Cardine, Nicolas Martin-Silva, Agathe Masseau, Françoise Mazingue, Etienne Merlin, Gérard Michel, Frédéric Millot, Charline Miot, Béatrice Monlibert, Fabrice Monpoux, Despina Moshous, Luc Mouthon, Martine Münzer, Robert Navarro, Bénédicte Neven, Dalila Nouar, Raphaële Nove-Josserand, Eric Oksenhendler, Marie Ouachée-Chardin, Anne Pagnier, Marlène Pasquet, Isabelle Pellier, Yves Perel, Antoinette Perlat, Christophe Piguet, Dominique Plantaz, Sophie Rivière, Pascal Roblot, Pierre-Simon Rohrlich, Bruno Royer, Valéry Salle, Françoise Sarrot-Reynauld, Amélie Servettaz, Jean-Louis Stephan, Nicolas Schleinitz, Harry Sokol, Felipe Suarez, Laure Swiader, Sophie Taque, Caroline Thomas, Olivier Tournilhac, Caroline Thumerelle, Jean-Pierre Vannier, and Jean-François Viallard
Subjects: Inflammation, Neoplasms, Immunology, Hypersensitivity, Immunologic Deficiency Syndromes, Immunology and Allergy, Humans, Autoimmunity, Retrospective Studies
Abstract: Noninfectious manifestations-allergy, autoimmunity/inflammation, lymphoproliferation, and malignancies-are known to exist in many primary immunodeficiency diseases (PID) and to participate in prognosis.To obtain a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French National Reference Center for Primary Immune Deficiencies (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry.These patients were followed for 10 years (2009-2018) by specialized centers in university hospitals. This study showed that 20.1% of patients without prior curative therapy (n = 1163) developed at least 1 manifestation (event) encompassing 277 events.Autoimmune/inflammatory events (n = 138) and malignancies (n = 85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 195 patients (14.2%) and were found to be causal in 43% of cases. Malignancies (odds ratio, 5.62; 95% confidence interval, 3.66-8.62) and autoimmunity (odds ratio, 1.9; 95% confidence interval, 1.27-2.84) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (mostly allogeneic hematopoietic stem cell transplantation, with a few cases of gene therapy or thymus transplantation) before the 10-year study period (n = 212) had comparatively reduced but still detectable clinical manifestations (n = 16) leading to death in 9.4% of them.This study points to the frequency and severity of noninfectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.
Published: 2021

76. A monocyte/dendritic cell molecular signature of SARS-CoV2-related multisystem inflammatory syndrome in children (MIS-C) with severe myocarditis

Author: Ludivine Grzelak, Maxime Beretta, Slimane Allali, Aude Magérus, Hugo Mouquet, Maxime Batignes, Isabelle Melki, Olivier Schwartz, Quentin Riller, Mehdi Oualha, Nicolas Cagnard, Christine Bole-Feysot, Camille de Cevins, James P. Di Santo, Christele Gras Leguen, Florence Moulin, Jean-Laurent Casanova, Cécile Masson, Aurélien Corneau, Damien Bonnet, Vithura Pirabarakan, Mickaël M. Ménager, Camille Bruneau, Brieuc P. Perot, Francesco Carbone, Darragh Duffy, Mohammed Zarhrate, Marie-Claude Stolzenberg, Alexandre Boullé, Mélanie Parisot, Boris Sorin, Ghaith Abdessalem, Alain Fischer, Marianne Leruez, Julie Toubiana, Victor Garcia-Paredes, Mathie Lorrot, Loïc de Pontual, Zahra Belhadjer, Bruno Charbit, Tinhinane Fali, Marine Luka, Nikaïa Smith, Brigitte Bader Meunier, Shen-Ying Zhang, Sonia Meynier, Fredéric Rieux Laucat, Julien Haroche, Pedro Gonçalves, Laura Barnabei, Inflammatory Responses and Transcriptomic Networks in diseases (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sanofi Aventis R&D [Chilly-Mazarin], Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris], Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Immunité Innée - Innate Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Rockefeller University [New York], 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), Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP Hôpital universitaire Robert-Debré [Paris], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département des urgences pédiatriques [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), Laboratoire de Virologie [CHU Necker], Département de Pédiatrie et maladies infectieuses [CHU Necker], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Pédiatrie [Jean Verdier], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Collège de France (CdF (institution)), Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, The study was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), by the 'URGENCE COVID-19' fundraising campaign of Institut Pasteur, by the Atip-Avenir, Emergence ville de Paris program and fond de dotation Janssen Horizon and by government grants managed by the Agence National de la Recherche as part of the 'Investment for the Future' program (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01, Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010, Laboratoire d’Excellence ‘‘Milieu Intérieur', grant ANR-10-LABX-69-01), the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), the Agence National de la Recherche (ANR-flash Covid19 'AIROCovid' to FRL and 'CoVarImm' to DD and JDS), and by the FAST Foundation (French Friends of Sheba Tel Hashomer Hospital). The LabTech Single Cell@Imagine is supported by the Paris Region and the 'Investissements d’avenir' program through the 2019 ATF funding – Sésame Filières PIA (Grant N°3877871). CdC is the recipient of a CIFRE-PhD (Sanofi). L.B. was a recipient of an Imagine institute PhD international program supported by the Fondation Bettencourt Schueller. L.B. was also supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) and is part of the Université de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its 'Investments for the Future' program. S.M. was a recipient of an INSERM and Institut Imagine post-doctorat program supported by the Fondation pour la Recherche Médicale (FRM N°SPF20170938825). NS was a recipient of the Pasteur-Roux-Cantarini Fellowship. VGP obtained an Imagine international PhD fellowship program supported by the Fondation Bettencourt Schueller. BPP is the recipient of an ANRS post-doctoral fellowship., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-18-RHUS-0010,ATRACTION,Autoimmunity/inflammation Through Rnaseq Analysis at the single Cell level for Therapeutic Innovation(2018), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), ANR-20-COVI-0022,AIROCovid19,Analyse Omics de la réponse immune aigue au cours de l'infection à Covid19: rationnel moléculaire pour un traitement ciblé(2020), ANR-17-EURE-0013,GENE,Génétique et Epigénétique Nouvelle Ecole(2017), ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), 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 Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)
Subjects: 0303 health sciences, Chemokine, Myocarditis, biology, business.industry, Monocyte, Dendritic cell, Gene signature, medicine.disease_cause, medicine.disease, Pathophysiology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, biology.protein, medicine, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, business, Oxidative stress, 030304 developmental biology
Abstract: SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis, characterized by sustained NF-κB activity, TNF-α signaling, associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1α and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology.
Published: 2021

77. Overview of STING-Associated Vasculopathy with Onset in Infancy (SAVI) Among 21 Patients

Author: Olivier Brocq, Pere Soler-Palacín, Jérôme Sirvente, Brigitte Bader-Meunier, Rawane Dagher, Naoki Kitabayashi, Laureline Berteloot, Sophie Willcocks, Nadia Jeremiah, Laura Barnabei, Stefano Volpi, Eline Van Aerde, Sylvain Breton, Damien Chan, Alice Hadchouel, Vincent Bondet, Eric Jeziorski, Despina Moshous, Antonella Insalaco, Jean-Christophe Dubus, Thierry Jo Molina, Isabelle Melki, Nathalie Stremler-Le Bel, Stéphane Blanche, Marie-Anne Morren, Alain Fischer, Mireia Lopez-Corbeto, Gillian I. Rice, Marie-Louise Frémond, Carine Wouters, Yanick J. Crow, Séverine Feuillet-Soummer, Jacques G. Rivière, Françoise Mazingue, Violaine Bresson, Bénédicte Neven, Alexandre Belot, Mathieu Fusaro, Guillaume Thouvenin, Darragh Duffy, Frédéric Rieux-Laucat, Caroline Thumerelle, Luis Seabra, Marco Gattorno, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), 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), Service de Pneumologie Allergologie [CHU Necker], 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 de Paris (UP), Service de radiologie pédiatrique [CHU Necker], AP-HP Hôpital universitaire Robert-Debré [Paris], Urgences pédiatriques [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Immunité et cancer (U932), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris], Hospices Civils de Lyon (HCL), Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Immunologie Translationnelle - Translational Immunology lab, Hôpital Princesse Grace [Monaco], Women’s and Children’s Hospital [Adelaide], CHU Notre Dame des Secours [Jbeil], Service de pédiatrie spécialisée et médecine infantile (neurologie, pneumologie, maladies héréditaires du métabolisme) [Hôpital de la Timone - APHM], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre chirurgical Marie Lannelongue, CHU Necker - Enfants Malades [AP-HP], IRCCS Istituto Giannina Gaslini [Genoa, Italy], IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Vall d'Hebron University Hospital [Barcelona], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University Hospitals Leuven [Leuven], Lausanne University Hospital, Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Service de Pneumologie pédiatrique [CHU Trousseau], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Queensland Children's Hospital, Partenaires INRAE, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Service de pathologie [CHU Necker], Collège de France (CdF (institution)), MRC Institute of Genetics and Molecular Medicine [Edinburgh] (IGMM), University of Edinburgh-Medical Research Council, M.-L. Frémond received a grant from the Institut National de la Santé et de la Recherche Médicale (reference: 000427993). Y. J. Crow acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the 'Investments for the Future' program bearing the reference ANR-10-IAHU-01. Y. J. Crow and D. Duffy acknowledge the National Research Agency (France) (grant CE17001002)., The authors wish to thank the patients and their families for their cooperation in this study. The authors are grateful to Elvira Duchesne (NP) and Samira Plassart (PhD) for their very helpful technical assistance. They thank Thomas Blauwblomme (MD, PhD, Neurosurgery Unit, Necker Hospital, Paris, France) for providing CSF from children with idiopathic hydrocephalus., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), European Project: 309449,EC:FP7:ERC,ERC-2012-StG_20111109,T1-IFN(2013), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Centre Chirurgical Marie Lannelongue (CCML), Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, medicine.medical_specialty, Adolescent, Late onset, Interstitial lung disease, Vasculopathy, Systemic inflammation, Gastroenterology, Nephropathy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Lymphopenia, medicine, Immunology and Allergy, Humans, 030212 general & internal medicine, Vascular Diseases, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, Child, Type I interferonopathy, Immunodeficiency, Inflammation, STING1, JAK inhibitors, business.industry, Infant, Membrane Proteins, medicine.disease, 3. Good health, Polyarthritis, 030228 respiratory system, Failure to thrive, Mutation, Aicardi–Goutières syndrome, medicine.symptom, Stimulator of interferon genes, business, Lung Diseases, Interstitial
Abstract: BACKGROUND: Gain-of-function mutations in STING1 underlie a type I interferonopathy termed SAVI (STING-associated vasculopathy with onset in infancy). This severe disease is variably characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease (ILD).OBJECTIVE: To describe a cohort of patients with SAVI.METHODS: Assessment of clinical, radiological and immunological data from 21 patients (17 families) was carried out.RESULTS: Patients carried heterozygous substitutions in STING1 previously described in SAVI, mainly the p.V155M. Most were symptomatic from infancy, but late onset in adulthood occurred in 1 patient. Systemic inflammation, skin vasculopathy, and ILD were observed in 19, 18, and 21 patients, respectively. Extensive tissue loss occurred in 4 patients. Severity of ILD was highly variable with insidious progression up to end-stage respiratory failure reached at teenage in 6 patients. Lung imaging revealed early fibrotic lesions. Failure to thrive was almost constant, with severe growth failure seen in 4 patients. Seven patients presented polyarthritis, and the phenotype in 1 infant mimicked a combined immunodeficiency. Extended features reminiscent of other interferonopathies were also found, including intracranial calcification, glaucoma and glomerular nephropathy. Increased expression of interferon-stimulated genes and interferon α protein was constant. Autoantibodies were frequently found, in particular rheumatoid factor. Most patients presented with a T-cell defect, with low counts of memory CD8+ cells and impaired T-cell proliferation in response to antigens. Long-term follow-up described in 8 children confirmed the clinical benefit of ruxolitinib in SAVI where the treatment was started early in the disease course, underlying the need for early diagnosis. Tolerance was reasonably good.CONCLUSION: The largest worldwide cohort of SAVI patients yet described, illustrates the core features of the disease and extends the clinical and immunological phenotype to include overlap with other monogenic interferonopathies.
Published: 2021
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78. Hematopoietic cell transplantation in severe combined immunodeficiency: The SCETIDE 2006-2014 European cohort

Author: Rita Beier, Marina Cavazzana, Figen Dogu, Yves Bertrand, Paul Veys, Francesca Ferrua, Robbert G. M. Bredius, Roland Meisel, Arnalda Lanfranchi, Renata Formankova, Stéphane Blanche, Virginie Courteille, Elena Soncini, Tayfun Güngör, Jolanta Gozdzik, Kim Vettenranta, Krzysztof Kałwak, Mikael Alligon, Natacha Entz-Werle, Ansgar Schulz, Nizar Mahlaoui, Savaş Kansoy, Wilhelm Friedrich, Amos Toren, Mehmet A. Yeşilipek, Alina Ferster, Andrew R. Gennery, Mary Slatter, Despina Moshous, Fulvio Porta, Marco Zecca, Anders Fasth, Karoline Ehlert, Gérard Michel, Bénédicte Neven, Victoria Bordon, Alphan Kupesiz, Mikael Sundin, Kanchan Rao, Cristina Diaz-de-Heredia, Isabelle Badell Serra, Michael H. Albert, Herbert Pichler, Arjan C. Lankester, Andrew J. Cant, Marta González-Vicent, Petr Sedlacek, Jose Moraleda, Caroline A. Lindemans, Peter Bader, Manfred Hoenig, Alain Fischer, Austen Worth, Dmitry Balashov, Erik G J von Asmuth, Carsten Speckmann, Nuno Miranda, Aydan Ikinciogullari, Clinicum, Children's Hospital, Lastentautien yksikkö, HUS Children and Adolescents, University of Zurich, Lankester, Arjan C, Institut Català de la Salut, [Lankester AC, von Asmuth EGJ] Pediatric Stem Cell Transplantation Program and Laboratory for Pediatric Immunology, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands. [Neven B] Unité d’Immuno-hematologie et Rhumatologie Pédiatrique, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. Université de Paris, Paris, France. Institut Imagine, INSERM UMR1163, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Paris, France. [Mahlaoui N, Courteille V, Alligon M] French National Reference Center for Primary Immunodeficiencies (CEREDIH) and European Registry for Stem Cell Transplantation for Primary Immunodeficiencies (SCETIDE), Hôpital Universitaire Necker-Enfants malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France. [Diaz-de-Heredia C] Servei d’Oncologia i Hematologia Pediàtriques, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Oncology, Transplantation Conditioning, medicine.medical_treatment, Hematopoietic stem cell transplantation, Cohort Studies, 0302 clinical medicine, conditioning, Immunology and Allergy, OUTCOMES, 0303 health sciences, Otros calificadores::Otros calificadores::/genética [Otros calificadores], Hematopoietic Stem Cell Transplantation, immune reconstitution, 3. Good health, surgical procedures, operative, medicine.anatomical_structure, Cohort, 2723 Immunology and Allergy, SURVIVAL, Malalties congènites, Unrelated Donors, medicine.medical_specialty, Immunology, 610 Medicine & health, pretransplantation infections, SCID, 03 medical and health sciences, Internal medicine, enfermedades y anomalías neonatales congénitas y hereditarias::enfermedades del recién nacido::inmunodeficiencia combinada grave [ENFERMEDADES], Other subheadings::Other subheadings::/genetics [Other subheadings], medicine, Humans, genetic subgroups, Interleukin-7 receptor, 030304 developmental biology, Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Infant, Newborn, Diseases::Severe Combined Immunodeficiency [DISEASES], 2403 Immunology, Severe combined immunodeficiency, Cèl·lules mare hematopoètiques - Trasplantació, business.industry, medicine.disease, Anti-thymocyte globulin, Transplantation, RECONSTITUTION, Graft-versus-host disease, 10036 Medical Clinic, 3121 General medicine, internal medicine and other clinical medicine, Severe Combined Immunodeficiency, Bone marrow, business, 030215 immunology
Abstract: Genetic subgroups; Immune reconstitution; Pretransplantation infections Subgrupos genéticos; Reconstitución inmune; Infecciones previas al trasplante Subgrups genètics; Reconstitució immune; Infeccions prèvies al trasplantament Background Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. Objective We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. Methods HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Results Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P < .001). The 2-year event-free survival (EFS) was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (P < .001). Genetic subgroups did not differ in 2-year OS (P = .1) and EFS (P = .073). In multivariate analysis, pretransplantation infections and use of MMRDs were associated with less favorable OS and EFS. With a median follow-up of 6.2 years (range, 2.0-11.8 years), 73 of 152 patients in the IR cohort were alive and well without Ig dependency. IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor–deficient SCID, myeloablative conditioning, matched donor HSCT, and naive CD4 T lymphocytes >0.5 × 10e3/μL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. Conclusion Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.
Published: 2022
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79. Is neutralization of IFN‐γ sufficient to control inflammation in HLH?

Author: Tatiana von Bahr Greenwood, Elisabet Bergsten, Kai Lehmberg, Alain Fischer, Jan-Inge Henter, Despina Moshous, Stephan Ehl, Kim E. Nichols, Gritta Janka, and Melissa Hines
Subjects: Inflammation, Oncology, business.industry, Pediatrics, Perinatology and Child Health, Immunology, Humans, Medicine, Hematology, medicine.symptom, business, Lymphohistiocytosis, Hemophagocytic, Neutralization
Published: 2021
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80. Marc Tardieu

Author: Alain Fischer
Published: 2021
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81. Préface

Author: Alain Fischer
Published: 2021
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82. A Monocyte/Dendritic Cell Molecular Signature of SARS-CoV-2 Related Multisystem Inflammatory Syndrome in Children (MIS-C) with Severe Myocarditis

Author: Camille de Cevins, Marine Luka, Nikaia Smith, Sonia Meynier, Aude Magérus, Francesco Carbone, Victor Garcia-Paredes, Laura Barnabei, Maxime Batignes, Alexandre Boullé, Marie-Claude Stolzenberg, Brieuc P. Pérot, Bruno Charbit, Tinhinane Fali, Vithura Pirabarakan, Boris Sorin, Quentin Riller, Ghaith Abdessalem, Maxime Beretta, Ludivine Grzelak, Pedro Goncalves, James Di Santo, Hugo Mouquet, Olivier Schwartz, Mohammed Zarhrate, Mélanie Parisot, Christine Bole-Feysot, Cécile Masson, Nicolas Cagnard, Aurelien Corneau, Camille Bruneau, Shen-Ying Zhang, Jean-Laurent Casanova, Brigitte Bader Meunier, Julien Haroche, Isabelle Melki, Mathie Lorrot, Mehdi Oualha, Florence Moulin, Damien Bonnet, Zahra Belhadjer, Mariane Leruez, Slimane Allali, Christele Gras Leguen, Loic de Pontual, Pediatric-Biocovid Study Group, Alain Fischer, Darragh Duffy, Frederic Rieux-Laucat, Julie Toubiana, and Mickaël Mathieu Ménager
Subjects: Gynecology, medicine.medical_specialty, Myocarditis, Coronavirus disease 2019 (COVID-19), business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Monocyte, education, Ethics committee, medicine.disease, medicine.anatomical_structure, Medicine, VEGF signaling, business
Abstract: SARS-CoV-2 infection in children is generally milder than in adults, yet a proportion of cases result in hyperinflammatory conditions often including myocarditis. To better understand these cases, we applied a multi-parametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. The most severe forms of MIS-C (multisystem inflammatory syndrome in children related to SARS-CoV-2), that resulted in myocarditis, were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomic analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis, characterized by sustained NF-κ B activity, TNF-α signaling, associated with decreased gene expression of NF-κ B inhibitors. We also found a weak response to type-I and type-II interferons, hyperinflammation and response to oxidative stress related to increased HIF-1α and VEGF signaling. These results provide potential for a better understanding of disease pathophysiology. Funding: The study was supported by the Institut National de la Sante et de la Recherche Medicale (INSERM), by the “URGENCE COVID-19” fundraising campaign of Institut Pasteur, by the Atip-Avenir, Emergence ville de Paris program and fond de dotation Janssen Horizon and by government grants managed by the Agence National de la Recherche as part of the “Investment for the Future” program (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01, Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010, Laboratoire d’Excellence ‘‘Milieu Interieur”, grant ANR-10-LABX-69-01), the Centre de Reference Deficits Immunitaires Hereditaires (CEREDIH), the Agence National de la Recherche (ANR-flash Covid19 “AIROCovid” to FRL and “CoVarImm” to DD and JDS), and by the FASTFoundation (French Friends of Sheba Tel Hashomer Hospital). The LabTech Single-Cell@Imagine is supported by the Paris Region and the “Investissements d’avenir” program through the 2019 ATF funding – Sesame Filieres PIA (Grant N°3877871).CdC is the recipient of a CIFRE-PhD (Sanofi). L.B. was a recipient of an Imagine institute PhD international program supported by the Fondation Bettencourt Schueller. L.B. was also supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) and is part of the Universite de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its“Investments for the Future” program. S.M. was a recipient of an INSERM and Institut Imagine post-doctorat program supported by the Fondation pour la Recherche Medicale (FRMN°SPF20170938825). NS was a recipient of the Pasteur-Roux-Cantarini Fellowship. VGP obtained an Imagine international PhD fellowship program supported by the Fondation Bettencourt Schueller. BPP is the recipient of an ANRS post-doctoral fellowship. Conflict of Interest: DD, FRL, JT and MMM are listed as inventors on a patent application related to this technology (European Patent Application no. EP21305197, entitled “Methods of predicting multisystem inflammatory syndrome (MIS-C) with severe myocarditis in subjects suffering from a SARS-CoV-2 infection”). Ethical Approval: The study was approved by the Ethics Committee (Comite de Protection des Personnes Ouest IV, n° DC-2017-2987).
Published: 2021
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83. List of Contributors

Author: Gregory Aaen, Israel F. Abroms, Ulrika Ådén, Gunnar Ahlsten, Robert B. Aird, Samiah A. Al-Zaidy, Fred Andermann, Banu Anlar, Alexis Arzimanoglou, Stephen Ashwal, Erika Augustine, Karen Ballaban-Gil, Nigel S. Bamford, Charles F. Barlow, Thomas Bast, David Bates, Robert J. Baumann, Enrico Bertini, Alidor Beya, Michael Blaw, John Bodensteiner, Daniel J. Bonthius, Amy E. Brin, Knut Brockmann, John Keith Brown, Stuart B. Brown, Audrey Christine Brumback, Michelle Bureau, James R. Burke, Annie Bye, Carol Camfield, Peter Camfield, Jaume Campistol Plana, Dee James Canale, Onasis Caneris, Roberto H. Caraballo, Alison Chantal Caviness, Hsiao-Tuan Chao, Catherine A. Chapman, Enrique Chaves-Carballo, Yoon-Jae Cho, Hans-Jürgen Christen, Harry T. Chugani, Giovanni Cioni, David Clark, Edward Robert Scheffer Cliff, Frederick B. Cochran, Bruce H. Cohen, Maynard M. Cohen, Kevin Collins, Athanasios Covanis, Macdonald Critchley, J. Helen Cross, Patricia K. Crumrine, Paolo Curatolo, Pamela A. Davies, Gabrielle deVeber, Darryl C. De Vivo, Linda S. de Vries, Liesbeth De Waele, William DeMyer, Anita Devlin, William B. Dobyns, W. Edwin Dodson, Kirsty Donald, Frank H. Duffy, David W. Dunn, Henry G. Dunn, Leon S. Dure, Paul Richard Dyken, Férechté Encha-Razavi, Gerald Erenberg, Melinda L. Estes, Philippe Evrard, Donna Ferriero, Peggy Ferry, Archie Fine, Edward J. Fine, John S. Fine, Richard S. Finkel, Alain Fischer, Christine Fischer, Lance Fogan, Glenn W. Fowler, Yitzchak Frank, Heather J. Fullerton, Tetsuo Furukawa, Ronald S. Gabriel, Aristea S. Galanopoulou, David Gardner-Medwin, Bhuwan Garg, Pierre Genton, Mark S. George, Thierry Gineste, Christopher C. Giza, Nathalie Goemans, Gerald S. Golden, Jeffrey Alan Golden, Gary W. Goldstein, Christopher Gomez, Manuel R. Gomez, Timothy Gomez, Howard P. Goodkin, Neil Gordon, Pierre Gressens, Helmut Groger, Renzo Guerrini, Christina A. Gurnett, Emanuela Gussoni, Richard Haas, Bengt Hagberg, Jerome S. Haller, Adam L. Hartman, Fred Haruda, Deborah Hirtz, Gwendolyn R. Hogan, Guy M. Hunt, Susan T. Iannaccone, Terrie Eleanor Inder, Victor Ionasescu, Katrien Jansen, Yuwu Jiang, Henry J. Kaminski, Shigehiko Kamoshita, Peter B. Kang, David M. Kaufman, Walter E. Kaufmann, Edward M. Kaye, Peter Kellaway, Rhona S. Kelley, Charles Kennedy, Young-Min Kim, Michael Kirby, Adam Kirton, Eliane Kobayashi, Eric H. Kossoff, Michail Koutroumanidis, Lauren Krupp, Bernadette M. Lange, Douglas J. Lanska, Mary Jo Lanska, Paul D. Larsen, Samuel J. Lassoff, John Laterra, Bernard Lemieux, Nicholas J. Lenn, William J. Logan, Elizabeth Lomax, Lawrence D. Longo, A. Lorris Betz, Bala V. Manyam, Warren A. Marks, E. Wayne Massey, Laszlo J. Mate, Ian McKinlay, William T. McLean, Ailsa McLellan, Mark F. Mehler, Johannes C. Melchior, David J. Michelson, Steven P. Miller, Suzanne L. Miller, J. Gordon Millichap, Robert A. Minns, Eli M. Mizrahi, Ann B. Moser, Solomon L. Moshé, Hiltrud Muhle, Francesco Muntoni, Sakkubai Naidu, Vinodh Narayanan, Nardo Nardocci, Jeffrey J. Neil, Ann Neumeyer, Michael J. Noetzel, Yoshiko Nomura, Douglas R. Nordli, Kathryn North, Yoko Ohtsuka, Finbar J.K. O’Callaghan, Roger J. Packer, Gregory M. Pastores, Marc C. Patterson, Phillip L. Pearl, Michel Philippart, Helena S. Pihko, Gordon Piller, Thomas F. Platz, Annapurna Poduri, Michael A. Pollack, Brenda E. Porter, Michèle Provis, Dietz Rating, Harold Reich, Bernd Remler, Jong M. Rho, Peter Richards, Edward P. Richardson, Sylvia O. Richardson, E. Steve Roach, Arthur L. Rose, Marvin P. Rozear, Lucien J. Rubinstein, Robert S. Rust, Arushi Gahlot Saini, Suzanne Saint-Anne Dargassies, Harvey B. Sarnat, Mohammad Sarwar, Richard Satran, Sanford Schneider, Waltraud Schrank, Rodney C. Scott, Syndi Seinfeld, Duygu Selcen, Nenad Sestan, Steven Shapiro, Elliott H. Sherr, Michael Shevell, Lloyd Shield, Richard L. Sidman, Faye S. Silverstein, Michael Sinnreich, O. Carter Snead, Regan Solomons, Emilio Soria-Duran, Carl E. Stafstrom, E. Steven Roach, Harold Stevens, Hans Michael Strassburg, David A. Stumpf, Thomas Sullivan, Herbert M. Swick, Charles N. Swisher, Takao Takahashi, Ingrid Tein, Laura Tochen, Eva E. Thomas, Alan Thompson, Svinder S. Toor, H. Richard Tyler, Peter Uldall, David K. Urion, Ahsan Moosa Naduvil Valappil, Ronald Van Toorn, Jennifer Vermilion, Doris Vidaver, Betty R. Vohr, Brigitte Vollmer, Joseph J. Volpe, Deborah P. Waber, Mark S. Wainwright, Lucius Waites, Christopher Walsh, Adolf Weindl, Mary Anne Whelan, Larry E. White, Vicky Holets Whittemore, Jo Wilmshurst, Elaine Wirrell, Nicole I. Wolf, Paul Youssef, John Zempel, Huda Y. Zoghbi, Sameer M. Zuberi, and Mary Zupanc
Published: 2021
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84. Coronavirus disease 2019 in patients with inborn errors of immunity: An international study

Author: Liliana Bezrodnik, Vijay G. Sankaran, Silvia Sánchez-Ramón, Peter Mustillo, Michael A. Keller, Isabelle Meyts, Giorgia Bucciol, Yesim Yilmaz Demirdag, Luis Ignacio Gonzalez-Granado, Andrew R. Gennery, Alexandra F. Freeman, Raffaele Badolato, Alain Fischer, Safa Baris, Federica Barzaghi, Sudhir Gupta, Carlo Agostini, Gulbu Uzel, Kissy Guevara-Hoyer, Isabella Quinti, M. Cecilia Poli, Charlotte Cunningham-Rundles, Stephen Jolles, Elif Karakoc-Aydiner, Alessandro Aiuti, Cinzia Milito, Fabian Hauck, Angel Robles-Marhuenda, Stuart G. Tangye, Marco Yamazaki-Nakashimada, Elena Seoane, Sara Elva Espinosa-Padilla, Pierre Yves Jeandel, Kathleen E. Sullivan, Klaus Warnatz, Claire Fieschi, Cedric Bosteels, Alessandro Plebani, Leonardo Oliveira Mendonça, Carla Gianelli, François Vermeulen, Bart N. Lambrecht, Annarosa Soresina, Virgil A. S. H. Dalm, Selma Scheffler-Mendoza, Catherine Paillard, Eduardo López-Granados, Vassilios Lougaris, Ahmet Ozen, Grant Hayman, Nizar Mahlaoui, Yazmin Espinosa, Bénédicte Neven, Giuseppe Spadaro, Roshini S. Abraham, Meyts, Isabelle, Bucciol, Giorgia, Quinti, Isabella, Neven, Bénédicte, Fischer, Alain, Seoane, Elena, Lopez-Granados, Eduardo, Gianelli, Carla, Robles-Marhuenda, Angel, Jeandel, Pierre-Yve, Paillard, Catherine, Sankaran, Vijay G, Demirdag, Yesim Yilmaz, Lougaris, Vassilio, Aiuti, Alessandro, Plebani, Alessandro, Milito, Cinzia, Dalm, Virgil Ash, Guevara-Hoyer, Kissy, Sánchez-Ramón, Silvia, Bezrodnik, Liliana, Barzaghi, Federica, Gonzalez-Granado, Luis Ignacio, Hayman, Grant R, Uzel, Gulbu, Mendonça, Leonardo Oliveira, Agostini, Carlo, Spadaro, Giuseppe, Badolato, Raffaele, Soresina, Annarosa, Vermeulen, Françoi, Bosteels, Cedric, Lambrecht, Bart N, Keller, Michael, Mustillo, Peter J, Abraham, Roshini S, Gupta, Sudhir, Ozen, Ahmet, Karakoc-Aydiner, Elif, Baris, Safa, Freeman, Alexandra F, Yamazaki-Nakashimada, Marco, Scheffler-Mendoza, Selma, Espinosa-Padilla, Sara, Gennery, Andrew R, Jolles, Stephen, Espinosa, Yazmin, Poli, M Cecilia, Fieschi, Claire, Hauck, Fabian, Cunningham-Rundles, Charlotte, Mahlaoui, Nizar, Warnatz, Klau, Sullivan, Kathleen E, Tangye, Stuart G, Meyts, I., Bucciol, G., Quinti, I., Neven, B., Fischer, A., Seoane, E., Lopez-Granados, E., Gianelli, C., Robles-Marhuenda, A., Jeandel, P. -Y., Paillard, C., Sankaran, V. G., Demirdag, Y. Y., Lougaris, V., Aiuti, A., Plebani, A., Milito, C., Dalm, V. A., Guevara-Hoyer, K., Sanchez-Ramon, S., Bezrodnik, L., Barzaghi, F., Gonzalez-Granado, L. I., Hayman, G. R., Uzel, G., Mendonca, L. O., Agostini, C., Spadaro, G., Badolato, R., Soresina, A., Vermeulen, F., Bosteels, C., Lambrecht, B. N., Keller, M., Mustillo, P. J., Abraham, R. S., Gupta, S., Ozen, A., Karakoc-Aydiner, E., Baris, S., Freeman, A. F., Yamazaki-Nakashimada, M., Scheffler-Mendoza, S., Espinosa-Padilla, S., Gennery, A. R., Jolles, S., Espinosa, Y., Poli, M. C., Fieschi, C., Hauck, F., Cunningham-Rundles, C., Mahlaoui, N., Warnatz, K., Sullivan, K. E., Tangye, S. G., Internal Medicine, Neven, Benedicte, Lopez-Grandos, Eduardo, Jeandel, Pierre-Yves, Sankaran, Vijay G., Lougaris, Vassilios, Dalm, Virgil A. S. H., Sanchez-Ramon, Silvia, Ignacio Gonzalez-Granado, Luis, Hayman, Grant R., Mendonca, Leonardo Oliveira, Vermeulen, Francois, Lambrecht, Bart N., Mustillo, Peter J., Abraham, Roshini S., Freeman, Alexandra F., Gennery, Andrew R., Poli, M. Cecilia, Warnatz, Klaus, Sullivan, Kathleen E., and Tangye, Stuart G.
Subjects: 0301 basic medicine, Male, inborn errors of immunity, X-CGD, X-linked chronic granulomatous disease, CGD, Chronic granulomatous disease, X-SCID, X-linked severe combined immunodeficiency, medicine.disease_cause, Severity of Illness Index, law.invention, HSCT, Hematopoietic stem cell transplantation, 0302 clinical medicine, law, Risk Factors, PID, Primary immunodeficiency, AIHA, Autoimmune hemolytic anemia, Medicine and Health Sciences, Immunology and Allergy, Child, Immunodeficiency, education.field_of_study, COVID-19, Coronavirus disease 2019, Middle Aged, Intensive care unit, ICU, Intensive care unit, Child, Preschool, ALPS, Autoimmune lymphoproliferative syndrome, Female, CVID, Common variable immune deficiency, primary immunodeficiencies, Adult, medicine.medical_specialty, IEI, Inborn errors of immunity, Adolescent, hypogammaglobulinemia, Population, Immunology, P, Patient, 03 medical and health sciences, Young Adult, immune dysregulation, Internal medicine, Intensive care, Severity of illness, medicine, Humans, education, Aged, Retrospective Studies, AR, Autosomal-recessive, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2, business.industry, SARS-CoV-2, AGS, Aicardi-Goutieres syndrome, Genetic Diseases, Inborn, Immunologic Deficiency Syndromes, Infant, Newborn, Infant, COVID-19, Retrospective cohort study, Immune dysregulation, medicine.disease, HLH, Hemophagocytic lymphohistiocytosis, 030104 developmental biology, Primary immunodeficiency, CID, Combined immunodeficiency, business, 030215 immunology
Abstract: BACKGROUND: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense. OBJECTIVE: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2. METHODS: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI. RESULTS: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died. CONCLUSIONS: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2. ispartof: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY vol:147 issue:2 pages:520-531 ispartof: location:United States status: published
Published: 2021

85. SOUS-CHAPITRE 9.3 Immunité anti-infectieuse innée et spécifique — Immunogénétique

Author: Alain Fischer, Jules Hoffmann, and Marc Bonneville
Published: 2020
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86. Safety and efficacy of brentuximab vedotin as a treatment for lymphoproliferative disorders in primary immunodeficiencies

Author: Morgane Cheminant, Felipe Suarez, Thomas Pincez, Elizabeth Macintyre, Laureline Berteloot, Julie Bruneau, Dominique Plantaz, Stéphane Blanche, Martin Castelle, Olivier Hermine, Ambroise Marçais, Bénédicte Neven, Alain Fischer, Eve Piekarski, Thierry Jo Molina, Nicolas Garcelon, Amélie Trinquand, Caroline Thomas, and Despina Moshous
Subjects: Oncology, Brentuximab Vedotin, medicine.medical_specialty, Immunoconjugates, business.industry, Hematopoietic stem cell, Lymphoproliferative disorders, Ki-1 Antigen, Hematology, medicine.disease, Lymphoproliferative Disorders, medicine.anatomical_structure, Treatment Outcome, Internal medicine, medicine, Humans, Brentuximab vedotin, business, Letters to the Editor, medicine.drug
Published: 2020

87. Rapid identification and characterization of infected cells in blood during chronic active Epstein-Barr virus infection

Author: Vincent Barlogis, David Boutboul, Thierry Jo Molina, Marion Malphettes, Martin Castelle, Felipe Suarez, Benjamin Fournier, Lionel Galicier, Despina Moshous, Isabelle Pellier, Sarah Winter, Julie Bruneau, Henri Jacques Delecluse, Cécile Boulanger, Bertrand Dunogué, Benjamin Terrier, Alain Fischer, Capucine Picard, Charline Miot, Bénédicte Neven, Sylvain Latour, Stephan Ehl, Stéphane Blanche, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique
Subjects: Adult, Male, Epstein-Barr Virus Infections, Herpesvirus 4, Human, Infectious disease and host defense, [SDV]Life Sciences [q-bio], T-Lymphocytes, Immunology, Cell, Lymphoproliferative disorders, Biology, Peripheral blood mononuclear cell, Technical Advances and Resources, Virus, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Plasma cell differentiation, medicine, Humans, Immunodeficiency, Immunology and Allergy, Child, Epstein–Barr virus infection, ComputingMilieux_MISCELLANEOUS, In Situ Hybridization, Fluorescence, 030304 developmental biology, B-Lymphocytes, 0303 health sciences, Viral Load, Flow Cytometry, medicine.disease, Phenotype, Lymphoproliferative Disorders, 3. Good health, Killer Cells, Natural, Leukemia & Lymphoma, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Chronic Disease, RNA, Viral, Female, Cytometry
Abstract: Diagnosis of EBV-driven T/NK-cell lymphoproliferative disorders and chronic active EBV diseases is often difficult. Fournier et al. report a flow-FISH cytometry assay allowing rapid identification of EBV-infected cells in blood and accurate diagnoses. It represents a powerful tool to study pathophysiological mechanisms of EBV-LPD., Epstein-Barr virus (EBV) preferentially infects epithelial cells and B lymphocytes and sometimes T and NK lymphocytes. Persistence of EBV-infected cells results in severe lymphoproliferative disorders (LPDs). Diagnosis of EBV-driven T or NK cell LPD and chronic active EBV diseases (CAEBV) is difficult, often requiring biopsies. Herein, we report a flow-FISH cytometry assay that detects cells expressing EBV-encoded small RNAs (EBERs), allowing rapid identification of EBV-infected cells among PBMCs. EBV-infected B, T, and/or NK cells were detectable in various LPD conditions. Diagnosis of CAEBV in 22 patients of Caucasian and African origins was established. All exhibited circulating EBV-infected T and/or NK cells, highlighting that CAEBV is not restricted to native American and Asian populations. Proportions of EBV-infected cells correlated with blood EBV loads. We showed that EBV-infected T cells had an effector memory activated phenotype, whereas EBV-infected B cells expressed plasma cell differentiation markers. Thus, this method achieves accurate and unambiguous diagnoses of different forms of EBV-driven LPD and represents a powerful tool to study their pathophysiological mechanisms.
Published: 2020
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88. Life-Saving, Dose-Adjusted, Targeted Therapy in a Patient with a STAT3 Gain-of-Function Mutation

Author: Eytan, Sarfati, Jérome, Hadjadj, Mathieu, Fusaro, Roman, Klifa, Marion, Grimaud, Laureline, Berteloot, Alice, Hadchouel, Cécile, Godot, Marie-Claude, Stolzenberg, Marie-Louise, Frémond, Claire, Pressiat, Thierry, Molina, Alain, Fischer, Capucine, Picard, Sylvain, Renolleau, Frederic, Rieux-Laucat, Stephane, Blanche, and Benedicte, Neven
Subjects: STAT3 Transcription Factor, Genotype, Disease Management, Phenotype, Treatment Outcome, Immune System Diseases, Gain of Function Mutation, Humans, Janus Kinase Inhibitors, Genetic Predisposition to Disease, Molecular Targeted Therapy, Tomography, X-Ray Computed, Alleles, Genetic Association Studies, Germ-Line Mutation
Published: 2020

89. Author response for 'Outcome of chronic granulomatous disease ‐ conventional treatment versus stem cell transplantation'

Author: Joachim Roesler, Jörn-Sven Kühl, Christian M. Hedrich, Nizar Mahlaoui, Alain Fischer, Johannes H. Schulte, Stéphane Blanche, Horst von Bernuth, Michael H. Albert, Cinzia Dedieu, Carsten Speckmann, Ulrich Baumann, Klaus Warnatz, and Fabian Hauck
Subjects: Transplantation, medicine.medical_specialty, Chronic granulomatous disease, business.industry, Internal medicine, Conventional treatment, Medicine, Stem cell, business, medicine.disease, Outcome (game theory), Gastroenterology
Published: 2020
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90. Outcome of chronic granulomatous disease - Conventional treatment vs stem cell transplantation

Author: Jörn-Sven Kühl, Joachim Roesler, Stéphane Blanche, Michael H. Albert, Nizar Mahlaoui, Carsten Speckmann, Alain Fischer, Johannes H. Schulte, Klaus Warnatz, Fabian Hauck, Ulrich Baumann, Horst von Bernuth, Cinzia Dedieu, and Christian M. Hedrich
Subjects: medicine.medical_specialty, conventional treatment, Transplantation Conditioning, Adolescent, medicine.medical_treatment, Immunology, Graft vs Host Disease, Hematopoietic stem cell transplantation, Disease, chronic granulomatous disease (CGD), Granulomatous Disease, Chronic, 03 medical and health sciences, 0302 clinical medicine, Chronic granulomatous disease, immune system diseases, Interquartile range, hemic and lymphatic diseases, medicine, Immunology and Allergy, Humans, In patient, 030212 general & internal medicine, Retrospective Studies, business.industry, fungal infection, Conventional treatment, Hematopoietic Stem Cell Transplantation, Infant, Newborn, hematopoietic stem cell transplantation (HSCT), medicine.disease, Surgery, Transplantation, surgical procedures, operative, Treatment Outcome, 030228 respiratory system, Child, Preschool, Pediatrics, Perinatology and Child Health, outcome, Stem cell, business, 600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
Abstract: Background: Hematopoietic stem cell transplantation (HSCT) can cure chronic granulomatous disease (CGD), but it remains debated whether all conventionally treated CGD patients benefit from HSCT. Methods: We retrospectively analyzed 104 conventionally treated CGD patients, of whom 50 patients underwent HSCT. Results: On conventional treatment, seven patients (13%) died after a median time of 16.2 years (interquartile range [IQR] 7.0-18.0). Survival without severe complications was 10 �� 3% (mean �� SD) at the age of 20 years; 85% of patients developed at least one infection, 76% one non-infectious inflammation. After HSCT, 44 patients (88%) were alive at a median follow-up of 2.3 years (IQR 0.8-4.9): Six patients (12%) died from infections. Survival after HSCT was significantly better for patients transplanted ��8 years (96 �� 4%) or for patients without active complications at HSCT (100%). Eight patients suffered from graft failure (16%); six (12%) developed acute graft-vs-host disease requiring systemic treatment. Conventionally treated patients developed events that required medical attention at a median frequency of 1.7 (IQR 0.8-3.2) events per year vs 0 (IQR 0.0-0.5) in patients beyond the first year post-HSCT. While most conventionally treated CGD patients failed to thrive, catch-up growth after HSCT in surviving patients reached the individual percentiles at the age of diagnosis of CGD. Conclusion: Chronic granulomatous disease patients undergoing HSCT until 8 years of age show excellent survival, but young children need more intense conditioning to avoid graft rejection. Risks and benefits of HSCT for adolescents and adults must still be weighed carefully.
Published: 2020

91. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Author: Aurélien Corneau, David Veyer, Tali Anne Szwebel, Nicolas Roche, Bruno Charbit, Darragh Duffy, Laura Barnabei, Hélène Péré, Flore Rozenberg, Nathalie Marin, Vincent Bondet, Benjamin Terrier, Pierre-Louis Tharaux, Solen Kernéis, Nader Yatim, Jeremy Boussier, Nikaïa Smith, Sarah H. Merkling, Alain Fischer, Nicolas Carlier, Frédéric Rieux-Laucat, Jean-Marc Treluyer, Camille Chenevier-Gobeaux, Paul Breillat, Rémy Gauzit, Luc Mouthon, Frédéric Pène, Jérôme Hadjadj, Caroline Morbieu, Catherine Blanc, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunogenetics of pediatric autoimmune diseases (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), Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Laboratoire de Virologie [Hôpital Européen Georges Pompidou - APHP], 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), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris] (IP), Diagnostic biologique automatisé [AP-HP Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Unité Equipe mobile d'Infectiologie [AP-HP Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Unité de Soins Intensifs [CHU Cochin], Interactions Virus-Insectes - Insect-Virus Interactions (IVI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Virologie [CHU Cochin], Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Epidémiologie et modélisation de la résistance aux antimicrobiens - Epidemiology and modelling of bacterial escape to antimicrobials (EMAE), Service de médecine interne et centre de référence des maladies rares [CHU Cochin], This study was supported by the Fonds IMMUNOV, for Innovation in Immunopathology. The study was also supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Institut Pasteur, by a government grant managed by the Agence National de la Recherche as part of the 'Investment for the Future' program (ANR-10-IAHU-01 and the Laboratoire d’Excellence ‘‘Milieu Intérieur', grant no. ANR-10-LABX-69-01), and by a grant from the Agence National de la Recherche (ANR-flash Covid19 'AIROCovid' to FRL and 'CoVarImm' to DD), and by the FAST Foundation (French Friends of Sheba Tel Hashomer Hospital). J.H. is a recipient of an Institut Imagine MD-PhD fellowship program supported by the Fondation Bettencourt Schueller. L.B. is supported by the EUR G.E.N.E. (reference #ANR-17-EURE-0013) program of the Université de Paris IdEx #ANR-18-IDEX-0001 funded by the French Government through its 'Investments for the Future' program., We acknowledge all health-care workers involved in the diagnosis and treatment of patients in Cochin Hospital, especially C. Azoulay L. Beaudeau, E. Canoui, P. Cohen, A. Contejean, B. Dunogué, D.Journois, P. Legendre, J. Marey and A. Régent. We thank Y. Gaudin for his advices on viral mechanism. We thank all the patients, supporters and our families for their confidence in our work., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Centre National de Référence Maladies auto-immunes Systémiques Rares [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-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)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Chaire Médecine expérimentale (A. Fischer)
Subjects: Male, 0302 clinical medicine, Interferon, T-Lymphocyte Subsets, 0303 health sciences, Multidisciplinary, biology, NF-kappa B, Interleukin, Middle Aged, Viral Load, 3. Good health, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Tumor necrosis factor alpha, Female, medicine.symptom, Coronavirus Infections, Viral load, medicine.drug, Signal Transduction, Adult, Critical Illness, Pneumonia, Viral, Alpha interferon, Inflammation, Interferon alpha-2, 03 medical and health sciences, Betacoronavirus, Immune system, medicine, Humans, Interleukin 6, Pandemics, 030304 developmental biology, Aged, business.industry, Interleukin-6, SARS-CoV-2, Tumor Necrosis Factor-alpha, Gene Expression Profiling, COVID-19, Interferon-alpha, Interferon-beta, Immunity, Innate, Cross-Sectional Studies, Immunology, biology.protein, business
Abstract: Interferons interfere with lung repair Interferons (IFNs) are central to antiviral immunity. Viral recognition elicits IFN production, which in turn triggers the transcription of IFN-stimulated genes (ISGs), which engage in various antiviral functions. Type I IFNs (IFN-α and IFN-β) are widely expressed and can result in immunopathology during viral infections. By contrast, type III IFN (IFN-λ) responses are primarily restricted to mucosal surfaces and are thought to confer antiviral protection without driving damaging proinflammatory responses. Accordingly, IFN-λ has been proposed as a therapeutic in coronavirus disease 2019 (COVID-19) and other such viral respiratory diseases (see the Perspective by Grajales-Reyes and Colonna). Broggi et al. report that COVID-19 patient morbidity correlates with the high expression of type I and III IFNs in the lung. Furthermore, IFN-λ secreted by dendritic cells in the lungs of mice exposed to synthetic viral RNA causes damage to the lung epithelium, which increases susceptibility to lethal bacterial superinfections. Similarly, using a mouse model of influenza infection, Major et al. found that IFN signaling (especially IFN-λ) hampers lung repair by inducing p53 and inhibiting epithelial proliferation and differentiation. Complicating this picture, Hadjadj et al. observed that peripheral blood immune cells from severe and critical COVID-19 patients have diminished type I IFN and enhanced proinflammatory interleukin-6– and tumor necrosis factor-α–fueled responses. This suggests that in contrast to local production, systemic production of IFNs may be beneficial. The results of this trio of studies suggest that the location, timing, and duration of IFN exposure are critical parameters underlying the success or failure of therapeutics for viral respiratory infections. Science , this issue p. 706 , p. 712 , p. 718 ; see also p. 626
Published: 2020
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92. Nocardiosis Associated with Primary Immunodeficiencies (Nocar-DIP): an International Retrospective Study and Literature Review

Author: Amit Rawat, Emmanuel Lafont, David Lebeaux, Olivier Lortholary, Stéphane Blanche, Miren Josebe Unzaga, Alain Fischer, Nizar Mahlaoui, Beatriz E. Marciano, Jacinta Bustamante, Steven M. Holland, Veronica Rodriguez-Nava, Bénédicte Neven, Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: 0301 basic medicine, medicine.medical_specialty, Pediatrics, Primary Immunodeficiency Diseases, Immunology, Nocardia Infections, Granulomatous Disease, Chronic, 03 medical and health sciences, 0302 clinical medicine, Medical microbiology, Chronic granulomatous disease, medicine, Immunology and Allergy, Humans, Public Health Surveillance, Registries, ComputingMilieux_MISCELLANEOUS, Nocardia farcinica, Retrospective Studies, biology, business.industry, Mortality rate, Incidence, Nocardiosis, Retrospective cohort study, Nocardia, medicine.disease, biology.organism_classification, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030104 developmental biology, Primary immunodeficiency, France, business, 030215 immunology
Abstract: Nocardiosis is a life-threatening infectious disease. We aimed at describing nocardiosis in patients with primary immunodeficiency diseases (PID). This international retrospective cohort included patients with PID and nocardiosis diagnosed and/or published from Jan 1, 2000, to Dec 31, 2016. To identify nocardiosis cases, we analyzed PID databases from the French National Reference Center for PID (Paris, France) and the National Institute of Health (NIH, United States of America) and we performed a literature review on PubMed. Forty-nine cases of nocardiosis associated with PID were included: median age at diagnosis of nocardiosis was 19 (0–56) years and most cases were observed among chronic granulomatous disease (CGD) patients (87.8%). Median time from symptoms to diagnosis of Nocardia infection was 20 (2–257) days. Most frequent clinical nocardiosis presentation was pneumonia (86.7%). Twelve-month mortality rate was 4.2%, and 11.9% of patients experienced a possible recurrence of infection. Nocardiosis more frequently led to the diagnosis of PID among non-CGD patients than in CGD patients. Non-CGD patients experienced more cerebral nocardiosis and more disseminated infections, but mortality and recurrence rates were similar. Highest incidences of nocardiosis among PID cohorts were observed among CGD patients (0.0057 and 0.0044 cases/patient-year in the USA and in France, respectively), followed by IL-12p40 deficiency. Among 49 cases of nocardiosis associated with PID, most patients had CGD and lung involvement. Both mortality and recurrence rates were low.
Published: 2020
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93. 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
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94. [What is the fair price of innovative therapy?]

Author: Alain, Fischer, Mathias, Dewatripont, and Michel, Goldman
Subjects: Biological Products, Social Responsibility, Biomedical Research, Drug Industry, Inventions, Therapies, Investigational, Humans, Genetic Therapy, Morals, Drug Costs, Health Services Accessibility
Abstract: L’innovation thérapeutique, à quel prix ?Comment préserver l’accessibilité aux nouveaux médicaments pour tous les patients qui en ont besoin ? La question se pose à la lumière des prix exorbitants auxquels les thérapies géniques, mais aussi les biothérapies et de nouvelles molécules chimiques, sont commercialisées. L’analyse montre qu’à court/moyen terme, l’arrivée sur le marché d’un nombre croissant de nouveaux traitements à haute valeur ajoutée mais à des prix très élevés deviendra insoutenable pour les organismes payeurs qui sous-tendent notre système de santé. Les arguments de rentabilité invoqués par les sociétés pharmaceutiques pour justifier les prix proposés sont à tout le moins contestables, d’autant plus qu’ils ne sont pas documentés de façon transparente et que cette industrie jouit déjà de marges bénéficiaires considérables, en comparaison de celles d’autres secteurs du monde économique. Quant aux promesses de guérison définitive assurée par certains traitements, il faudra encore attendre quelques années pour en vérifier le fondement. À l’aube d’une réforme qui apparaît incontournable, nous formulons plusieurs propositions pour faire avancer le débat, en particulier : (1) mettre en œuvre la résolution avancée par plusieurs états membres de l’Organisation mondiale de la santé (OMS) pour assurer la transparence des coûts de développement des nouveaux médicaments ; (2) imposer une clause de prix raisonnable dans les accords qui régissent le transfert de technologies entre les institutions académiques soutenues par des fonds publics et les entreprises privées ; (3) instituer une instance européenne commune de négociation des prix des médicaments adaptée aux conditions socioéconomiques de chaque pays ; (4) conditionner le remboursement des traitements innovants à leur commercialisation par des entreprises - ou des filiales de celles-ci - répondant à des normes certifiant leur responsabilité sociétale et (5) développer en Europe des partenariats public-privé à but non lucratif, pour la création de quelques unités de production de biothérapies et thérapies géniques. L’objectif général de ces mesures serait de fixer un cadre qui permette de définir des prix qui garantissent un juste retour de l’investissement public vers le système de santé tout en assurant pour les entreprises un profit d’un niveau conforme au marché et une incitation suffisante à investir dans les domaines prioritaires pour la santé publique.
Published: 2020

95. Primary Immunodeficiencies

Author: Alain Fischer, Durandy Anne, and Claude Griscelli
Published: 2020
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96. Impaired type I interferon activity and exacerbated inflammatory responses in severe Covid-19 patients

Author: Hélène Péré, Laura Barnabei, Luc Mouthon, Bruno Charbit, Jérôme Hadjadj, Nathalie Marin, Vincent Bondet, Jean-Marc Treluyer, Darragh Duffy, Aurélien Corneau, Caroline Morbieu, Remy Gauzit, Nader Yatim, Nikaïa Smith, Pierre-Louis Tharaux, Frédéric Rieux-Laucat, Camille Chenevier-Gobeaux, Tali-Anne Szwebel, Alain Fischer, Jeremy Boussier, Benjamin Terrier, Nicolas Carlier, Catherine Blanc, Paul Breillat, Frédéric Pène, Flore Rozenberg, Sarah H. Merkling, Nicolas Roche, Solen Kernéis, and David Veyer
Subjects: 0303 health sciences, Chemokine, education.field_of_study, Innate immune system, biology, business.industry, medicine.medical_treatment, Population, Interleukin, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cytokine, Interferon, 030220 oncology & carcinogenesis, Immunology, biology.protein, Medicine, Tumor necrosis factor alpha, business, education, 030304 developmental biology, medicine.drug
Abstract: BackgroundCoronavirus disease 2019 (Covid-19) is a major global threat that has already caused more than 100,000 deaths worldwide. It is characterized by distinct patterns of disease progression implying a diverse host immune response. However, the immunological features and molecular mechanisms involved in Covid-19 severity remain so far poorly known.MethodsWe performed an integrated immune analysis that included in-depth phenotypical profiling of immune cells, whole-blood transcriptomic and cytokine quantification on a cohort of fifty Covid19 patients with a spectrum of disease severity. All patient were tested 8 to 12 days following first symptoms and in absence of anti-inflammatory therapy.ResultsA unique phenotype in severe and critically ill patients was identified. It consists in a profoundly impaired interferon (IFN) type I response characterized by a low interferon production and activity, with consequent downregulation of interferon-stimulated genes. This was associated with a persistent blood virus load and an exacerbated inflammatory response that was partially driven by the transcriptional factor NFĸB. It was also characterized by increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 production and signaling as well as increased innate immune chemokines.ConclusionWe propose that type-I IFN deficiency in the blood is a hallmark of severe Covid-19 and could identify and define a high-risk population. Our study provides a rationale for testing IFN administration combined with adapted anti-inflammatory therapy targeting IL-6 or TNF-α in most severe patients. These data also raise concern for utilization of drugs that interfere with the IFN pathway.
Published: 2020
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97. Topoisomerase 2β mutation impairs early B-cell development

Author: Klaus Okkenhaug, Olivier Hermine, Ali Alisaac, Sven Kracker, Mailis Maes, Siobhan O. Burns, Anne Durandy, Eugenie Basseres, Adriana S. Albuquerque, Alain Fischer, Davide Eletto, Sarah Inglott, Olivier Papapietro, Anita Chandra, James Curtis, Vincent Plagnol, Capucine Picard, Sergey Nejentsev, Delphine Cuchet-Lourenço, Molecular cell biology and Immunology, and AII - Inflammatory diseases
Subjects: Male, Immunology, Biochemistry, Article, medicine, Humans, Poly-ADP-Ribose Binding Proteins, B cell, B-Lymphocytes, biology, Topoisomerase, Immunologic Deficiency Syndromes, Cell Biology, Hematology, Prognosis, Phenotype, Hematopoiesis, Pedigree, Haematopoiesis, DNA Topoisomerases, Type II, medicine.anatomical_structure, Mutation, Mutation (genetic algorithm), Cancer research, biology.protein, Female
Published: 2020
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98. Kinesin-1 regulates antigen cross-presentation through the scission of tubulations from early endosomes in dendritic cells

Author: Fernando E. Sepulveda, Jian-Dong Huang, Sophia Maschalidi, Geneviève de Saint Basile, Mathieu Kurowska, Alain Fischer, Peter van Endert, Nicolas Goudin, Gaël Ménasché, Meriem Belabed, François-Xavier Mauvais, Laboratory of Molecular Basis of Altered Immune Homeostasis [Paris], 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 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), Cell Imaging Facility [Paris], The University of Hong Kong (HKU), Immunology and Pediatric Hematology Department [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), This work was funded by INSERM, the ARC foundation (PJA 20161204628, PJA 20181207755), and La Ligue Contre le Cancer (JML/NF-RS17/75-2, RS19/75-1, RS20/75-1). M.B. received a doctoral fellowship from the Ministère de l’Education Nationale de la Recherche et de la Technologie and Imagine Thesis Award (2019). P.V.E. was funded by ANR-14-CE11-0014-01 and FRM DEQ20130326539. This work was supported by State funding from Agence Nationale de la Recherche under 'Investissement d’Avenir' programme (grant: ANR-10-IAHU-01)., ANR-14-CE11-0014,ENDOREG,Caractérisation d'endosomes régulateurs dans les cellules dendritiques et mastocytes(2014), Bodescot, Myriam, Appel à projets générique - Caractérisation d'endosomes régulateurs dans les cellules dendritiques et mastocytes - - ENDOREG2014 - ANR-14-CE11-0014 - Appel à projets générique - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Chaire Médecine expérimentale (A. Fischer)
Subjects: 0301 basic medicine, General Physics and Astronomy, Kinesins, Membrane trafficking, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Microtubules, environment and public health, 0302 clinical medicine, Neoplasms, lcsh:Science, Mice, Knockout, education.field_of_study, Antigen Presentation, Multidisciplinary, biology, Chemistry, Cross-presentation, Kinesin, Endocytosis, Cell biology, Vesicular transport protein, Endosome, Ovalbumin, Science, Population, Antigen-presenting cells, Bone Marrow Cells, Mice, Transgenic, Endosomes, macromolecular substances, Major histocompatibility complex, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Antigen, Antigens, CD, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Antigens, education, Cell Proliferation, Histocompatibility Antigens Class I, General Chemistry, Dendritic Cells, 030104 developmental biology, Solubility, biology.protein, lcsh:Q, Acids, 030217 neurology & neurosurgery
Abstract: Dendritic cells (DCs) constitute a specialized population of immune cells that present exogenous antigen (Ag) on major histocompatibility complex (MHC) class I molecules to initiate CD8 + T cell responses against pathogens and tumours. Although cross-presentation depends critically on the trafficking of Ag-containing intracellular vesicular compartments, the molecular machinery that regulates vesicular transport is incompletely understood. Here, we demonstrate that mice lacking Kif5b (the heavy chain of kinesin-1) in their DCs exhibit a major impairment in cross-presentation and thus a poor in vivo anti-tumour response. We find that kinesin-1 critically regulates antigen cross-presentation in DCs, by controlling Ag degradation, the endosomal pH, and MHC-I recycling. Mechanistically, kinesin-1 appears to regulate early endosome maturation by allowing the scission of endosomal tubulations. Our results highlight kinesin-1’s role as a molecular checkpoint that modulates the balance between antigen degradation and cross-presentation., Kinesin-1 is a motor protein transporting cargo along microtubules. Here the authors show that kinesin-1 is required for antigen cross-presentation and coordinates endosome scission from early endosomes to allow sorting internalized cargoes towards the recycling endosomal or lysosomal compartments.
Published: 2020
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99. Efficacy of ruxolitinib in subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis

Author: Fernando E. Sepulveda, Alain Fischer, Geneviève de Saint Basile, Romain Lévy, Mathieu Fusaro, Bénédicte Neven, Frédéric Guerin, Ahmed Chetouani, Despina Moshous, Chaire Médecine expérimentale (A. Fischer), and Collège de France (CdF (institution))
Subjects: 0301 basic medicine, Ruxolitinib, Panniculitis, Cyclophosphamide, Lymphoma, T-Cell, Lymphohistiocytosis, Hemophagocytic, 03 medical and health sciences, 0302 clinical medicine, Subcutaneous Panniculitis-Like T-Cell Lymphoma, hemic and lymphatic diseases, Nitriles, medicine, Humans, Myelofibrosis, ComputingMilieux_MISCELLANEOUS, Hemophagocytic lymphohistiocytosis, business.industry, Hematology, medicine.disease, 3. Good health, Lymphoma, Transplantation, 030104 developmental biology, Pyrimidines, 030220 oncology & carcinogenesis, Immunology, Prednisolone, [SDV.IMM]Life Sciences [q-bio]/Immunology, Pyrazoles, Exceptional Case Report, business, medicine.drug
Abstract: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a distinct subset of cutaneous lymphomas in which neoplastic cytotoxic α/β CD8+ T cells infiltrate subcutaneous adipose tissue.1-3 SPTCL may affect both children and adults.4 Systemic symptoms such as fever, asthenia, and weight loss, associated with cytopenias and liver dysfunction, are common. In addition, hemophagocytic lymphohistiocytosis (HLH) is observed in 20% of cases,3 which is associated with poor prognosis and may be the leading cause of death.3 There is no standardized therapy for SPTCL alone or in association with HLH. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone is frequently used, with an overall remission rate of 50%.1 Immunosuppressive regimens, particularly cyclosporine A (CsA), may be also effective.5 In some severe cases, stem cell transplantation has been attempted.1 Recently, germline mutations causing loss of function of T-cell immunoglobulin mucin 3 (TIM-3) were identified in 60% to 85% of SPTCL patients.6,7 In these patients, TIM-3 deficiency was shown to promote T-lymphocyte and -macrophage activation and the production of proinflammatory cytokines, challenging the malignant nature of skin T-lymphocyte infiltration.6 Ruxolitinib is a selective JAK1/JAK2 inhibitor licensed for treatment of myelofibrosis and polycythemia vera in adults.8,9 Studies in animal models of HLH support the efficacy of this drug to prevent and treat HLH in these models.10,11 Anecdotal experiences of successful use of ruxolitinib to control refractory primary HLH or secondary HLH are also reported in humans.12-19 JAK1/JAK2 inhibitors are also increasingly used in inflammatory diseases. We herein report the use and efficacy of ruxolitinib in a patient with recurrence of SPTCL and HLH and in whom TIM-3 deficiency was recently identified.6
Published: 2020
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100. Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation

Author: Tracy A Briggs, Emmanuel Martin, Sylvia Sanquer, Alain Fischer, Capucine Picard, Norbert Minet, Claire Soudais, Maria Leites-de-Moraes, Smita Y. Patel, Anne-Claire Boschat, Robert Wynn, Jean-Pierre de Villartay, Stephen M. Hughes, Tim Bourne, Sylvain Latour, Steicy Sobrino, Sophie Hambleton, Peter D. Arkwright, Monica G. Lawrence, Christelle Lenoir, Centre d'études spatiales de la biosphère (CESBIO), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Institut des Vaisseaux et du Sang, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie métabolique [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), 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), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Centre d'étude des Déficits Immunitaires, Génétique Humaine des Maladies Infectieuses (Inserm U980), Newcastle University [Newcastle], Nuffield Department of Surgery, University of Oxford [Oxford], Royal Manchester Children's Hospital, University of Manchester [Manchester], Dept Clin Biochem & Immunol, Cambridge University Hospitals NHS Foundation Trust, Addenbrookes Hospital, Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Leite de Moraes, Maria do Carmo, University Paris Descartes Sorbonne Paris Cité, Imagine Institute, Paris, University of Oxford, Magellium, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Chaire Médecine expérimentale (A. Fischer), and Collège de France (CdF (institution))
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Lymphocyte, T cell, T-cell leukemia, Lymphocytes/immunology, Lymphocyte Activation, Cell Line, Immunophenotyping, Frameshift mutation, Jurkat Cells, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, Carbon-Nitrogen Ligases, Lymphocytes, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Chemistry, Cell growth, Homozygote, Cell Differentiation, General Medicine, Natural killer T cell, Acquired immune system, Molecular biology, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Mutation, Carbon-Nitrogen Ligases/genetics, CRISPR-Cas Systems, Research Article
Abstract: International audience; Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1 T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1 T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1 T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1 T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.
Published: 2020
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