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1. Case report: Success of allogeneic hematopoietic stem cell transplantation for refractory systemic-onset juvenile idiopathic arthritis

Author: Camille Beaufils, Catherine Proulx, Annaliesse Blincoe, Pierre Teira, Henrique Bittencourt, Sonia Cellot, Michel Duval, Marie-Paule Morin, Jean Jacques De Bruycker, Julie Couture, Kathryn Samaan, Hélène Decaluwe, Niina Kleiber, Ramy El-Jalbout, Fabien Touzot, Elie Haddad, and Julie Barsalou
Subjects: systemic-onset juvenile idiopathic arthritis, juvenile idiopathic arthritis, pediatric rheumatic disease, allogeneic hematopoietic stem cell transplantation, bone marrow transplantation, Medicine (General), R5-920
Abstract: ObjectivesThis study reports cases of systemic-onset juvenile idiopathic arthritis (sJIA) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center and reviews published outcomes of allo-HSCT in sJIA.MethodsWe present a case report of two patients with sJIA who underwent allo-HSCT at a tertiary pediatric hospital. Each patient’s disease course and allo-HSCT protocol/outcome are described. Outcomes of published cases of allo-HSCT in sJIA were compared to our experience.ResultsTwo patients with sJIA had allo-HSCT. Both failed multiple lines of disease-modifying anti-rheumatic drugs and experienced severe disease/treatment-related complications. Despite post-HSCT complications, both recovered without sequelae. Five years post-HSCT, patient 1 is in complete remission (CR) and is off medications. Patient 2 was in CR until 11 months post-HSCT after which he developed three disease flares. At 4 years post-HSCT he is currently in CR on Adalimumab monotherapy. Engraftment was excellent with a donor chimerism of 100% for patient 1 and 93% for patient 2. In the literature, the outcome of allo-HSCT is reported in 13 sJIA patients. When merging those with our 2 patients, 1/15 patients died and 13/14 achieved CR, of which 12 are off medications (median [range] follow-up: 2.2 [0.2–7.0] years). Extended follow-up data on 11 of the 13 reported sJIA patients showed that an additional 3 patients flared at 3, 4, and 10 years post-HSCT.ConclusionWe report two patients with severe/refractory sJIA who underwent successful allo-HSCT and achieved CR. Allo-HSCT is a potential curative option for severe/refractory sJIA. It should be considered only after failure of conventional sJIA treatments and when an HLA-matched donor is available in order to lower transplant-related mortality. The outcomes of reported sJIA patients who received allo-HSCT are encouraging but long-term follow-up data are needed to better characterized the risk–benefit ratio of this procedure.
Published: 2023
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2. Epstein–Barr virus seroprevalence and viral load at disease onset in children with inflammatory bowel disease

Author: Gaël Kornitzer, Michelle Rosenstein, Marie‐Catherine Turcotte, David Godin, Véronique Groleau, Christian Renaud, Fabien Touzot, Prevost Jantchou, Philippe Ovetchkine, and Colette Deslandres
Subjects: Crohn's disease, Epstein–Barr virus, inflammatory bowel disease, ulcerative colitis, viral load, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Abstract Background and Aim Patients with inflammatory bowel disease (IBD) are at increased risk for life‐threatening complications of Epstein–Barr virus (EBV), including lymphoproliferative diseases. These complications are likely related to inherent immune dysfunction and immunomodulating therapies often used. We aimed to determine the seroprevalence of EBV at diagnosis in our population, its impact on disease at onset, and the risk of active EBV infection. Methods We included patients newly diagnosed with IBD for whom an EBV serology was performed over a 2‐year period. Demographic information and data on disease characteristics were collected retrospectively. Stored serum from the time of diagnosis was retrieved when available for the patients with positive EBV serology, and quantitative polymerase chain reaction testing was performed to assess the pre‐treatment viral load of EBV. Results One hundred twenty patients were included in the study. Fifty‐three patients (44.2%) had positive EBV serology at diagnosis. Stratified by age group, the prevalence of seropositive patients was for 0 to
Published: 2022
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3. Safety of CD34+ Hematopoietic Stem Cells and CD4+ T Lymphocytes Transduced with LVsh5/C46 in HIV-1 Infected Patients with High-Risk Lymphoma

Author: Marianne Delville, Fabien Touzot, Chloé Couzin, Isabelle Hmitou, Lounes Djerroudi, Amani Ouedrani, François Lefrère, Caroline Tuchman-Durand, Chloé Mollet, Jean-Roch Fabreguettes, Nicolas Ferry, Laurent Laganier, Alessandra Magnani, Elisa Magrin, Valérie Jolaine, Asier Saez-Cirion, Orit Wolstein, Geoffrey Symonds, Pierre Frange, Hélène Moins-Teisserenc, Marie-Laure Chaix-Baudier, Antoine Toubert, Jérôme Larghero, Nathalie Parquet, Anne C. Brignier, Françoise Barré-Sinoussi, Eric Oksenhendler, and Marina Cavazzana
Subjects: Genetics, QH426-470, Cytology, QH573-671
Abstract: Although the risk of developing lymphoma has decreased in the highly active antiretroviral therapy era, this cancer remains the major cause of mortality in HIV-infected patients. Autologous hematopoietic stem cell transplantation (ASCT) outcome does not differ for HIV-infected versus HIV-uninfected patients. We propose to develop a new treatment for HIV-associated high-risk lymphoma based on autologous transplantation of two genetically modified products: CD4+ T lymphocytes and CD34+ hematopoietic stem cells (HSPCs). The cells will be transduced ex vivo with the Cal-1 lentiviral vector encoding for both a short hairpin RNA (shRNA) against CCR5 (sh5) and the HIV-1 fusion inhibitor C46. The transduced cells will be resistant to HIV infection by two complementary mechanisms: impaired binding of the virus to the cellular CCR5 co-receptor and decreased fusion of the virus as C46 interacts with gp41 and inhibits HIV infection. This phase I/II pilot study, also entitled GENHIV, will involve two French participating centers: Saint Louis Hospital and Necker Hospital in Paris. We plan to enroll five HIV-1-infected patients presenting with high-risk lymphoma and require a treatment with ASCT. The primary objective of this study is to evaluate the safety, feasibility, and success of engraftment of Cal-1 gene-transduced CD4+ T lymphocytes and CD34+ HSPCs.
Published: 2019
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4. Extensive multilineage analysis in patients with mixed chimerism after allogeneic transplantation for sickle cell disease: insight into hematopoiesis and engraftment thresholds for gene therapy

Author: Alessandra Magnani, Corinne Pondarré, Naïm Bouazza, Jeremy Magalon, Annarita Miccio, Emmanuelle Six, Cecile Roudaut, Cécile Arnaud, Annie Kamdem, Fabien Touzot, Aurélie Gabrion, Elisa Magrin, Chloé Couzin, Mathieu Fusaro, Isabelle André, Jean-Paul Vernant, Eliane Gluckman, Françoise Bernaudin, Dominique Bories, and Marina Cavazzana
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Although studies of mixed chimerism following hematopoietic stem cell transplantation in patients with sickle cell disease (SCD) may provide insights into the engraftment needed to correct the disease and into immunological reconstitution, an extensive multilineage analysis is lacking. We analyzed chimerism simultaneously in peripheral erythroid and granulomonocytic precursors/progenitors, highly purified B and T lymphocytes, monocytes, granulocytes and red blood cells (RBC). Thirty-four patients with mixed chimerism and ≥12 months of follow-up were included. A selective advantage of donor RBC and their progenitors/precursors led to full chimerism in mature RBC (despite partial engraftment of other lineages), and resulted in the clinical control of the disease. Six patients with donor chimerism
Published: 2020
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5. Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

Author: Fabien Touzot, Laetitia Kermasson, Laurent Jullien, Despina Moshous, Christelle Ménard, Aydan Ikincioğullari, Figen Doğu, Sinan Sari, Vannina Giacobbi-Milet, Amos Etzioni, Jean Soulier, Arturo Londono-Vallejo, Alain Fischer, Isabelle Callebaut, Jean-Pierre de Villartay, Thierry Leblanc, Caroline Kannengiesser, and Patrick Revy
Subjects: Specialties of internal medicine, RC581-951
Abstract: Abstract: Telomeres are repetitive hexameric sequences located at the end of linear chromosomes. They adopt a lariat-like structure, the T-loop, to prevent them from being recognized as DNA breaks by the DNA repair machinery. RTEL1 is a DNA helicase required for proper telomere replication and stability. In particular, it has been postulated that RTEL1 is involved in the opening of the T-loop during telomere replication to avoid sudden telomere deletion and telomere circle (T-circle) formation. In humans, biallelic RTEL1 mutations cause Hoyeraal-Hreidarsson syndrome (HH), a rare and severe telomere biology disorder characterized by intrauterine growth retardation, bone marrow failure, microcephaly and/or cerebellar hypoplasia, and immunodeficiency. To date, 18 different RTEL1 mutations have been described in 19 cases of HH with short telomeres. The impaired T-loop resolution has been proposed to be a major cause of telomere shortening in RTEL1 deficiency. However, the biological and clinical consequences of this disorder remain incompletely documented. Here, we describe 4 new patients harboring biallelic RTEL1 mutations, including 2 novel missense mutations located in the C-terminal end of RTEL1 (p.Cys1268Arg and p.Val1294Phe). Clinical characteristics from these 4 patients were collected as those from 4 other RTEL1-deficient patients previously reported. In addition, we assessed whether T-circles, the product of improper T-loop resolution, were detected in our RTEL1-deficient patients. Overall, our study broadens and refines the clinical and biological spectrum of human RTEL1 deficiency.
Published: 2016
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6. Rapamycin as an Adjunctive Therapy for NLRC4 Associated Macrophage Activation Syndrome

Author: Julie Barsalou, Annaliesse Blincoe, Isabel Fernandez, Dorothée Dal-Soglio, Lorie Marchitto, Silvia Selleri, Elie Haddad, Aissa Benyoucef, and Fabien Touzot
Subjects: macrophage activation syndrome, NLRC4, inflammasome, mTOR, rapamycin, IL-18, Immunologic diseases. Allergy, RC581-607
Abstract: Gain of function (GOF) mutations affecting the inflammasome component NLRC4 are known to cause early-onset macrophage activation syndrome (MAS) and neonatal enterocolitis. Here we report a patient with a NLRC4 GOF mutation presenting with neonatal MAS efficiently treated with a combination of anakinra and rapamycin. Through in vitro studies, we show that rapamycin reduces both IL-1β and IL-18 secretion by the patient's phagocytic cells. The reduction of cytokine secretion is associated with a reduction of caspase-1 activation regardless of the pathogen- or danger-associated molecular patterns triggering the activation of the inflammasome. This study suggests that patients with inherited auto-inflammatory disorders could benefit from an adjunctive therapy with rapamycin.
Published: 2018
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7. Very Early-Onset Inflammatory Manifestations of X-Linked Chronic Granulomatous Disease

Author: Roxane Labrosse, Jane Abou-Diab, Annaliesse Blincoe, Guilhem Cros, Thuy Mai Luu, Colette Deslandres, Martha Dirks, Laura Fazilleau, Philippe Ovetchkine, Pierre Teira, Françoise LeDeist, Isabel Fernandez, Fabien Touzot, Helene Decaluwe, Ugur Halac, and Elie Haddad
Subjects: chronic granulomatous disease, X-linked, gastric outlet obstruction, colitis, eosinophilia, Mycobacterium avium, Immunologic diseases. Allergy, RC581-607
Abstract: Chronic granulomatous disease (CGD) is a rare primary immune deficiency caused by mutations in genes coding for components of the nicotinamide adenine dinucleotide phosphate oxidase, characterized by severe and recurrent bacterial and fungal infections, together with inflammatory complications. Dysregulation of inflammatory responses are often present in this disease and may lead to granulomatous lesions, most often affecting the gastrointestinal (GI) and urinary tracts. Treatment of inflammatory complications usually includes corticosteroids, whereas antimicrobial prophylaxis is used for infection prevention. Curative treatment of both infectious susceptibility and inflammatory disease can be achieved by hematopoietic stem cell transplantation. We report herein three patients with the same mutation of the CYBB gene who presented with very early-onset and severe GI manifestations of X-linked CGD. The most severely affected patient had evidence of antenatal inflammatory involvement of the GI and urinary tracts. Extreme hyperleukocytosis with eosinophilia and high inflammatory markers were observed in all three patients. A Mycobacterium avium lung infection and an unidentified fungal lung infection occurred in two patients both during their first year of life, which is indicative of the severity of the disease. All three patients underwent bone marrow transplantation and recovered fully from their initial symptoms. To our knowledge, these are the first reports of patients with such an early-onset and severe inflammatory manifestations of CGD.
Published: 2017
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8. <scp>Epstein–Barr</scp> virus seroprevalence and viral load at disease onset in children with inflammatory bowel disease

Author: Gaël Kornitzer, Michelle Rosenstein, Marie‐Catherine Turcotte, David Godin, Véronique Groleau, Christian Renaud, Fabien Touzot, Prevost Jantchou, Philippe Ovetchkine, and Colette Deslandres
Subjects: Hepatology, Gastroenterology
Abstract: Patients with inflammatory bowel disease (IBD) are at increased risk for life-threatening complications of Epstein-Barr virus (EBV), including lymphoproliferative diseases. These complications are likely related to inherent immune dysfunction and immunomodulating therapies often used. We aimed to determine the seroprevalence of EBV at diagnosis in our population, its impact on disease at onset, and the risk of active EBV infection.We included patients newly diagnosed with IBD for whom an EBV serology was performed over a 2-year period. Demographic information and data on disease characteristics were collected retrospectively. Stored serum from the time of diagnosis was retrieved when available for the patients with positive EBV serology, and quantitative polymerase chain reaction testing was performed to assess the pre-treatment viral load of EBV.One hundred twenty patients were included in the study. Fifty-three patients (44.2%) had positive EBV serology at diagnosis. Stratified by age group, the prevalence of seropositive patients was for 0 to10 years 35%, 10 to17 years 46%, and ≥17 years 50%. Overall, therapies started within 6 months of diagnosis were similar in both the seropositive and seronegative groups. Within the seropositive group, 66% received systemic corticosteroids, 32.1% infliximab, 5.7% adalimumab, and 5.7% azathioprine.EBV seroprevalence is high in pediatric patients with IBD. EBV seropositivity did not seem to influence the severity of disease at onset or initial choice of therapy.
Published: 2022
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9. Lupus Vulgaris Revealing an IκBα Gain of Function Variant

Author: Bruce Tapiero, Catherine Maari, Victor Kokta, Isabel Fernandez, and Fabien Touzot
Subjects: Immunology, Immunology and Allergy
Published: 2022
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10. Hematopoietic Cell Transplantation in 240 Patients with Chronic Granulomatous Disease: A Pidtc Report

Author: Danielle E. Arnold, Suhag Parikh, Brent Logan, Rebecca Marsh, Linda M. Griffith, Ruizhe Wu, Kanwaldeep Mallhi, Deepak Chellapandian, Stephanie Si, Eyal Grunebaum, Larisa Broglie, Vinod K. Prasad, Jennifer Heimall, Nancy J. Bunin, Pierre Teira, Fabien Touzot, Lauri M. Burroughs, Aleksandra Petrovic, Jack J. Bleesing, Sharat Chandra, Neena Kapoor, Jasmeen Dara, Morna Dorsey, Olatundun Williams, Malika Kapadia, Jeffrey Bednarski, Ahmad Rayes, Karin Chen, Hey Chong, Geoff D.E. Cuvelier, Lisa R. Forbes, Caridad Martinez, Mark T. Vander Lugt, Lolie C. Yu, Shanmuganathan Chandrakasan, Avni Joshi, Susan E. Prockop, Blachy J. Davila Saldana, Victor Aquino, Christen L. Ebens, Lisa Madden, Kenneth DeSantes, Jordan Milner, Hemalatha G. Rangarajan, Ami J Shah, Alfred P. Gillio, Alan P. Knutsen, Holly K. Miller, Theodore B. Moore, Nicola Wright, Morton J. Cowan, Christopher C. Dvorak, Elie Haddad, Donald B. Kohn, Luigi D. Notarangelo, Sung-Yun Pai, Jennifer Puck, Mike A. Pulsipher, Troy Torgerson, Harry L. Malech, Elizabeth M. Kang, and Jennifer W. Leiding
Subjects: Transplantation, Molecular Medicine, Immunology and Allergy, Cell Biology, Hematology
Published: 2022
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11. Allogenic Hematopoietic Cell Transplantations Are Effective in Patients with p47phox Chronic Granulomatous Disease: A Primary Immune Deficiency Treatment Consortium Study

Author: Eyal Grunebaum, Danielle E. Arnold, Brent Logan, Suhag Parikh, Rebecca A. Marsh, Linda M. Griffith, Kanwaldeep Mallhi, Deepak Chellapandian, Stephanie Si Lim, Christin L. Deal, Luis Murguía-Favela, Talal I. Mousallem, Prof. Vinod K. Prasad, Pierre Teira, Fabien Touzot, Nancy J. Bunin, Jennifer R. Heimall, Lauri M. Burroughs, Malika Kapadia, Susan Prockop, Sharat Chandra, Shanmuganathan Chandrakasan, Sonali Chaudhury, Larisa Broglie, Richard J. O’Reilly, Blachy J. Dávila Saldaña, Edo Schaefer, Hey Chong, Jeffrey J. Bednarski, Ahmad Rayes, Kenneth DeSantes, Donald B. Kohn, Luigi D. Notarangelo, Sung-Yun Pai, Jennifer Puck, Troy Torgerson, Morton J. Cowan, Christopher C. Dvorak, Lisa Forbes Satter, Elie Haddad, Michael Pulsipher, Harry L. Malech, Elizabeth M. Kang, and Jennifer W. Leiding
Subjects: Transplantation, Molecular Medicine, Immunology and Allergy, Cell Biology, Hematology
Published: 2023
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12. Idiopathic Acute Eosinophilic Pneumonia

Author: Fabien Touzot, Brigitte Bader-Meunier, Christophe Delacourt, Alice Hadchouel, Jean Bergounioux, Laure De Saint Blanca, and Philippe Hubert
Subjects: Pulmonary and Respiratory Medicine, Pediatrics, medicine.medical_specialty, Pathology, medicine.diagnostic_test, business.industry, Corticosteroid treatment, Acute respiratory distress, respiratory system, Lung injury, respiratory tract diseases, Acute hypoxia, Bronchoalveolar lavage, Respiratory failure, Pediatrics, Perinatology and Child Health, Immunology and Allergy, Medicine, Idiopathic acute eosinophilic pneumonia, business, Pulmonary Eosinophilia
Abstract: Idiopathic acute eosinophilic pneumonia (IAEP) is characterized by febrile hypoxic respiratory failure with diffuse radiographic infiltrates and peripheral and pulmonary eosinophilia in a previously healthy child. Diagnosis is by exclusion, but promptness is imperative, as IAEP can lead to life-threatening acute lung injury and acute respiratory distress syndrome. Prognosis is usually good after steroid treatment with total recovery and absence of relapse in reported cases. We report a case of a previously healthy 14-year-old boy with this diagnosis who presented with acute hypoxia and characteristic radiographic and bronchoalveolar lavage findings. He had full recovery after corticosteroid treatment. This case report highlights the diagnostic approach to a patient with IAEP, an uncommon diagnosis, and one of the exclusions, in children.
Published: 2022

13. Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

Author: Steicy Sobrino, Alessandra Magnani, Michaela Semeraro, Loredana Martignetti, Akira Cortal, Adeline Denis, Chloé Couzin, Capucine Picard, Jacinta Bustamante, Elisa Magrin, Laure Joseph, Cécile Roudaut, Aurélie Gabrion, Tayebeh Soheili, Corinne Cordier, Olivier Lortholary, François Lefrere, Frédéric Rieux-Laucat, Jean-Laurent Casanova, Sylvain Bodard, Nathalie Boddaert, Adrian J. Thrasher, Fabien Touzot, Sophie Taque, Felipe Suarez, Ambroise Marcais, Agathe Guilloux, Chantal Lagresle-Peyrou, Anne Galy, Antonio Rausell, Stephane Blanche, Marina Cavazzana, and Emmanuelle Six
Subjects: General Biochemistry, Genetics and Molecular Biology
Published: 2023
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14. Innovative Curative Treatment of Beta Thalassemia: Cost-Efficacy Analysis of Gene Therapy Versus Allogenic Hematopoietic Stem-Cell Transplantation

Author: Etienne Lissillour, Fabien Touzot, Semir Benaouadi, Setti Rais, Lise Rochaix, Pierre Taupin, Mariem Ghardallou, Thomas Brice, Laure Boquet, S. Coquerelle, Isabelle Durand-Zaleski, Elisa Magrin, Stéphane Blanche, Caroline Tuchmann-Durand, Marina Cavazzana, and Jean Antoine Ribeil
Subjects: medicine.medical_specialty, Adolescent, Total cost, Cost-Benefit Analysis, medicine.medical_treatment, Genetic enhancement, Genetic Vectors, Graft vs Host Disease, Hematopoietic stem cell transplantation, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, Genetics, medicine, Humans, Transplantation, Homologous, Vector (molecular biology), Child, Molecular Biology, Retrospective Studies, 030304 developmental biology, Clinical Trials as Topic, 0303 health sciences, business.industry, beta-Thalassemia, Hematopoietic Stem Cell Transplantation, Infant, Beta thalassemia, Retrospective cohort study, Genetic Therapy, Health Care Costs, Prognosis, medicine.disease, Tissue Donors, Transplantation, Treatment Outcome, Curative treatment, Child, Preschool, 030220 oncology & carcinogenesis, Molecular Medicine, business
Abstract: Seventy-five percent of patients with beta thalassemia (β-thalassemia) do not have human leukocyte antigen-matched siblings and until recently had no access to a curative treatment. Gene therapy is a promising treatment that can be proposed to these patients. This study estimates its cost and efficacy. In a monocentric retrospective study and cost-efficacy analysis, this study compared the two-year outcomes and costs of patients with β-thalassemia treated by gene therapy and hematopoietic stem-cell transplantation (HSCT). Grade III and grade IV complications, hospitalizations, and length of stay were extracted from the hospital discharge data. Costs were estimated from hospital accounting information and national cost studies. A total of seven patients with β-thalassemia treated between 2009 and 2016 were included, of whom four received gene therapy. Patients treated by gene therapy were older and had fewer complications and hospital admissions. Infectious complications were three times more frequent for patients treated with HSCT than for gene therapy. Average costs were €608,086 for patients treated by gene therapy and €215,571 for HSCT. The total cost of the vector was 48% of the total cost of gene therapy. Gene therapy as a curative alternative for patients lacking human leukocyte antigen-matched donors was costlier but resulted in fewer complications than HSCT.
Published: 2019
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15. Successful in utero stem cell transplantation in X-linked severe combined immunodeficiency

Author: Aurélie Gabrion, Elisabeth A. Macintyre, Emmanuel Clave, Anne-Marie Darras, Alessandra Magnani, Stéphane Blanche, Brigitte Ternaux, Antoine Toubert, Capucine Picard, Marina Cavazzana, Cécile Roudaut, Laure Caccavelli, Jérémie Rosain, Elisa Magrin, Nizar Mahlaoui, Jennifer Nisoy, Fabien Touzot, Marion Alcantara, Isabelle Radford-Weiss, Jean-Marie Jouannic, Sven Kracker, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre pluridisciplinaire de diagnostic prénatal [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], CHU Necker - Enfants Malades [AP-HP], Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: Transplantation Conditioning, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Hematopoietic stem cell transplantation, X-Linked Combined Immunodeficiency Diseases, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, X-linked severe combined immunodeficiency, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Severe combined immunodeficiency, business.industry, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Stimulus Report, 3. Good health, Transplantation, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, In utero, Child, Preschool, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Bone marrow, Stem cell, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Key Points IUT enables rapid immune reconstitution and avoids many clinical and economic problems; however, the indication is still limited. IUT may be a treatment option in select cases, eg, fetuses exposed to a significant infectious risk, where a matched sibling donor exists.
Published: 2019
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16. Successful management of familial hemophagocytic lymphohistiocytosis by the JAK 1/2 inhibitor ruxolitinib

Author: Pierre Teira, Marie-Paule Morin, Isabel Fernandez, Sonia Cellot, Elie Haddad, Michel Duval, Louis Marois, Jean Jacques De Bruycker, Fabien Touzot, Hélène Decaluwe, and Henrique Bittencourt
Subjects: Oncology, medicine.medical_specialty, Ruxolitinib, Janus kinase 1, business.industry, MEDLINE, Hematology, Familial Hemophagocytic Lymphohistiocytosis, Lymphohistiocytosis, Hemophagocytic, Pyrimidines, Internal medicine, Pediatrics, Perinatology and Child Health, Nitriles, medicine, Humans, Pyrazoles, business, medicine.drug
Published: 2021

17. Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects

Author: Laëtitia Kermasson, Dmitri Churikov, Aya Awad, Riham Smoom, Elodie Lainey, Fabien Touzot, Séverine Audebert-Bellanger, Sophie Haro, Lauréline Roger, Emilia Costa, Maload Mouf, Adriana Bottero, Matias Oleastro, Chrystelle Abdo, Jean-Pierre de Villartay, Vincent Géli, Yehuda Tzfati, Isabelle Callebaut, Silvia Danielian, Gabriela Soares, Caroline Kannengiesser, Patrick Revy, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), Alexander Silberman Institute of Life Science, The Hebrew University of Jerusalem (HUJ), Hôpital Robert Debré, CHU Sainte Justine [Montréal], Hôpital Morvan - CHRU de Brest (CHU - BREST ), Muséum national d'Histoire naturelle (MNHN), Centro Hospitalar Universitário do Porto, Hospital Nacional de Pediatría Prof. Dr Juan P. Garrahan [Buenos Aires], Hospital Nacional de Pediatría J.P. Garrahan, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), 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), 'Juan Pedro Garrahan' National Hospital of Pediatrics, Buenos Aires, Centro de Genética Jacinto Magalhães [Porto], Hospital de São João [Porto], AP-HP - Hôpital Bichat - Claude Bernard [Paris], and ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018)
Subjects: Fetal Growth Retardation, [SDV]Life Sciences [q-bio], Intellectual Disability, Immunology, Mutation, Microcephaly, Humans, Cell Biology, Hematology, Telomere, Biochemistry, Dyskeratosis Congenita
Abstract: Inherited bone marrow failure syndromes (IBMFSs) are a group of disorders typified by impaired production of 1 or several blood cell types. The telomere biology disorders dyskeratosis congenita (DC) and its severe variant, Høyeraal-Hreidarsson (HH) syndrome, are rare IBMFSs characterized by bone marrow failure, developmental defects, and various premature aging complications associated with critically short telomeres. We identified biallelic variants in the gene encoding the 5′-to-3′ DNA exonuclease Apollo/SNM1B in 3 unrelated patients presenting with a DC/HH phenotype consisting of early-onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation. All 3 patients carry a homozygous or compound heterozygous (in combination with a null allele) missense variant affecting the same residue L142 (L142F or L142S) located in the catalytic domain of Apollo. Apollo-deficient cells from patients exhibited spontaneous chromosome instability and impaired DNA repair that was complemented by CRISPR/Cas9-mediated gene correction. Furthermore, patients’ cells showed signs of telomere fragility that were not associated with global reduction of telomere length. Unlike patients’ cells, human Apollo KO HT1080 cell lines showed strong telomere dysfunction accompanied by excessive telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. Collectively, these findings define human Apollo as a genome caretaker and identify biallelic Apollo variants as a genetic cause of a hitherto unrecognized severe IBMFS that combines clinical hallmarks of DC/HH with normal telomere length.
Published: 2021
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18. Long-term outcomes of lentiviral gene therapy for the β-hemoglobinopathies: the HGB-205 trial

Author: Elisa Magrin, Michaela Semeraro, Nicolas Hebert, Laure Joseph, Alessandra Magnani, Anne Chalumeau, Aurélie Gabrion, Cécile Roudaut, Jouda Marouene, Francois Lefrere, Jean-Sebastien Diana, Adeline Denis, Bénédicte Neven, Isabelle Funck-Brentano, Olivier Negre, Sylvain Renolleau, Valentine Brousse, Laurent Kiger, Fabien Touzot, Catherine Poirot, Philippe Bourget, Wassim El Nemer, Stéphane Blanche, Jean-Marc Tréluyer, Mohammed Asmal, Courtney Walls, Yves Beuzard, Manfred Schmidt, Salima Hacein-Bey-Abina, Vahid Asnafi, Isabelle Guichard, Maryline Poirée, Fabrice Monpoux, Philippe Touraine, Chantal Brouzes, Mariane de Montalembert, Emmanuel Payen, Emmanuelle Six, Jean-Antoine Ribeil, Annarita Miccio, Pablo Bartolucci, Philippe Leboulch, and Marina Cavazzana
Subjects: Male, Young Adult, Treatment Outcome, Adolescent, Lentivirus, beta-Thalassemia, Humans, Female, General Medicine, Anemia, Sickle Cell, Genetic Therapy, General Biochemistry, Genetics and Molecular Biology
Abstract: Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34
Published: 2020

19. Neuroinflammatory disease as an isolated manifestation of hemophagocytic lymphohistiocytosis

Author: Salah Ali, Yenan T. Bryceson, Marina Garcia-Prat, Maximilian Heeg, Jeffrey J. Bednarski, Carsten Speckmann, Jelena Rascon, Viktorija Kenina, Annaliesse Blincoe, Melissa Hines, Rebecca A. Marsh, Elie Haddad, Julie-An Talano, Anne Lortie, Patrick Campbell, Natalja Kurjane, Geertje E. Legger, Amer Khojah, Fabien Touzot, yasmine El Chazli, Julia T. Warren, Erica G. Schmitt, Marisa Klein-Gitelman, Stephan Ehl, Laura C. Alonso, Austen Worth, Maria C. Putti, Joerg Krueger, Evangeline Wassmer, Jacques G. Rivière, Kai Lehmberg, Itziar Astigarraga, Gal Goldstein, Kuang-Yueh Chiang, Inita Bulina, Claire Booth, Arjan C. Lankester, Michael M. Henry, Sarah Maier, Marwa Abd El-Maksoud, and Steven M. Holland
Subjects: Male, PRF1, Biopsy, CHILDREN, Gastroenterology, Leukoencephalopathy, Immunology and Allergy, Age of Onset, Child, CNS disease, Hematopoietic Stem Cell Transplantation, NERVOUS-SYSTEM INVOLVEMENT, Familial Hemophagocytic Lymphohistiocytosis, Magnetic Resonance Imaging, PERFORIN, Phenotype, Child, Preschool, Disease Progression, Female, GENOTYPE-PHENOTYPE, Symptom Assessment, medicine.symptom, Encephalitis, Adult, medicine.medical_specialty, Ataxia, Adolescent, Genotype, Immunology, Neuroimaging, FREQUENCY, Lymphohistiocytosis, Hemophagocytic, Young Adult, MUNC13-4, Internal medicine, Familial hemophagocytic lymphohistiocytosis, medicine, Humans, Genetic Predisposition to Disease, UNC13D, Alleles, Cytopenia, Hemophagocytic lymphohistiocytosis, SPECTRUM, therapy, business.industry, MUTATIONS, Multiple sclerosis, Infant, medicine.disease, CNS inflammation, Mutation, ONSET, business, Biomarkers
Abstract: Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.
Published: 2020

20. Multicentric Castleman disease revealing complete signal transducer and activator of transcription 1 deficiency treated by JAK1/2 inhibition

Author: Jean-Jacques De Bruycker, Camille Beaufils, Jean-François Soucy, Philippe Ovetchkine, Luc L. Oligny, Marie-Paule Morin, Sonia Cellot, Isabel Fernandez, Elie Haddad, Lorie Marchitto, and Fabien Touzot
Subjects: STAT3 Transcription Factor, Hemophagocytic lymphohistiocytosis, Ruxolitinib, business.industry, Castleman Disease, Janus Kinase 1, medicine.disease, STAT1 Transcription Factor, Cancer research, medicine, STAT protein, Primary immunodeficiency, Humans, Immunology and Allergy, Multicentric Castleman Disease, business, medicine.drug
Published: 2021
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21. CRISPR gene-engineered CYBB

Author: Aissa, Benyoucef, Lorie, Marchitto, and Fabien, Touzot
Subjects: Inflammation, Phagocytes, Base Sequence, Inflammasomes, THP-1 Cells, Macrophages, NADPH Oxidases, Granulomatous Disease, Chronic, Cell Line, Mutation, NADPH Oxidase 2, Humans, Clustered Regularly Interspaced Short Palindromic Repeats, Female, Reactive Oxygen Species, NADP
Published: 2019

22. Extensive multilineage analysis in patients with mixed chimerism after allogeneic transplantation for sickle cell disease: insight into hematopoiesis and engraftment thresholds for gene therapy

Author: Alessandra, Magnani, Corinne, Pondarré, Naïm, Bouazza, Jeremy, Magalon, Annarita, Miccio, Emmanuelle, Six, Cecile, Roudaut, Cécile, Arnaud, Annie, Kamdem, Fabien, Touzot, Aurélie, Gabrion, Elisa, Magrin, Chloé, Couzin, Mathieu, Fusaro, Isabelle, André, Jean-Paul, Vernant, Eliane, Gluckman, Françoise, Bernaudin, Dominique, Bories, and Marina, Cavazzana
Subjects: Transplantation Chimera, Red Cell BIology & its Disorders, Hematopoietic Stem Cell Transplantation, Humans, Transplantation, Homologous, Anemia, Sickle Cell, Genetic Therapy, Articles, Chimerism, Hematopoiesis
Abstract: Although studies of mixed chimerism following hematopoietic stem cell transplantation in patients with sickle cell disease (SCD) may provide insights into the engraftment needed to correct the disease and into immunological reconstitution, an extensive multilineage analysis is lacking. We analyzed chimerism simultaneously in peripheral erythroid and granulomonocytic precursors/progenitors, highly purified B and T lymphocytes, monocytes, granulocytes and red blood cells (RBC). Thirty-four patients with mixed chimerism and ≥12 months of follow-up were included. A selective advantage of donor RBC and their progenitors/precursors led to full chimerism in mature RBC (despite partial engraftment of other lineages), and resulted in the clinical control of the disease. Six patients with donor chimerism 10 g/dL) and three with AS donors (hemoglobin
Published: 2019

23. Genetic, Cellular and Clinical Features of ICF Syndrome: a French National Survey

Author: Felipe Suarez, Fabien Touzot, Nizar Mahlaoui, Alain Fischer, Guillaume Velasco, Claire Francastel, Delphine Sterlin, Capucine Picard, Despina Moshous, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), and Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)
Subjects: Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Immunology, Autoimmunity, Hematopoietic stem cell transplantation, Immunologic Tests, Infections, Compound heterozygosity, Thyroiditis, 03 medical and health sciences, 0302 clinical medicine, Outcome Assessment, Health Care, medicine, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Genetic Testing, Child, ComputingMilieux_MISCELLANEOUS, Immunodeficiency, Hepatitis, Bronchiectasis, business.industry, Immunologic Deficiency Syndromes, Infant, Newborn, Disease Management, Infant, medicine.disease, Pancytopenia, 3. Good health, Phenotype, 030104 developmental biology, Child, Preschool, Population Surveillance, Mutation, Primary immunodeficiency, Female, France, business, 030215 immunology
Abstract: Autosomal recessive deficiencies of DNMT3B or ZBTB24 account for two-thirds of cases of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). This primary immunodeficiency (PID) is characterized mainly by an antibody deficiency, facial abnormalities and centromeric instability. We analyzed the national cohort of patients with ICF syndrome with the aim of providing a more detailed description of the phenotype and management of patients with ICF syndrome.Demographic, genetic, immunological, and clinical features were recorded for each patient.In the French cohort, seven of the nine patients carried DNMT3B mutations, six of which had never been described before. One patient had compound heterozygous ZBTB24 mutations. All patients were found to lack CD19(+)CD27(+) memory B cells. This feature is a major diagnostic criterion for both ICF1 and ICF2. Patients suffered both bacterial and viral infections, and three patients developed bronchiectasis. Autoimmune manifestations (hepatitis, nephritis and thyroiditis) not previously reported in ICF1 patients were also detected in two of our ICF1 patients. The mode of treatment and outcome of the French patients are reported, by genetic defect, and compared with those for 68 previously reported ICF patients. Immunoglobulin (Ig) replacement treatment was administered to all nine French patients. One ICF1 patient presented severe autoimmune manifestations and pancytopenia and underwent allogeneic hematopoietic stem cell transplantation (HSCT), but she died from unknown causes 6 years post-transplant.Autoimmune signs are uncommon in ICF syndrome, but, when present, they affect patient outcome and require immunosuppressive treatment. The long-term outcome of ICF patients has been improved by the combination of IgG replacement and antibiotic prophylaxis.
Published: 2016
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24. CRISPR gene-engineered CYBBko THP-1 cell lines highlight the crucial role of NADPH-induced reactive oxygen species for regulating inflammasome activation

Author: Aissa Benyoucef, Fabien Touzot, and Lorie Marchitto
Subjects: 0301 basic medicine, chemistry.chemical_classification, Reactive oxygen species, Immunology, Inflammasome, Phenotype, THP-1 Cell Lines, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, chemistry, Cell culture, 030220 oncology & carcinogenesis, medicine, Immunology and Allergy, CRISPR, Secretion, Gene, medicine.drug
Abstract: Summary CRISPR-Cas9 engineered CYBBko THP-1 cell lines display an inflammatory profile with increased IL-1β, IL-6 and TNF-α secretion as consequence of NADPH-induced ROS deficiency. This phenotype is reminiscent of the one observed in phagocytes from CGD patients.
Published: 2020
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25. Mo1902 NON-MONOGENIC VERY EARLY ONSET INFLAMMATORY BOWEL DISEASE: A TERTIARY CENTER SIX YEARS RETROSPECTIVE EXPERIENCE

Author: Laurence Chapuy David Godin, Colette Deslandres, Fabien Touzot, Natalie Patey, and Prevost Jantchou
Subjects: Pediatrics, medicine.medical_specialty, Hepatology, business.industry, Gastroenterology, medicine, Center (algebra and category theory), medicine.disease, business, Inflammatory bowel disease, Very early onset
Published: 2020
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26. Tu1876 A PILOT DOUBLE-BLIND RANDOMIZED CONTROLLED TRIAL ON VITAMIN D3 IN CHILDREN WITH NEWLY DIAGNOSED CROHN'S DISEASE

Author: Fabien Touzot, Jacques Lacroix, Sonia Alexandra Tchogna, Samuel Sassine, Nathalie Alos, Benoît Mâsse, Prevost Jantchou, Geneviève Mailhot, Lucy Clayton, Colette Deslandres, and Ali Khamessan
Subjects: Vitamin, Pediatrics, medicine.medical_specialty, Crohn's disease, Hepatology, business.industry, Gastroenterology, Newly diagnosed, medicine.disease, law.invention, Double blind, chemistry.chemical_compound, Randomized controlled trial, chemistry, law, medicine, business
Published: 2020
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27. Functional classification of ATM variants in ataxia-telangiectasia patients

Author: Khadija Abidallah, Felipe Suarez, Emmanuelle Ginglinger, Bertrand Degos, Céline Bellesme, Jean‐Paul Carriere, Nizar Mahlaoui, Guillaume Rieunier, Dorine Bellanger, Patrick Calvas, Olivier Flabeau, Dominique Stoppa-Lyonnet, Christelle Rougeot, Diane Doummar, Noel Philippe, Nathalie Auger, Virginie Moncoutier, Michèle Mathieu-Dramard, Christine Ioos, Anna Castrioto, Marie Hully, Béatrice Parfait, François Tison, Agnès Collet, Marie-Christine Nougues, Catherine Dubois d'Enghien, Alice Masurel, Karine Dahan, Thilo Dörk, Hélène Antoine-Poirel, Cecilia Altuzarra, François Demeocq, Alice Fiévet, Pierre Bordigoni, Nathalie Aladjidi, Claire Ewenczyk, Aurélie Siri, Karine Nguyen, Mathieu Anheim, Fabienne Prieur, Marc-Henri Stern, Caroline Bourjault, Fabien Touzot, Julia Sophie, Fanny Couderc, and Agathe Roubertie
Subjects: Genotype, DNA Mutational Analysis, Disease, Ataxia Telangiectasia Mutated Proteins, Biology, medicine.disease_cause, Cell Line, 03 medical and health sciences, Ataxia Telangiectasia, Immune system, Genetics, medicine, Humans, splice, Genetic Predisposition to Disease, Genetics (clinical), Genetic Association Studies, 030304 developmental biology, 0303 health sciences, Mutation, Kinase, 030305 genetics & heredity, Cell Cycle, Genetic Variation, Subcellular localization, medicine.disease, Phenotype, Alternative Splicing, Ataxia-telangiectasia
Abstract: Ataxia-telangiectasia (A-T) is a recessive disorder caused by biallelic pathogenic variants of ataxia-telangiectasia mutated (ATM). This disease is characterized by progressive ataxia, telangiectasia, immune deficiency, predisposition to malignancies, and radiosensitivity. However, hypomorphic variants may be discovered associated with very atypical phenotypes, raising the importance of evaluating their pathogenic effects. In this study, multiple functional analyses were performed on lymphoblastoid cell lines from 36 patients, comprising 49 ATM variants, 24 being of uncertain significance. Thirteen patients with atypical phenotype and presumably hypomorphic variants were of particular interest to test strength of functional analyses and to highlight discrepancies with typical patients. Western-blot combined with transcript analyses allowed the identification of one missing variant, confirmed suspected splice defects and revealed unsuspected minor transcripts. Subcellular localization analyses confirmed the low level and abnormal cytoplasmic localization of ATM for most A-T cell lines. Interestingly, atypical patients had lower kinase defect and less altered cell-cycle distribution after genotoxic stress than typical patients. In conclusion, this study demonstrated the pathogenic effects of the 49 variants, highlighted the strength of KAP1 phosphorylation test for pathogenicity assessment and allowed the establishment of the Ataxia-TeLangiectasia Atypical Score to predict atypical phenotype. Altogether, we propose strategies for ATM variant detection and classification.
Published: 2018

28. Hepatitis E virus in hematopoietic stem cell donors: Towards a systematic HEV screening of donors?

Author: Fabien Touzot, Marianne Leruez-Ville, Pierre Frange, Despina Moshous, Alain Fischer, Anne-Marie Roque-Afonso, Marina Cavazzana, Bénédicte Neven, and Stéphane Blanche
Subjects: Microbiology (medical), Bone marrow transplantation, business.industry, medicine.medical_treatment, Hematopoietic stem cell, Hematopoietic stem cell transplantation, medicine.disease_cause, Virology, Hepatitis E, Infectious Diseases, medicine.anatomical_structure, Hepatitis E virus, Humans, Medicine, business
Published: 2015
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29. Unraveling the pathogenesis of Hoyeraal-Hreidarsson syndrome, a complex telomere biology disorder

Author: Galina Glousker, Sharon A. Savage, Fabien Touzot, Patrick Revy, and Yehuda Tzfati
Subjects: Genetics, Mutation, Fetal Growth Retardation, Genetic disorder, Telomere Homeostasis, Hoyeraal-Hreidarsson syndrome, Hematology, Disease, Telomere, Biology, medicine.disease, medicine.disease_cause, Article, Dyskeratosis Congenita, Germline mutation, Intellectual Disability, Microcephaly, medicine, Humans, Dyskeratosis congenita
Abstract: Summary Hoyeraal–Hreidarsson (HH) syndrome is a multisystem genetic disorder characterized by very short telomeres and considered a clinically severe variant of dyskeratosis congenita. The main cause of mortality, usually in early childhood, is bone marrow failure. Mutations in several telomere biology genes have been reported to cause HH in about 60% of the HH patients, but the genetic defects in the rest of the patients are still unknown. Understanding the aetiology of HH and its diverse manifestations is challenging because of the complexity of telomere biology and the multiple telomeric and non-telomeric functions played by telomere-associated proteins in processes such as telomere replication, telomere protection, DNA damage response and ribosome and spliceosome assembly. Here we review the known clinical complications, molecular defects and germline mutations associated with HH, and elucidate possible mechanistic explanations and remaining questions in our understanding of the disease.
Published: 2015
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30. Gene therapy for primary immunodeficiencies

Author: Marina Cavazzana, Fabien Touzot, S. Hacein-Bey Abina, and Alain Fischer
Subjects: 0303 health sciences, Severe combined immunodeficiency, Genetic enhancement, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, Haematopoiesis, Combined immunodeficiencies, 0302 clinical medicine, 030220 oncology & carcinogenesis, Immunology, Genetics, medicine, T-Cell Immunodeficiency, Stem cell, Progenitor cell, Genetics (clinical), Ex vivo, 030304 developmental biology
Abstract: Gene therapy has effectively entered Medicine via the field of primary immunodeficiencies (PID). Because hematopoietic stem cells are accessible and because it was understood that genetic correction of lymphocyte progenitor cells carrying a genetic defect impairing differentiation, could result in the production of long-lived T lymphocytes, it was reasoned that ex vivo gene transfer in hematopoietic cells could lead to disease phenotype correction. Retroviral vectors were designed to ex vivo transduce such cells. This has indeed been shown to lead to sustained correction of the T cell immunodeficiency associated with two forms of severe combined immunodeficiencies (SCID) for now more than ten years. Occurrence in some patients of genotoxicity related to retroviral vectors integration close to and transactivation of oncogenes has led to the development of retroviral vectors devoid of its enhancer element. Results of recent trials performed for several forms of PID indeed suggest that their use is both safe and efficacious. It is thus anticipated that their application to the treatment of many more life threatening PID will be developed over the coming years.
Published: 2015
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31. Inherited Immunodeficiency: A New Association With Early-Onset Childhood Panniculitis

Author: Christine Bodemer, Fabien Touzot, Frédéric Rieux-Laucat, Brigitte Bader-Meunier, Marie-Louise Frémond, Sylvie Fraitag, and Isabelle André-Schmutz
Subjects: Male, medicine.medical_specialty, Panniculitis, T-Lymphocytes, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Postoperative Complications, NF-kappa B p52 Subunit, medicine, Humans, Immunodeficiency, Early onset, Bone Marrow Transplantation, B-Lymphocytes, medicine.diagnostic_test, biology, business.industry, Autoantibody, Acute-phase protein, Immunologic Deficiency Syndromes, Immunoglobulins, Intravenous, Infant, medicine.disease, Dermatology, Nucleotidyltransferases, medicine.anatomical_structure, Lymphocyte Specific Protein Tyrosine Kinase p56(lck), 030220 oncology & carcinogenesis, Child, Preschool, Pediatrics, Perinatology and Child Health, Skin biopsy, Mutation, biology.protein, Female, Bone marrow, Antibody, business
Abstract: We report on 4 children who presented with aseptic panniculitis associated with inherited immunodeficiency. Three patients had a B-cell immunodeficiency resulting from mutations in the TRNT1 and NF-κb2 genes (no mutation was found in the third patient), and 1 had a T-cell deficiency (mutation in the LCK gene). Panniculitis occurred before the age of 2 years in the 4 patients and preceded the onset of recurrent infections because of immunodeficiency in 2. It presented either as nodules, which resolved spontaneously within 1 to 2 weeks (3 patients), or chronic ulcerative lesions (1 patient) associated with unexplained fever and elevated acute phase reactants, without evidence of infection or high-titer autoantibodies. Febrile nodules relapsed in 2 patients, and recurrent attacks of unexplained fever (without relapse of panniculitis) occurred in the third. Skin biopsy revealed predominantly lympho-histiocytic or septal neutrophilic panniculitis in 1 and 3 patients, respectively. Panniculitis was associated with dermal involvement in the 4 patients. Patients with B-cell deficiency received monthly intravenous immunoglobulin replacement. Two patients who underwent bone marrow transplant died of bone marrow transplant-related complications. The 2 remaining patients had persistent, mild autoinflammatory disease, which did not require specific treatment. In these cases, the need for careful immunologic evaluation of patients who present with unexplained panniculitis, especially early-onset panniculitis before the age of 2 years, is highlighted.
Published: 2017

32. Understanding therapeutic emergencies in acute hemolysis

Author: Fabien Touzot, David Boutboul, and Raphael Szalat
Subjects: medicine.medical_specialty, Plasma Exchange, business.industry, Pain medicine, MEDLINE, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, medicine.disease, Hematologic Diseases, Hemolysis, Thrombocytopenia, 03 medical and health sciences, 0302 clinical medicine, Anesthesiology, Acute Disease, medicine, Humans, Emergencies, Intensive care medicine, business, 030215 immunology
Published: 2017

33. Inherited CD70 deficiency in humans reveals a critical role for the CD70–CD27 pathway in immunity to Epstein-Barr virus infection

Author: Jean-Pierre de Villartay, Julie Bruneau, Kazushi Izawa, Fabien Touzot, Isabelle Callebaut, Rémy Rodriguez, Capucine Picard, Despina Moshous, Alain Fischer, Christelle Lenoir, Claire Soudais, Andrew D. Hislop, Caroline Besson, Sylvain Latour, Emmanuel Martin, David Boutboul, 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), Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 (UPD7)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), School of Cancer Sciences, University of Birmingham [Birmingham], Centre d'étude des Déficits Immunitaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), 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), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Biodiversité et Biotechnologie Fongiques (BBF), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), 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), Collège de France - Chaire Médecine expérimentale (A. Fischer), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Observatoire Midi-Pyrénées (OMP), Université Fédérale Toulouse Midi-Pyrénées-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Diderot - Paris 7 (UPD7)-CHU Saint Louis [APHP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: 0301 basic medicine, Male, Epstein-Barr Virus Infections, T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, Receptors, Antigen, T-Cell, Biology, Lymphocyte Activation, Article, 03 medical and health sciences, Interleukin 21, immune system diseases, hemic and lymphatic diseases, medicine, Immunology and Allergy, Cytotoxic T cell, Humans, IL-2 receptor, Antigen-presenting cell, Child, B cell, Research Articles, B-Lymphocytes, ZAP70, Natural killer T cell, 3. Good health, Tumor Necrosis Factor Receptor Superfamily, Member 7, B-1 cell, 030104 developmental biology, medicine.anatomical_structure, Codon, Nonsense, [SDV.IMM]Life Sciences [q-bio]/Immunology, CD27 Ligand, Signal Transduction
Abstract: Izawa et al. identify the first patient with CD70 deficiency suffering from recurrent EBV-induced B cell proliferations including Hodgkin’s lymphoma. Expression of CD70 on B cells is necessary to induce proliferation of EBV-specific T cells., Epstein-Barr virus (EBV) infection in humans is a major trigger of malignant and nonmalignant B cell proliferations. CD27 is a co-stimulatory molecule of T cells, and inherited CD27 deficiency is characterized by high susceptibility to EBV infection, though the underlying pathological mechanisms have not yet been identified. In this study, we report a patient suffering from recurrent EBV-induced B cell proliferations including Hodgkin’s lymphoma because of a deficiency in CD70, the ligand of CD27. We show that EBV-specific T lymphocytes did not expand properly when stimulated with CD70-deficient EBV-infected B cells, whereas expression of CD70 in B cells restored expansion, indicating that CD70 on B cells but not on T cells is required for efficient proliferation of T cells. CD70 was found to be up-regulated on B cells when activated and during EBV infection. The proliferation of T cells triggered by CD70-expressing B cells was dependent on CD27 and CD3 on T cells. Importantly, CD27-deficient T cells failed to proliferate when stimulated with CD70-expressing B cells. Thus, the CD70–CD27 pathway appears to be a crucial component of EBV-specific T cell immunity and more generally for the immune surveillance of B cells and may be a target for immunotherapy of B cell malignancies.
Published: 2017
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34. Stem cell transplantation for primary immunodeficiencies

Author: Fabien Touzot, Stéphane Blanche, Alain Fischer, Marina Cavazzana, Despina Moshous, and Bénédicte Neven
Subjects: medicine.medical_specialty, medicine.medical_treatment, Genetic enhancement, Immunology, Hematopoietic stem cell transplantation, Immune system, medicine, Humans, Immunology and Allergy, media_common.cataloged_instance, European Union, European union, Intensive care medicine, media_common, Heterogeneous group, business.industry, Common variable immunodeficiency, Hematopoietic Stem Cell Transplantation, Allografts, medicine.disease, Europe, Transplantation, Common Variable Immunodeficiency, surgical procedures, operative, Stem cell, business
Abstract: Purpose of review Primary immunodeficiencies (PIDs) constitute a heterogeneous group of inherited disorders affecting the development and/or function of the immune system. This review focuses on the recent advances in hematopoietic stem cell transplantation (HSCT) for PIDs, as it remains the only potentially curative option for many of these diseases. Recent findings We report on the most recent HSCT European results and suggest some opportunities for better treatment of certain PIDs. Progress on gene therapy is also discussed, as it emerges as an interesting option for PIDs management. Summary Progress in the treatment of primary immune deficiency with HSCT requires a better understanding of the pathophysiology and specificity of each of these diseases, allowing us to determine the best options in terms of donor, conditioning regimen, modification of the allograft and immunosuppressive therapy. Alternative therapies - such as gene therapy - emerge as an interesting option for some PIDs.
Published: 2014
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35. Circulating endothelial cells as markers of endothelial dysfunction during hematopoietic stem cell transplantation for pediatric primary immunodeficiency

Author: Despina Moshous, Fabien Touzot, Pierre Frange, Guilhem Cros, Maryline Chomton, Marie-Louise Frémond, Alain Fischer, Bénédicte Neven, Dominique Helley, Marina Cavazzana, and Stéphane Blanche
Subjects: Clinical trial, Endothelial stem cell, business.industry, medicine.medical_treatment, Immunology, Primary immunodeficiency, Immunology and Allergy, Medicine, Hematopoietic stem cell transplantation, Endothelial dysfunction, business, medicine.disease
Published: 2014
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36. Gene therapy for inherited immunodeficiency

Author: Fabien Touzot, Salima Hacein-Bey-Abina, Alain Fischer, and Marina Cavazzana
Subjects: Adenosine Deaminase, Genetic enhancement, Clinical Biochemistry, Biology, Granulomatous Disease, Chronic, X-Linked Combined Immunodeficiency Diseases, Viral vector, Agammaglobulinemia, Drug Discovery, medicine, Animals, Humans, Immunodeficiency, Pharmacology, Severe combined immunodeficiency, Genetic Therapy, medicine.disease, Wiskott-Aldrich Syndrome, Adenosine deaminase deficiency, Treatment Outcome, Immunology, Primary immunodeficiency, Severe Combined Immunodeficiency, T-Cell Immunodeficiency, Stem cell, Forecasting
Abstract: During the last decade, gene therapy has emerged as a convincing therapy for primary immunodeficiencies (PIDs). Ex vivo gene transfer into autologous hematopoietic stem cells (HSCs) via viral vectors permits sustained correction of T cell immunodeficiency in two forms of severe combined immunodeficiency: X-linked SCID (SCID-X1) (γ chain [γc] deficiency) and adenosine deaminase deficiency. However, this success has been balanced by the occurrence of genotoxicity generated by the integration of first-generation retroviral vectors. Recently, the development of safer self-inactivating vectors has led to the initiation of new studies with the hope of equivalent efficacy and a better safety profile.This review article focuses on the updated results of gene therapy trials for PIDs - from early studies to ongoing clinical trials. We detail the major advances made in gene transfer and repair technologies, and discuss the many ways to extend our present experience.With optimization in terms of safety and efficacy, gene therapy by lentiviral transduction could become a compelling alternative to allogeneic HSC transplantation, and thus may take center stage in the management of PIDs in coming years.
Published: 2014
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37. βeta-thalassémie majeure : analyse coût-efficacité de la thérapie génique versus l’allogreffe de cellules souches hématopoïétique

Author: M. Ghardallou, Fabien Touzot, S. Rais, S. Coquerelle, Isabelle Durand-Zaleski, M. Cavazzana, and Pierre Taupin
Subjects: Epidemiology, Public Health, Environmental and Occupational Health
Abstract: Introduction Actuellement, 75 % des patients βeta-thalassemiques ne disposent pas de donneurs apparentes Human leukocyte antigen (HLA) compatible et n’avaient, jusqu’a present, pas acces a des traitements curatifs. La therapie genique est un traitement prometteur qui pourrait etre propose a ces patients. Notre analyse a estime son cout et son efficacite. Patients et methode Nous avons mene une analyse cout-efficacite retrospective, mono centrique comparant les resultats et les couts de prise en charge a deux ans des patients atteints de β-thalassemie severe et traites pas therapie genique ou par allogreffe de cellules souches hematopoietique (HSCT). Les complications de grade III et IV, les diagnostics, examens et soins realises ainsi que le type d’hospitalisations et les durees de sejour ont ete extraites de la base ENCC de l’hopital Necker. Les couts ont ete estimes selon la perspective du producteur de soins. Resultats Sept patients atteints de βeta-thalassemie majeure et traites entre 2009 et 2016 ont ete inclus, quatre furent traites par therapie genique. Les patients traites par therapie genique etaient plus âges, avaient moins de complications et de re-hospitalisations apres traitement. Les complications infectieuses etaient trois fois plus frequentes chez les patients traites par HSCT que pour ceux traites par therapie genique. Le cout moyen a deux ans etait de 608 086 € pour les patients traites par therapie genique versus 215 571 € pour ceux ayant beneficie d’une HSCT. Le cout total du vecteur representait 48 % du montant total du traitement par therapie genique. Pour les deux traitements les couts les plus importants apparaissaient pendant la procedure (acte de greffe ou therapie genique). Conclusion La therapie genique, bien que plus couteuse que l’allogreffe de cellules souches hematopoietique, est une alternative curative interessante pour les patients ne disposant pas de donneurs apparentes HLA compatible. Les patients traites par therapie genique, bien que plus âges, ont eu, apres traitement, moins de complications que ceux traites par HSCT.
Published: 2019
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38. Temporal and Spatial Compartmentalization of Drug-Resistant Cytomegalovirus (CMV) in a Child with CMV Meningoencephalitis: Implications for Sampling in Molecular Diagnosis

Author: Fabien Touzot, David Boutolleau, Despina Moshous, Stéphane Blanche, Alain Fischer, Sébastien Héritier, Pierre Frange, Bénédicte Neven, Guilhem Cros, and Marianne Leruez-Ville
Subjects: Male, Microbiology (medical), Time Factors, medicine.medical_treatment, Congenital cytomegalovirus infection, Cytomegalovirus, Case Reports, Hematopoietic stem cell transplantation, Drug resistance, Biology, Antiviral Agents, Polymerase Chain Reaction, law.invention, Viral Proteins, Meningoencephalitis, law, Drug Resistance, Viral, medicine, Humans, Sampling (medicine), Dna viral, Polymerase chain reaction, Hematopoietic Stem Cell Transplantation, virus diseases, Infant, Compartmentalization (psychology), medicine.disease, Virology, Blood, Amino Acid Substitution, Cytomegalovirus Infections, DNA, Viral, Immunology
Abstract: We describe a case of antiviral-resistant cytomegalovirus meningoencephalitis occurring after hematopoietic stem cell transplantation. Antiviral-resistant cytomegalovirus was identified in blood 16 months earlier. However, wild-type cytomegalovirus was evidenced in blood when the meningoencephalitis was diagnosed. Treatment of meningoencephalitis should be adapted to all previously identified resistance mutations in any compartment.
Published: 2013
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39. In hematopoietic cells with a germline mutation of CBL, loss of heterozygosity is not a signature of juvenile myelo-monocytic leukemia

Author: Arnaud Petit, Aurélie Caye, Marion Strullu, Claire Galambrun, Christine Chomienne, O Fenneteau, Fabien Touzot, Bruno Cassinat, Thierry Leblanc, Rémy Rodriguez, André Baruchel, Thomas Blauwblomme, Hélène Cavé, Vincent Barlogis, and Sylvain Latour
Subjects: Male, Cancer Research, Loss of Heterozygosity, Bone Marrow Cells, Biology, Loss of heterozygosity, Germline mutation, hemic and lymphatic diseases, medicine, Humans, Juvenile, Proto-Oncogene Proteins c-cbl, Germ-Line Mutation, fungi, Infant, Hematology, medicine.disease, Molecular biology, Pedigree, Leukemia, Haematopoiesis, Leukemia, Myelomonocytic, Juvenile, Oncology, Child, Preschool, Cancer research, Monocytic leukemia, Female
Abstract: In hematopoietic cells with a germline mutation of CBL , loss of heterozygosity is not a signature of juvenile myelo-monocytic leukemia
Published: 2013
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40. Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations

Author: Laurent Jullien, Patrick Revy, Fabien Touzot, Alain Fischer, Laetitia Kermasson, Arturo Londoño-Vallejo, Isabelle Callebaut, Sinan Sari, Christelle Ménard, Figen Dogu, Vannina Giacobbi-Milet, Aydan Ikinciogullari, Amos Etzioni, Thierry Leblanc, Jean-Pierre de Villartay, Jean Soulier, Caroline Kannengiesser, Despina Moshous, Département de Chimie - ENS Paris, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), 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), Estación Experimental Agropecuaria Mendoza (EEA), Instituto Nacional de Tecnología Agropecuaria, Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie pédiatrique [Robert-Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], École normale supérieure - Paris (ENS-PSL), Processus d'Activation Sélective par Transfert d'Energie Uni-électronique ou Radiatif (UMR 8640) (PASTEUR), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Genetics, Microcephaly, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, DNA repair, Hematopoiesis and Stem Cells, [SDV]Life Sciences [q-bio], Bone marrow failure, Helicase, Hematology, medicine.disease, Telomere, 03 medical and health sciences, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, hemic and lymphatic diseases, biology.protein, medicine, Missense mutation, Cerebellar hypoplasia, Immunodeficiency, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Telomeres are repetitive hexameric sequences located at the end of linear chromosomes. They adopt a lariat-like structure, the T-loop, to prevent them from being recognized as DNA breaks by the DNA repair machinery. RTEL1 is a DNA helicase required for proper telomere replication and stability. In particular, it has been postulated that RTEL1 is involved in the opening of the T-loop during telomere replication to avoid sudden telomere deletion and telomere circle (T-circle) formation. In humans, biallelic RTEL1 mutations cause Hoyeraal-Hreidarsson syndrome (HH), a rare and severe telomere biology disorder characterized by intrauterine growth retardation, bone marrow failure, microcephaly and/or cerebellar hypoplasia, and immunodeficiency. To date, 18 different RTEL1 mutations have been described in 19 cases of HH with short telomeres. The impaired T-loop resolution has been proposed to be a major cause of telomere shortening in RTEL1 deficiency. However, the biological and clinical consequences of this disorder remain incompletely documented. Here, we describe 4 new patients harboring biallelic RTEL1 mutations, including 2 novel missense mutations located in the C-terminal end of RTEL1 (p.Cys1268Arg and p.Val1294Phe). Clinical characteristics from these 4 patients were collected as those from 4 other RTEL1-deficient patients previously reported. In addition, we assessed whether T-circles, the product of improper T-loop resolution, were detected in our RTEL1-deficient patients. Overall, our study broadens and refines the clinical and biological spectrum of human RTEL1 deficiency.
Published: 2016
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41. Corrigendum: Evidence of innate lymphoid cell redundancy in humans

Author: Frédéric, Vély, Vincent, Barlogis, Blandine, Vallentin, Bénédicte, Neven, Christelle, Piperoglou, Thibaut, Perchet, Maxime, Petit, Nadia, Yessaad, Fabien, Touzot, Julie, Bruneau, Nizar, Mahlaoui, Nicolas, Zucchini, Catherine, Farnarier, Gérard, Michel, Despina, Moshous, Stéphane, Blanche, Arnaud, Dujardin, Hergen, Spits, Jörg H W, Distler, Andreas, Ramming, Capucine, Picard, Rachel, Golub, Alain, Fischer, and Eric, Vivier
Subjects: body regions, skin and connective tissue diseases, Article
Abstract: Innate lymphoid cells (ILCs) have potent immune functions in experimental conditions in mice, but their contribution to immunity in natural conditions in humans remains unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in SCID patients carrying mutations of IL2RG or JAK3. T cell reconstitution was observed in SCID patients upon hematopoietic stem cell transplantation (HSCT), but the patients still exhibited drastic reduction of ILCs in the absence of myeloablation, at the exception of rare cases of ILC1 reconstitution. Remarkably, the observed ILC deficiencies were not associated with any particular susceptibility to disease, with a follow-up extending from 7 to 39 years after HSCT. We thus report here the first cases of selective ILC deficiency in humans, and show that ILCs may be dispensable in natural conditions, if T cells are present and B cell function is preserved.
Published: 2016

42. Evidence of innate lymphoid cell redundancy in humans

Author: Frédéric Vély, Despina Moshous, Julie Bruneau, Catherine Farnarier, Andreas Ramming, Jörg H W Distler, Blandine Vallentin, Stéphane Blanche, Nicolas Zucchini, Mikael Ebbo, Rachel Golub, Capucine Picard, Alain Fischer, Nadia Yessaad, Maxime Petit, Fabien Touzot, Gérard Michel, Nizar Mahlaoui, Bénédicte Neven, Thibaut Perchet, Arnaud Dujardin, Vincent Barlogis, Christelle Piperoglou, Eric Vivier, Hergen Spits, Laboratoire d'Immunologie [Hôpital de la Conception - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION )-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Pédiatrie et oncologie pédiatrique [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Mi-mAbs (C/O CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), CHU Necker - Enfants Malades [AP-HP], BD Biosciences, Innate Pharma, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), Department of Internal Medicine and Institute for Clinical Immunology, Friedrich Alexander University [Erlangen-Nürnberg], Collège de France (CdF), We thank all patients and their families for participating in the study, C. Bonnafous and N. Anceriz (Innate-Pharma) for monoclonal antibody to NKp46, F. Suarez (Paris), N. Schleinitz (Marseille) and Y. Bertrand (Lyon) for enrolling patients in the study, and the Laboratory of Hematology (P.E. Morange, Marseille) for sample storage. Supported by the European Research Council (THINK Advanced Grant for the E.V. laboratory), the Ligue Nationale contre le Cancer (Equipe Labellisée, E.V. laboratory), institutional grants from INSERM, CNRS and Aix-Marseille University to CIML (E.V. laboratory), the Institut Universitaire de France (E.V.), the European Research Council (Pidimmune Advanced Grant for the A.F. laboratory), institutional grants from INSERM, Paris Descartes University and Collège de France (A.F. laboratory), Investissements d’Avenir Instituts Hospitaliers Universitaires (A.F. laboratory), institutional grants from Institut Pasteur, INSERM, Université Paris Diderot and the Agence Nationale de la Recherche ('Myeloten', R.G. group), the Institut National du Cancer (R.G. group) and Université Sorbonne Paris Cité ('Mucocell', R.G. group), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital de la Conception [CHU - APHM] (LA CONCEPTION)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Cell Biology and Histology, Experimental Immunology, Chaire Médecine expérimentale (A. Fischer), Assistance Publique - Hôpitaux de Marseille ( APHM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ) -Centre National de la Recherche Scientifique ( CNRS ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Hôpital de la Conception [CHU - APHM] ( LA CONCEPTION ), Lymphopoïèse, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Paris Diderot - Paris 7 ( UPD7 ) -PRES Sorbonne Paris Cité, Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Innate-Pharma, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ), and Collège de France ( CdF )
Subjects: 0301 basic medicine, T cell, medicine.medical_treatment, Immunology, Hematopoietic stem cell transplantation, Biology, 03 medical and health sciences, 0302 clinical medicine, Immunity, medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, skin and connective tissue diseases, B cell, Severe combined immunodeficiency, Innate lymphoid cell, medicine.disease, 3. Good health, body regions, 030104 developmental biology, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokine receptor, Tyrosine kinase, 030215 immunology
Abstract: International audience; Innate lymphoid cells (ILCs) have potent immunological functions in experimental conditions in mice, but their contributions to immunity in natural conditions in humans have remained unclear. We investigated the presence of ILCs in a cohort of patients with severe combined immunodeficiency (SCID). All ILC subsets were absent in patients with SCID who had mutation of the gene encoding the common γ-chain cytokine receptor subunit IL-2Rγ or the gene encoding the tyrosine kinase JAK3. T cell reconstitution was observed in patients with SCID after hematopoietic stem cell transplantation (HSCT), but the patients still had considerably fewer ILCs in the absence of myeloablation than did healthy control subjects, with the exception of rare cases of reconstitution of the ILC1 subset of ILCs. Notably, the ILC deficiencies observed were not associated with any particular susceptibility to disease, with follow-up extending from 7 years to 39 years after HSCT. We thus report here selective ILC deficiency in humans and show that ILCs might be dispensable in natural conditions, if T cells are present and B cell function is preserved.
Published: 2016
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43. mTOR INHIBITION COUNTERBALANCES THE INFLAMMATORY STATUS OF IMMUNE CELLS IN CHRONIC GRANULOMATOUS DISEASE

Author: Fabien Touzot
Published: 2016
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44. The Immunologic Complications and Genetic Origins of Telomere Disorders

Author: Fabien Touzot and Patrick Revy
Subjects: Genome instability, Premature aging, medicine.anatomical_structure, Immunology, medicine, Bone marrow failure, Hoyeraal-Hreidarsson syndrome, Bone marrow, Biology, medicine.disease, Dyskeratosis congenita, Immunodeficiency, Telomere
Abstract: Telomeres correspond to the ends of linear chromosomes. Their length and structure have to be tightly regulated to avoid genomic instability, cell death, or premature senescence. In humans, defective telomere maintenance causes the dyskeratosis congenita (DC) condition characterized by a bone marrow failure associated with other premature aging features such as mucocutaneous abnormalities and cancer predisposition. Hoyeraal–Hreidarsson syndrome (HH) represents the severe form of DC and consists of an early-onset bone marrow failure, immunodeficiency, intrauterine growth retardation, and cerebellar hypoplasia. DC and HH patients exhibit progressive immunodeficiency principally caused by declining bone marrow function. In this article, we review our current knowledge on the etiology of DC and HH and summarize the immunologic characteristics of DC-HH and the genes responsible for these telomere disorders.
Published: 2016
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45. Primary Microcephaly, Impaired DNA Replication, and Genomic Instability Caused by Compound HeterozygousATRMutations

Author: Houda Mokrani-Benhelli, Fabien Touzot, Nadia Vasquez, Laetitia Gaillard, Alain Fischer, Jun Komatsu, Marina Cavazzana-Calvo, Anne Durandy, Emmanuel Conseiller, Eliane Gluckman, Jean Soulier, Christine Francannet, Tangui Le Guen, Patrick Revy, Patricia Biasutto, Jean-Pierre de Villartay, and Capucine Picard
Subjects: DNA Replication, Male, Genome instability, Heterozygote, DNA damage, RNA Splicing, Blotting, Western, Molecular Sequence Data, Mutation, Missense, DNA, Single-Stranded, Fluorescent Antibody Technique, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Protein Serine-Threonine Kinases, Biology, medicine.disease_cause, Genomic Instability, Cell Line, Mice, Genetics, medicine, Animals, Humans, DNA Breaks, Double-Stranded, Child, Alleles, In Situ Hybridization, Fluorescence, Genetics (clinical), Comparative Genomic Hybridization, Mutation, Base Sequence, Tumor Suppressor Proteins, DNA replication, Fibroblasts, medicine.disease, DNA-Binding Proteins, Seckel syndrome, Ataxia-telangiectasia, Microcephaly, Female, Ataxia telangiectasia and Rad3 related, Gene Deletion, Genome-Wide Association Study, Signal Transduction
Abstract: Ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases are two key regulators of DNA-damage responses (DDR) that are mainly activated in response to DNA double-strand breaks and single-stranded DNA damages, respectively. Seckel syndrome, a rare genetic disorder characterized by a microcephaly and a markedly reduced body size, has been associated with defective ATR-dependent DNA damage signaling. However, the only human genetic ATR defect reported so far is a hypomorphic splicing mutation identified in five related individuals with Seckel syndrome. Here, we report the first case of primary microcephaly with compound heterozygous mutations in ATR: a 540 kb genomic deletion on one allele and a missense mutation leading to splice dysregulation on the other, which ultimately lead to a sharp decrease in ATR expression. DNA combing technology revealed a profound spontaneous alteration of several DNA replication parameters in patient's cells and FISH analyses highlighted the genomic instability caused by ATR deficiency. Collectively, our results emphasize the crucial role for ATR in the control of DNA replication, and reinforce the complementary and nonredundant contributions of ATM and ATR in human cells to face DNA damages and warrant genome integrity.
Published: 2012
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46. Prevalence and Clinical Impact of Norovirus Fecal Shedding in Children with Inherited Immune Deficiencies

Author: Fabien Touzot, Marianne Debré, Alain Fischer, Guilhem Cros, Christine Rouzioux, Véronique Avettand-Fenoel, Stéphane Blanche, Sébastien Héritier, Pierre Frange, and Marianne Leruez-Ville
Subjects: Male, viruses, Viremia, medicine.disease_cause, Virus, Feces, Immunocompromised Host, fluids and secretions, Immune system, Prevalence, Humans, Immunology and Allergy, Medicine, Prospective Studies, Viral shedding, Child, Prospective cohort study, Caliciviridae Infections, business.industry, Norovirus, Immunologic Deficiency Syndromes, Infant, Newborn, Infant, virus diseases, medicine.disease, Virology, Hospitals, digestive system diseases, Gastroenteritis, Virus Shedding, Infectious Diseases, Child, Preschool, Concomitant, Immunology, Female, business
Abstract: We report the first prospective study describing the prevalence and clinical consequences of norovirus infection in hospitalized children with primary immunodeficiencies. Fecal samples from 62 children were systematically screened for virus. Norovirus was the most frequent pathogen (11 of 24 positive samples) found in both combined and humoral immunocompromised children. Norovirus shedding was associated with gastrointestinal symptoms and concomitant viremia in 54.5% and 25% of cases, respectively. Norovirus excretion was prolonged: 57.1% of fecal samples were still positive after a median of 9.5-months follow-up. Further large longitudinal studies are needed to evaluate the clinical consequences of norovirus shedding in patients with primary immunodeficiencies.
Published: 2012
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47. Nouvelles formes de dyskératoses congénitales

Author: Fabien Touzot, Jean-Pierre de Villartay, Tangui Le Guen, and Patrick Revy
Subjects: Premature aging, Telomerase, DNA damage, Genetic disorder, Cancer, General Medicine, Biology, medicine.disease, Molecular biology, General Biochemistry, Genetics and Molecular Biology, Telomere, Nucleoprotein, medicine, Dyskeratosis congenita
Abstract: Telomeres are nucleoprotein structures at the end of linear chromosomes. Their length, structure, and integrity are regulated by the telomerase complex, the shelterins and components of the DNA damage response. In human subjects, defects in telomere maintenance are responsible for Dyskeratosis Congenita (DC), a rare genetic disorder characterized by aplastic anaemia, premature aging and predisposition to cancer. Recent data from the study of patients with Hoyeraal-Hreidarsson syndrome, a severe variant of DC, demonstrate the great molecular heterogeneity of this disease. While most cases of DC are associated with defects in factors involved in telomere length regulation, some severe forms of the disease seem to be rather associated with defects in telomere replication and protection.
Published: 2012
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48. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency)

Author: Pierre Bordigoni, Danielle Canioni, Michèle Milili, Nathalie Lambert, Claire Galambrun, Marie Ouachée-Chardin, Filomeen Haerynck, Françoise Le Deist, Despina Moshous, Christelle Lenoir, Stephanie Rigaud, Lionel Galicier, Fabien Touzot, Capucine Picard, Mohamed Hamidou, Hirokazu Kanegane, Ester Mejstrikova, Helen Chapel, Eduardo López-Granados, Stéphane Blanche, Alain Dabadie, Jana Pachlopnik Schmid, Pierre-Simon Rohrlich, Fabian Hauck, Geneviève de Saint Basile, Claudin Schiff, Jean-Louis Stephan, Alain Fischer, Isabelle Pellier, Nizar Mahlaoui, Sylvain Latour, Alain Fourmaintraux, Vincent Barlogis, IFR Necker-Enfants Malades (IRNEM), 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), 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), Service d'anatomie pathologique [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), Graduate School of Medicine, University of Toyama, Department of pediatrics, University of Oxford [Oxford], Teaching Hospital Motol and 2nd Medical School, Charles University, Department of Pediatric Hematology and Oncology, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'immuno-hématologie pédiatrique [CHU Necker], Service d'Hématologie pédiatrique, Hôpital de la Timone, Marseille, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'hématologie pédiatrique, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Groupe Hospitalier Sud Réunion (GHSR), Centre Hospitalier Universitaire [Rennes], Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Department of Paediatric Pulmonology, Ghent University Hospital, Service d'hématologie et immunologie pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Département de pédiatrie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Hôpital Saint-Jacques, CHU Saint-Etienne, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'étude des Déficits Immunitaires, Assistance Publique-Hôpitaux de Paris, Service d'Immunologie et d'Hématologie Pédiatrique, Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), University of Oxford, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Collège de France - Chaire Médecine expérimentale (A. Fischer), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Faculté de Médecine d'Angers-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS)-Hôpital Laennec-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôtel-Dieu de Nantes, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Robert Debré-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Saint-Jacques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), IFR Necker-Enfants Malades ( IRNEM ), Assistance publique - Hôpitaux de Paris (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 ), 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 Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Centre Hospitalier Régional Universitaire de Nancy ( CHRU Nancy ), Groupe Hospitalier Sud Réunion ( GHSR ), Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 ( UPD7 ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Saint-Jacques, Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), and Assistance publique - Hôpitaux de Paris (AP-HP)
Subjects: Male, MESH : Retrospective Studies, MESH: X-Linked Inhibitor of Apoptosis Protein, MESH : Aged, MESH : Child, Preschool, Biochemistry, Cohort Studies, Immunoenzyme Techniques, Hypogammaglobulinemia, MESH: Lymphoproliferative Disorders, 0302 clinical medicine, MESH : Child, MESH: Child, hemic and lymphatic diseases, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, MESH : Female, XIAP Deficiency, Signaling Lymphocytic Activation Molecule Associated Protein, X-Linked Lymphoproliferative Syndrome, Child, MESH: Cohort Studies, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH : Lymphoproliferative Disorders, Intracellular Signaling Peptides and Proteins, MESH : Infant, Hematology, MESH : Adult, Middle Aged, MESH : Survival Rate, MESH: Infant, 3. Good health, Survival Rate, MESH : Phenotype, Phenotype, MESH: Young Adult, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH : Mutation, Adult, medicine.medical_specialty, MESH: Mutation, Adolescent, MESH: Survival Rate, MESH : Male, Immunology, MESH : Young Adult, MESH : Cohort Studies, X-Linked Inhibitor of Apoptosis Protein, Biology, MESH: Phenotype, Virus, Young Adult, 03 medical and health sciences, MESH : Intracellular Signaling Peptides and Proteins, MESH : Immunoenzyme Techniques, MESH : Adolescent, MESH: Intracellular Signaling Peptides and Proteins, medicine, Humans, MESH : Middle Aged, MESH: Immunoenzyme Techniques, Aged, Retrospective Studies, 030304 developmental biology, MESH: Adolescent, Hemophagocytic lymphohistiocytosis, Cytopenia, MESH: Humans, MESH : Humans, MESH: Child, Preschool, Infant, X-linked lymphoproliferative disease, MESH: Adult, MESH: Retrospective Studies, Cell Biology, medicine.disease, Lymphoproliferative Disorders, MESH: Male, MESH : X-Linked Inhibitor of Apoptosis Protein, Mutation, Histopathology, MESH: Female, 030215 immunology
Abstract: X-linked lymphoproliferative syndromes (XLP) are primary immunodeficiencies characterized by a particular vulnerability toward Epstein-Barr virus infection, frequently resulting in hemophagocytic lymphohistiocytosis (HLH). XLP type 1 (XLP-1) is caused by mutations in the gene SH2D1A (also named SAP), whereas mutations in the gene XIAP underlie XLP type 2 (XLP-2). Here, a comparison of the clinical phenotypes associated with XLP-1 and XLP-2 was performed in cohorts of 33 and 30 patients, respectively. HLH (XLP-1, 55%; XLP-2, 76%) and hypogammaglobulinemia (XLP-1, 67%; XLP-2, 33%) occurred in both groups. Epstein-Barr virus infection in XLP-1 and XLP-2 was the common trigger of HLH (XLP-1, 92%; XLP-2, 83%). Survival rates and mean ages at the first HLH episode did not differ for both groups, but HLH was more severe with lethal outcome in XLP-1 (XLP-1, 61%; XLP-2, 23%). Although only XLP-1 patients developed lymphomas (30%), XLP-2 patients (17%) had chronic hemorrhagic colitis as documented by histopathology. Recurrent splenomegaly often associated with cytopenia and fever was preferentially observed in XLP-2 (XLP-1, 7%; XLP-2, 87%) and probably represents minimal forms of HLH as documented by histopathology. This first phenotypic comparison of XLP subtypes should help to improve the diagnosis and the care of patients with XLP conditions.
Published: 2011
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49. An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation

Author: Wassila Carpentier, Isabelle Callebaut, Capucine Picard, Nada Jabado, Patrick Revy, Alain Fischer, Fabien Touzot, Laetitia Kermasson, Nathalie Lambert, Tangui Le Guen, Marina Cavazzana, Patrick Nitschke, Jean Soulier, Chantal Lagresle-Peyrou, Jean-Pierre de Villartay, Annick Lim, Christine Bole-Feysot, Isabelle André-Schmutz, Imagine - Institut des maladies génétiques (IMAGINE - U1163), 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), CIC-BT 502 INSERM, Departement de Biotherapie, the Study Center of Primary Immunodeficiencies, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Bioinformatique, Plateforme Post-génomique de la Pitié-Salpêtrière (P3S), UMS omique (OMIQUE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de génomique [SFR Necker], 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)-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), Département d'Immunologie - Department of Immunology, Institut Pasteur [Paris] (IP), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS), INSERM U944 Laboratoire de Pathologie et Virologie Moléculaire, Laboratoire de Pathologie et Virologie Moléculaire, the Genome Quebec Innovation Centre, McGill University = Université McGill [Montréal, Canada], Collège de France - Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Plateforme Post-génomique de la Pitié-Salpêtrière ( P3S ), UMS omique ( OMIQUE ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Structure Fédérative de Recherche Necker ( SFR Necker - UMS 3633 / US24 ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Assistance publique - Hôpitaux de Paris (AP-HP), Département d'Immunologie, Institut Pasteur [Paris], Institut de minéralogie, de physique des matériaux et de cosmochimie ( IMPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Muséum National d'Histoire Naturelle ( MNHN ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de recherche pour le développement [IRD] : UR206, McGill University, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), 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)-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), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Male, T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, Biology, Lymphopenia, MYSM1, medicine, Immunology and Allergy, Gene silencing, Missense mutation, Humans, histone deubiquitinase, MYB, Transcription factor, Gene, Genetics, B-Lymphocytes, Hematopoietic stem cell homeostasis, [ SDV ] Life Sciences [q-bio], Lymphocyte differentiation, Immunologic Deficiency Syndromes, Hematopoietic stem cell, Infant, Cell Differentiation, genetic reversion, 3. Good health, Hematopoiesis, DNA-Binding Proteins, medicine.anatomical_structure, Mutation, Trans-Activators, Ubiquitin-Specific Proteases, immunodeficiency, Transcription Factors
Abstract: Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119- monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities. Objectives: We sought to characterize the underlying genetic cause of this syndrome. Methods: We performed genome-wide homozygosity mapping, followed by whole-exome sequencing. Results: Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell. Conclusions: We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency.
Published: 2015
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50. Specific T cells for the treatment of cytomegalovirus and/or adenovirus in the context of hematopoietic stem cell transplantation

Author: Jean-Marc Luby, Patrice Chevallier, Sébastien Héritier, Brigitte Ternaux, Rita Creidy, Salima Hacein-Bey-Abina, Xavier Thomas, Stéphane Blanche, Jennifer Nisoy, Jean-Hugues Dalle, Despina Moshous, Caroline Elie, Jean-Marc Treluyer, Laetitia Souchet, Sébastien Maury, Aurélie Gabrion, Marina Cavazzana, Liliane Dal Cortivo, Benedicte Neven, Aliénor Xhaard, Marie Ouachée-Chardin, Fabien Touzot, C Picard, Marianne Leruez-Ville, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, 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), Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Infections à Vih, Réservoirs, Pharmacologie des Antirétroviraux et Prévention de la Transmission Mère Enfant, Université Paris Descartes - Paris 5 (UPD5), Laboratoire de Virologie [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), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Centre hospitalier universitaire de Nantes (CHU Nantes), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-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)-CHU Necker - Enfants Malades [AP-HP], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_treatment, viruses, Cells, Adenoviridae Infections, T-Lymphocytes, Congenital cytomegalovirus infection, Cytomegalovirus, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Hematopoietic stem cell transplantation, Bioinformatics, CXCR4, Adenoviridae, immunology, 03 medical and health sciences, Young Adult, Medicine, Immunology and Allergy, Humans, ComputingMilieux_MISCELLANEOUS, Genome, business.industry, microbiology, Hematopoietic Stem Cell Transplantation, virus diseases, Infant, Middle Aged, medicine.disease, Virology, 3. Good health, 030104 developmental biology, surgical procedures, operative, Child, Preschool, Cytomegalovirus Infections, Female, France, business, Laboratories, transplantation, Stem Cell Transplantation
Abstract: International audience
Published: 2015
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