B-cell function; CD8(+) T cells; SCID; enteric virus; gene therapy; interferon; transplantation; Humans; CD8-Positive T-Lymphocytes; Severe Combined Immunodeficiency/therapy; Severe Combined Immunodeficiency/etiology; Hematopoietic Stem Cell Transplantation/adverse effects; Hematopoietic Stem Cell Transplantation/methods; Virus Diseases/etiology; Hepatitis/etiology; Enterovirus Infections; Hematopoietic Stem Cell Transplantation; Hepatitis; Severe Combined Immunodeficiency; Virus Diseases; Immunology and Allergy; Immunology
Abstract :
[en] [en] BACKGROUND: Allogenic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT) are potentially curative treatments for severe combined immunodeficiency (SCID). Late-onset posttreatment manifestations (such as persistent hepatitis) are not uncommon.
OBJECTIVE: We sought to characterize the prevalence and pathophysiology of persistent hepatitis in transplanted SCID patients (SCIDH+) and to evaluate risk factors and treatments.
METHODS: We used various techniques (including pathology assessments, metagenomics, single-cell transcriptomics, and cytometry by time of flight) to perform an in-depth study of different tissues from patients in the SCIDH+ group and corresponding asymptomatic similarly transplanted SCID patients without hepatitis (SCIDH-).
RESULTS: Eleven patients developed persistent hepatitis (median of 6 years after HSCT or GT). This condition was associated with the chronic detection of enteric viruses (human Aichi virus, norovirus, and sapovirus) in liver and/or stools, which were not found in stools from the SCIDH- group (n = 12). Multiomics analysis identified an expansion of effector memory CD8+ T cells with high type I and II interferon signatures. Hepatitis was associated with absence of myeloablation during conditioning, split chimerism, and defective B-cell function, representing 25% of the 44 patients with SCID having these characteristics. Partially myeloablative retransplantation or GT of patients with this condition (which we have named as "enteric virus infection associated with hepatitis") led to the reconstitution of T- and B-cell immunity and remission of hepatitis in 5 patients, concomitantly with viral clearance.
CONCLUSIONS: Enteric virus infection associated with hepatitis is related to chronic enteric viral infection and immune dysregulation and is an important risk for transplanted SCID patients with defective B-cell function.
Disciplines :
Genetics & genetic processes
Author, co-author :
Riller, Quentin ; University of Paris Cité, Paris, France, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France
Fourgeaud, Jacques; University of Paris Cité, Paris, France, Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France, Prise en Charge des Anomalies Congénitales et leur Traitement, Unit 7328, Imagine Institute, University of Paris Cité, Paris, France
Bruneau, Julie; University of Paris Cité, Paris, France, Pathology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, Imagine Institute, INSERM UMR 1163, Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implications, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
De Ravin, Suk See; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
Smith, Grace; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Md
Fusaro, Mathieu; Study Center for Primary Immunodeficiencies, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Meriem, Samy; Laboratory of Biostatistics, University of Paris Cité, Paris, France
Magerus, Aude; University of Paris Cité, Paris, France, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France
Luka, Marine; Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, France
Abdessalem, Ghaith; Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, France
Lhermitte, Ludovic; University of Paris Cité, Paris, France, Laboratory of Onco-Haematology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, the Institut Necker-Enfants Malades (INEM), INSERM UMR 1151, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Jamet, Anne; University of Paris Cité, Paris, France, Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, the Institut Necker-Enfants Malades (INEM), INSERM UMR 1151, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Six, Emmanuelle; University of Paris Cité, Paris, France, Laboratory of Human Lympho-Hematopoiesis, Imagine Institute, INSERM UMR 1163, Paris, France
Magnani, Alessandra; Department of Biotherapy, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Castelle, Martin; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Lévy, Romain; University of Paris Cité, Paris, France, Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Lecuit, Mathilde M; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Fournier, Benjamin; University of Paris Cité, Paris, France, Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Winter, Sarah; University of Paris Cité, Paris, France, Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Semeraro, Michaela; University of Paris Cité, Paris, France, Clinical Investigation Center, Clinical Research Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Pinto, Graziella; Pediatric Endocrinology, Gynecology, Diabetology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Abid, Hanène; University of Paris Cité, Paris, France, Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Mahlaoui, Nizar; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Cheikh, Nathalie; Pediatric Hematology Oncology Unit, University Hospital of Besançon, Besançon, France
Florkin, Benoit ; Université de Liège - ULiège ; Immuno-Hémato-Rhumatologie Pédiatrique, Service de Pédiatrie, CHR Citadelle, Liege, Belgium
Frange, Pierre; University of Paris Cité, Paris, France, Microbiology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Jeziorski, Eric; Department of Pediatrics, Infectious Diseases, and Immunology, University of Montpellier, CHU Montpellier, Montpellier, France
Suarez, Felipe; University of Paris Cité, Paris, France, Imagine Institute, INSERM UMR 1163, Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implications, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, Hematology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Sarrot-Reynauld, Françoise; Service de Médecine Interne, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
Nouar, Dalila; Service d'Immunologie Clinique et d'Allergologie, Centre Hospitalier Régional Universitaire, Tours, France
Debray, Dominique; Pediatric Liver Unit, National Reference Center for Rare Diseases, Biliary Atresia and Genetic Cholestasis, Inflammatory Biliary Diseases and Autoimmune Hepatitis, ERN Rare Liver, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Lacaille, Florence; Gastroenterology-Hepatology-Nutrition Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Picard, Capucine; Study Center for Primary Immunodeficiencies, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Imagine Institute, INSERM UMR 1163, Paris, France
Pérot, Philippe; Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France, OIE Collaborating Center for the Detection and Identification in Humans of Emerging Animal Pathogens, Institut Pasteur, Paris, France
Regnault, Béatrice; Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France, OIE Collaborating Center for the Detection and Identification in Humans of Emerging Animal Pathogens, Institut Pasteur, Paris, France
Da Rocha, Nicolas; Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France, OIE Collaborating Center for the Detection and Identification in Humans of Emerging Animal Pathogens, Institut Pasteur, Paris, France
de Cevins, Camille; University of Paris Cité, Paris, France, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France, Artificial Intelligence & Deep Analytics (AIDA) Group, Data & Data Science (DDS), Sanofi R&D, Chilly-Mazarin, France
Delage, Laure; University of Paris Cité, Paris, France, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France
Pérot, Brieuc P; University of Paris Cité, Paris, France, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France
Vinit, Angélique; Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, Paris, France
Carbone, Francesco; University of Paris Cité, Paris, France, Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, France, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France
Brunaud, Camille; University of Paris Cité, Paris, France, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France
Marchais, Manon; University of Paris Cité, Paris, France, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France
Stolzenberg, Marie-Claude; University of Paris Cité, Paris, France, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France
Asnafi, Vahid; University of Paris Cité, Paris, France, Laboratory of Onco-Haematology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, the Institut Necker-Enfants Malades (INEM), INSERM UMR 1151, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Molina, Thierry; University of Paris Cité, Paris, France, Pathology Department, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Rieux-Laucat, Frédéric; University of Paris Cité, Paris, France, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France
Notarangelo, Luigi D; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
Pittaluga, Stefania; National Cancer Institute, National Institutes of Health, Bethesda, Md
Jais, Jean Philippe; University of Paris Cité, Paris, France, Laboratory of Biostatistics, University of Paris Cité, Paris, France
Moshous, Despina; University of Paris Cité, Paris, France, Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer, Imagine Institute, INSERM UMR 1163, Paris, France
Blanche, Stephane; University of Paris Cité, Paris, France, Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
Malech, Harry; Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
Eloit, Marc; Pathogen Discovery Laboratory, Institut Pasteur, Université de Paris, Paris, France, OIE Collaborating Center for the Detection and Identification in Humans of Emerging Animal Pathogens, Institut Pasteur, Paris, France, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
Cavazzana, Marina; University of Paris Cité, Paris, France, Laboratory of Onco-Haematology, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, Laboratory of Human Lympho-Hematopoiesis, Imagine Institute, INSERM UMR 1163, Paris, France
Fischer, Alain; Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France, Collège de France, Paris, France
Ménager, Mickaël M; University of Paris Cité, Paris, France, Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, Paris, France, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, Imagine Institute, INSERM UMR 1163, Paris, France
Neven, Bénédicte; University of Paris Cité, Paris, France, Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Imagine Institute, INSERM UMR 1163, Paris, France, Pediatric Hematology-Immunology and Rheumatology Unit, Necker-Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. Electronic address: benedicte.neven@aphp.fr
Q.R. is a recipient of an Institut Imagine MD-PhD fellowship (funded by the Fondation Bettencourt Schueller, France) and a Société Nationale Française de Médecine Interne fellowship. The work was funded by 2 grants from the Centre de Référence et d'Etude des Déficits Immunitaire (CEREDIH).
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