Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature

Bosticardo M 1 , Dobbs K 1 , Delmonte OM 1 , Martins AJ 2 , Pala F 1 , Kawai T 1 Show all authors , Kenney H 1 , Magro G 1 , Rosen LB 1 , Yamazaki Y 1 , Yu HH 1 , Calzoni E 1 , Lee YN 3 , Liu C 2 , Stoddard J 4 , Niemela J 4 , Fink D 5 , Castagnoli R 1 , Ramba M 6 , Cheng A 1 , Riley D 7 , Oikonomou V 1 , Shaw E 1 , Belaid B 8 , Keles S 9 , Al-Herz W 10 , Cancrini C 11 , Cifaldi C 11 , Baris S 12 , Sharapova S 13 , Schuetz C 14 , Gennery AR 15 , Freeman AF 1 , Somech R 3 , Choo S 16 , Giliani SC 17 , Güngör T 18 , Drozdov D 18 , Meyts I 19 , Moshous D 20 , Neven B 20 , Abraham RS 21 , El-Marsafy A 22 , Kanariou M 23 , King A 24 , Licciardi F 25 , Cruz-Muñoz ME 26 , Palma P 11 , Poli C 27 , Adeli M 28 , Algeri M 29 , Alroqi FJ 30 , Bastard P 31 , Bergerson JRE 1 , Booth C 32 , Brett A 33 , Burns SO 34 , Butte MJ 35 , Padem N 36 , de la Morena M 37 , Dbaibo G 38 , de Ravin SS 1 , Dimitrova D 39 , Djidjik R 8 , Dorna MB 40 , Dutmer CM 41 , Elfeky R 42 , Facchetti F 43 , Fuleihan RL 44 , Geha RS 45 , Gonzalez-Granado LI 46 , Haljasmägi L 47 , Ale H 48 , Hayward A 49 , Hifanova AM 50 , Ip W 32 , Kaplan B 51 , Kapoor N 52 , Karakoc-Aydiner E 12 , Kärner J 47 , Keller MD 53 , Dávila Saldaña BJ 53 , Kiykim A 54 , Kuijpers TW 55 , Kuznetsova EE 56 , Latysheva EA 57 , Leiding JW 58 , Locatelli F 29 , Alva-Lozada G 59 , McCusker C 60 , Celmeli F 61 , Morsheimer M 62 , Ozen A 12 , Parvaneh N 63 , Pasic S 64 , Plebani A 65 , Preece K 66 , Prockop S 67 , Sakovich IS 13 , Starkova EE 68 , Torgerson T 69 , Verbsky J 70 , Walter JE 71 , Ward B 72 , Wisner EL 73 , Draper D 1 , Myint-Hpu K 1 , Truong PM 1 , Lionakis MS 1 , Similuk MB 74 , Centralized Sequencing Program Group§§ , Walkiewicz MA 74 , Klion A 75 , Holland SM 1 , Oguz C 76 , Bogunovic D 77 , Kisand K 47 , Su HC 1 , Tsang JS 2 , Kuhns D 5 , Villa A 78 , Rosenzweig SD 4 , Pittaluga S 7 , Notarangelo LD 1 , Centralized Sequencing Program Group

Affiliations 

  • 1 Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
  • 2 Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA
  • 3 Pediatric Department A and the Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, 52621 Tel HaShomer, Israel
  • 4 Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD, USA
  • 5 Neutrophil Monitoring Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA
  • 6 Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
  • 7 Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  • 8 Department of Medical Immunology, Beni Messous University Hospital Center, Faculty of Pharmacy, University of Algiers, Algiers, Algeria
  • 9 Division of Pediatric Allergy and Immunology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
  • 10 Department of Pediatrics, College of Medicine, Kuwait University, Safat, Kuwait City, Kuwait
  • 11 Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
  • 12 Faculty of Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
  • 13 Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
  • 14 Department of Paediatrics, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
  • 15 Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
  • 16 Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, VIC, Australia
  • 17 Angelo Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
  • 18 Division of Hematology/Oncology/Immunology, Gene-Therapy, and Stem Cell Transplantation, University Children's Hospital Zürich, Zürich, Switzerland
  • 19 Department of Immunology and Microbiology, Inborn Errors of Immunity, KU Leuven, Leuven, Belgium
  • 20 Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France
  • 21 Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA
  • 22 Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
  • 23 Department of Immunology-Histocompatibility, Specialized & Referral Center for Primary Immunodeficiencies-Paediatric Immunology, "Aghia Sophia" Children's Hospital, Athens, Greece
  • 24 Departamento de Pediatría, Hospital Luis Calvo Mackenna, Santiago, Chile
  • 25 Immuno-reumatologia, Pediatria Specialistica Universitaria, Ospedale Infantile Regina Margherita, Torino, Italy
  • 26 Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, Mexico
  • 27 Faculty of Medicine, Clínica Alemana Universidad del Desarrollo Roberto del Rio, Santiago, Chile
  • 28 Department of Immunology, Sidra Medicine, Ar-Rayyan, Qatar
  • 29 Department of Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
  • 30 King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
  • 31 Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
  • 32 Molecular and Cellular Immunology, UCL Great Ormond Street Institute of Child Health, London, UK
  • 33 Hospital Pediátrico, Unidade Local de Saúde de Coimbra, Coimbra, Portugal
  • 34 Institute of Immunity and Transplantation, University College London, London, UK
  • 35 Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, University of California, Los Angeles, Los Angeles, CA, USA
  • 36 Division of Pediatric Pulmonology, Allergy-Immunology and Sleep Medicine, Riley Hospital for Children/Indiana University, Indianapolis, IN, USA
  • 37 Division of Immunology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA
  • 38 Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
  • 39 Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  • 40 Division of Allergy and Immunology, Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
  • 41 Allergy and Immunology Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA
  • 42 Department of Clinical Immunology, Royal Free Hospital, London, UK
  • 43 Section of Pathology, Department of Molecular and Translational Medicine, University of Brescia, Spedali Civili di Brescia, Brescia, Italy
  • 44 Division of Allergy & Immunology, Columbia University Irving Medical Center, New York, NY, USA
  • 45 Division of Immunology, Boston Children's Hospital, Boston, MA, USA
  • 46 Primary Immunodeficiency Unit, Pediatrics, Hospital 12 Octubre, Madrid, Spain
  • 47 Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
  • 48 Division of Immunology, Allergy and Rheumatology, Joe DiMaggio Children's Hospital, Memorial Healthcare System, Hollywood, FL, USA
  • 49 Division of Infectious Diseases, Department of Pediatrics, Brown University and Rhode Island Hospital, Providence, RI, USA
  • 50 Department of Pediatric Infectious Diseases and Pediatric Immunology, Shupyk National Healthcare University of Ukraine, Kiev, Ukraine
  • 51 Division of Allergy, Asthma and Immunology, Cohen Children's Medical Center, Northwell Health, New Hyde Park, NY, USA
  • 52 Children's Hospital of Los Angeles, Los Angeles, CA, USA
  • 53 Division of Allergy and Immunology, Children's National Hospital, Washington, DC, USA
  • 54 Division of Pediatric Allergy and Immunology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
  • 55 Department of Pediatric Immunology, Amsterdam UMC Locatie AMC, Amsterdam, Netherlands
  • 56 Hematology Department, Regional Clinical Hospital, Orenburg, Russia
  • 57 Immunopathology Department, NRC Institute of Immunology FMBA, Pigorov Russian National Research Medical University, Moscow, Russia
  • 58 Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA
  • 59 Allergy and Immunology Division Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru
  • 60 Division of Allergy and Clinical Immunology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada
  • 61 Immunology and Allergy Diseases, Saglık Bilimleri University, Antalya Training and Research Hospital Pediatric, Antalya, Turkey
  • 62 Division of Allergy, Immunology and Transplantation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
  • 63 Infectious Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
  • 64 Department of Pediatric Immunology, Mother and Child Health Institute, Medical Faculty, University of Belgrade, Belgrade, Serbia
  • 65 University of Brescia, Brescia, Italy
  • 66 Department of Immunology, John Hunter Children's Hospital, Newcastle, NSW, Australia
  • 67 Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA
  • 68 Clinical Department, Regional Clinical Hospital No. 2, Orenburg, Russia
  • 69 Allen Institute for Immunology, Seattle, WA, USA
  • 70 Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI, USA
  • 71 Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA
  • 72 Division of Rheumatology, Allergy and Immunology, Virginia Commonwealth University, Richmond, VA, USA
  • 73 Division of Allergy Immunology, Department of Pediatrics, Louisiana State University Health Sciences Center New Orleans, New Orleans, LA, USA
  • 74 Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
  • 75 Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD, USA
  • 76 Integrated Data Sciences Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
  • 77 Center for Genetic Errors of Immunity, Columbia University Medical Center, New York City, NY, USA
  • 78 Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy
Sci Immunol, 2025 Jan 10;10(103):eadq1697.
PMID: 39792639 DOI: 10.1126/sciimmunol.adq1697

Abstract

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of RAG-mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic RAG variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (TH2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage-specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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