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

doi:10.1126/sciimmunol.adq1697

. 2025 Jan 10;10(103):eadq1697.

doi: 10.1126/sciimmunol.adq1697. Epub 2025 Jan 10.

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

Marita Bosticardo¹, Kerry Dobbs¹, Ottavia M Delmonte¹, Andrew J Martins², Francesca Pala¹, Tomoki Kawai¹, Heather Kenney¹, Gloria Magro¹, Lindsey B Rosen¹, Yasuhiro Yamazaki¹, Hsin-Hui Yu^{1

3}, Enrica Calzoni¹, Yu Nee Lee⁴, Can Liu², Jennifer Stoddard⁵, Julie Niemela⁵, Danielle Fink⁶, Riccardo Castagnoli¹, Meredith Ramba⁷, Aristine Cheng¹, Deanna Riley⁸, Vasileios Oikonomou¹, Elana Shaw¹, Brahim Belaid⁹, Sevgi Keles¹⁰, Waleed Al-Herz^{11

12}, Caterina Cancrini^{13

14}, Cristina Cifaldi¹³, Safa Baris^{15

16}, Svetlana Sharapova¹⁷, Catharina Schuetz¹⁸, Andrew R Gennery¹⁹, Alexandra F Freeman¹, Raz Somech⁴, Sharon Choo²⁰, Silvia C Giliani^{21

22

23}, Tayfun Güngör^{24

25}, Daniel Drozdov^{24

25

26}, Isabelle Meyts^{27

28}, Despina Moshous^{29

30}, Benedicte Neven^{29

30}, Roshini S Abraham³¹, Aisha El-Marsafy³², Maria Kanariou³³, Alejandra King³⁴, Francesco Licciardi³⁵, Mario E Cruz-Muñoz³⁶, Paolo Palma^{13

37}, Cecilia Poli³⁸, Mehdi Adeli³⁹, Mattia Algeri^{40

41}, Fayhan J Alroqi⁴², Paul Bastard^{43

44}, Jenna R E Bergerson¹, Claire Booth⁴⁵, Ana Brett^{46

47}, Siobhan O Burns^{48

49}, Manish J Butte⁵⁰, Nurcicek Padem⁵¹, M de la Morena⁵², Ghassan Dbaibo^{53

54}, Suk See de Ravin¹, Dimana Dimitrova⁵⁵, Reda Djidjik⁹, Mayra B Dorna⁵⁶, Cullen M Dutmer⁵⁷, Reem Elfeky⁵⁸, Fabio Facchetti⁵⁹, Ramsay L Fuleihan⁶⁰, Raif S Geha⁶¹, Luis I Gonzalez-Granado^{62

63

64}, Liis Haljasmägi⁶⁵, Hanadys Ale^{66

67}, Anthony Hayward⁶⁸, Anna M Hifanova⁶⁹, Winnie Ip⁴⁵, Blanka Kaplan^{70

71}, Neena Kapoor⁷², Elif Karakoc-Aydiner^{15

16}, Jaanika Kärner⁶⁵, Michael D Keller⁷³, Blachy J Dávila Saldaña⁷³, Ayça Kiykim⁷⁴, Taco W Kuijpers⁷⁵, Elena E Kuznetsova⁷⁶, Elena A Latysheva⁷⁷, Jennifer W Leiding^{78

79

80}, Franco Locatelli^{40

41}, Guisela Alva-Lozada⁸¹, Christine McCusker⁸², Fatih Celmeli⁸³, Megan Morsheimer⁸⁴, Ahmet Ozen^{15

16}, Nima Parvaneh⁸⁵, Srdjan Pasic⁸⁶, Alessandro Plebani⁸⁷, Kahn Preece⁸⁸, Susan Prockop⁸⁹, Inga S Sakovich¹⁷, Elena E Starkova⁹⁰, Troy Torgerson⁹¹, James Verbsky⁹², Jolan E Walter⁹³, Brant Ward⁹⁴, Elizabeth L Wisner⁹⁵, Deborah Draper¹, Katherine Myint-Hpu¹, Pooi M Truong¹, Michail S Lionakis¹, Morgan B Similuk⁹⁶; Centralized Sequencing Program Group§§; Magdalena A Walkiewicz⁹⁶, Amy Klion⁹⁷, Steven M Holland¹, Cihan Oguz⁹⁸, Dusan Bogunovic⁹⁹, Kai Kisand⁶⁵, Helen C Su^{1

100}, John S Tsang², Douglas Kuhns⁶, Anna Villa^{101

102}, Sergio D Rosenzweig⁵, Stefania Pittaluga⁸, Luigi D Notarangelo¹; Centralized Sequencing Program Group

Collaborators, Affiliations

Collaborators

Rajarshi Ghosh, Bryce Siefert, Mari Tokita, Jia Yan, Colleen Jodarski, Mike Kamen, Rachel Gore, Nadjalisse Reynolds-Lallement, Katie Lewis, Sarah Bannon, Adrienne Borges, Nicole Gentile

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 Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan.
⁴ 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.
⁵ Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD, USA.
⁶ Neutrophil Monitoring Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
⁷ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
⁸ Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁹ Department of Medical Immunology, Beni Messous University Hospital Center, Faculty of Pharmacy, University of Algiers, Algiers, Algeria.
¹⁰ Division of Pediatric Allergy and Immunology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey.
¹¹ Department of Pediatrics, College of Medicine, Kuwait University, Safat, Kuwait City, Kuwait.
¹² Allergy and Clinical Immunology Unit, Pediatric Department, Al-Sabah Hospital, Kuwait City, Kuwait.
¹³ Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
¹⁴ Research Unit of Primary Immunodeficiencies, Academic Department of Pediatrics, Bambino Gesu' Children's Hospital, Scientific Institute for Research and Heathcare (IRCCS), Rome, Italy.
¹⁵ Faculty of Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey.
¹⁶ Isil Berat Barlan Center for Translational Medicine, Istanbul Jeffrey Modell Foundation Diagnostic Center for Primary Immune Deficiencies, Istanbul, Turkey.
¹⁷ Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus.
¹⁸ Department of Paediatrics, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁹ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
²⁰ Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, VIC, Australia.
²¹ Angelo Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
²² Laboratory Department, Spedali Civili, Brescia, Italy.
²³ National Center for Gene Therapy and Drugs based on RNA Technology, CN3, Brescia, Italy.
²⁴ Division of Hematology/Oncology/Immunology, Gene-Therapy, and Stem Cell Transplantation, University Children's Hospital Zürich, Zürich, Switzerland.
²⁵ Eleonore Foundation & Children's Research Center (CRC), Zürich, Switzerland.
²⁶ Division of Pediatric Hematology and Oncology, Department of Pediatrics, Kantonsspital Aarau, Aarau, Switzerland.
²⁷ Department of Immunology and Microbiology, Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.
²⁸ University Hospitals Leuven and ERN-RITA Core Center, Leuven, Belgium.
²⁹ Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France.
³⁰ Institut Imagine, Université Paris Cité, Paris, France.
³¹ Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
³² Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt.
³³ Department of Immunology-Histocompatibility, Specialized & Referral Center for Primary Immunodeficiencies-Paediatric Immunology, "Aghia Sophia" Children's Hospital, Athens, Greece.
³⁴ Departamento de Pediatría, Hospital Luis Calvo Mackenna, Santiago, Chile.
³⁵ Immuno-reumatologia, Pediatria Specialistica Universitaria, Ospedale Infantile Regina Margherita, Torino, Italy.
³⁶ Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, Mexico.
³⁷ Clinical Immunology and Vaccinology Unit, Children's Hospital "Bambino Gesu," Rome, Italy.
³⁸ Faculty of Medicine, Clínica Alemana Universidad del Desarrollo Roberto del Rio, Santiago, Chile.
³⁹ Department of Immunology, Sidra Medicine, Ar-Rayyan, Qatar.
⁴⁰ Department of Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
⁴¹ Catholic University of the Sacred Heart, Rome, Italy.
⁴² King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
⁴³ Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
⁴⁴ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
⁴⁵ Molecular and Cellular Immunology, UCL Great Ormond Street Institute of Child Health, London, UK.
⁴⁶ Hospital Pediátrico, Unidade Local de Saúde de Coimbra, Coimbra, Portugal.
⁴⁷ Clínica Universitária de Pediatria, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
⁴⁸ Institute of Immunity and Transplantation, University College London, London, UK.
⁴⁹ Department of Immunology, Royal Free London NHS Foundation Trust, London, UK.
⁵⁰ Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, University of California, Los Angeles, Los Angeles, CA, USA.
⁵¹ Division of Pediatric Pulmonology, Allergy-Immunology and Sleep Medicine, Riley Hospital for Children/Indiana University, Indianapolis, IN, USA.
⁵² Division of Immunology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
⁵³ Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
⁵⁴ Center for Infectious Diseases Research (CIDR) and WHO Collaborating Center for Reference and Research on Bacterial Pathogens, American University of Beirut, Beirut, Lebanon.
⁵⁵ Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵⁶ Division of Allergy and Immunology, Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
⁵⁷ Allergy and Immunology Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA.
⁵⁸ Department of Clinical Immunology, Royal Free Hospital, London, UK.
⁵⁹ Section of Pathology, Department of Molecular and Translational Medicine, University of Brescia, Spedali Civili di Brescia, Brescia, Italy.
⁶⁰ Division of Allergy & Immunology, Columbia University Irving Medical Center, New York, NY, USA.
⁶¹ Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
⁶² Primary Immunodeficiency Unit, Pediatrics, Hospital 12 Octubre, Madrid, Spain.
⁶³ Instituto de Investigation Hospital 12 Octubre (imas12), Madrid, Spain.
⁶⁴ School of Medicine Complutense University, Madrid, Spain.
⁶⁵ Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
⁶⁶ Division of Immunology, Allergy and Rheumatology, Joe DiMaggio Children's Hospital, Memorial Healthcare System, Hollywood, FL, USA.
⁶⁷ Florida International University Herbert Wertheim College of Medicine, Miami, FL, USA.
⁶⁸ Division of Infectious Diseases, Department of Pediatrics, Brown University and Rhode Island Hospital, Providence, RI, USA.
⁶⁹ Department of Pediatric Infectious Diseases and Pediatric Immunology, Shupyk National Healthcare University of Ukraine, Kiev, Ukraine.
⁷⁰ Division of Allergy, Asthma and Immunology, Cohen Children's Medical Center, Northwell Health, New Hyde Park, NY, USA.
⁷¹ Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
⁷² Children's Hospital of Los Angeles, Los Angeles, CA, USA.
⁷³ Division of Allergy and Immunology, Children's National Hospital, Washington, DC, USA.
⁷⁴ Division of Pediatric Allergy and Immunology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
⁷⁵ Department of Pediatric Immunology, Amsterdam UMC Locatie AMC, Amsterdam, Netherlands.
⁷⁶ Hematology Department, Regional Clinical Hospital, Orenburg, Russia.
⁷⁷ Immunopathology Department, NRC Institute of Immunology FMBA, Pigorov Russian National Research Medical University, Moscow, Russia.
⁷⁸ Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA.
⁷⁹ Institute for Clinical and Translational Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
⁸⁰ Cancer and Blood Disorders Institute, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
⁸¹ Allergy and Immunology Division Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru.
⁸² Division of Allergy and Clinical Immunology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada.
⁸³ Immunology and Allergy Diseases, Saglık Bilimleri University, Antalya Training and Research Hospital Pediatric, Antalya, Turkey.
⁸⁴ Division of Allergy, Immunology and Transplantation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁸⁵ Infectious Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran.
⁸⁶ Department of Pediatric Immunology, Mother and Child Health Institute, Medical Faculty, University of Belgrade, Belgrade, Serbia.
⁸⁷ University of Brescia, Brescia, Italy.
⁸⁸ Department of Immunology, John Hunter Children's Hospital, Newcastle, NSW, Australia.
⁸⁹ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
⁹⁰ Clinical Department, Regional Clinical Hospital No. 2, Orenburg, Russia.
⁹¹ Allen Institute for Immunology, Seattle, WA, USA.
⁹² Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI, USA.
⁹³ Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
⁹⁴ Division of Rheumatology, Allergy and Immunology, Virginia Commonwealth University, Richmond, VA, USA.
⁹⁵ Division of Allergy Immunology, Department of Pediatrics, Louisiana State University Health Sciences Center New Orleans, New Orleans, LA, USA.
⁹⁶ Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁹⁷ Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD, USA.
⁹⁸ Integrated Data Sciences Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁹⁹ Center for Genetic Errors of Immunity, Columbia University Medical Center, New York City, NY, USA.
¹⁰⁰ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰¹ Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy.
¹⁰² San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), IRCSS San Raffaele Scientific Institute, Milan 20132, Italy.

PMID: 39792639
PMCID: PMC12087669 (available on 2026-01-10)
DOI: 10.1126/sciimmunol.adq1697

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

Marita Bosticardo et al. Sci Immunol. 2025.

. 2025 Jan 10;10(103):eadq1697.

doi: 10.1126/sciimmunol.adq1697. Epub 2025 Jan 10.

Authors

Collaborators

Rajarshi Ghosh, Bryce Siefert, Mari Tokita, Jia Yan, Colleen Jodarski, Mike Kamen, Rachel Gore, Nadjalisse Reynolds-Lallement, Katie Lewis, Sarah Bannon, Adrienne Borges, Nicole Gentile

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 Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan.
⁴ 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.
⁵ Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD, USA.
⁶ Neutrophil Monitoring Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
⁷ Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
⁸ Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁹ Department of Medical Immunology, Beni Messous University Hospital Center, Faculty of Pharmacy, University of Algiers, Algiers, Algeria.
¹⁰ Division of Pediatric Allergy and Immunology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey.
¹¹ Department of Pediatrics, College of Medicine, Kuwait University, Safat, Kuwait City, Kuwait.
¹² Allergy and Clinical Immunology Unit, Pediatric Department, Al-Sabah Hospital, Kuwait City, Kuwait.
¹³ Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
¹⁴ Research Unit of Primary Immunodeficiencies, Academic Department of Pediatrics, Bambino Gesu' Children's Hospital, Scientific Institute for Research and Heathcare (IRCCS), Rome, Italy.
¹⁵ Faculty of Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey.
¹⁶ Isil Berat Barlan Center for Translational Medicine, Istanbul Jeffrey Modell Foundation Diagnostic Center for Primary Immune Deficiencies, Istanbul, Turkey.
¹⁷ Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus.
¹⁸ Department of Paediatrics, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁹ Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
²⁰ Department of Allergy and Immunology, Royal Children's Hospital, Melbourne, VIC, Australia.
²¹ Angelo Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
²² Laboratory Department, Spedali Civili, Brescia, Italy.
²³ National Center for Gene Therapy and Drugs based on RNA Technology, CN3, Brescia, Italy.
²⁴ Division of Hematology/Oncology/Immunology, Gene-Therapy, and Stem Cell Transplantation, University Children's Hospital Zürich, Zürich, Switzerland.
²⁵ Eleonore Foundation & Children's Research Center (CRC), Zürich, Switzerland.
²⁶ Division of Pediatric Hematology and Oncology, Department of Pediatrics, Kantonsspital Aarau, Aarau, Switzerland.
²⁷ Department of Immunology and Microbiology, Inborn Errors of Immunity, KU Leuven, Leuven, Belgium.
²⁸ University Hospitals Leuven and ERN-RITA Core Center, Leuven, Belgium.
²⁹ Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France.
³⁰ Institut Imagine, Université Paris Cité, Paris, France.
³¹ Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
³² Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt.
³³ Department of Immunology-Histocompatibility, Specialized & Referral Center for Primary Immunodeficiencies-Paediatric Immunology, "Aghia Sophia" Children's Hospital, Athens, Greece.
³⁴ Departamento de Pediatría, Hospital Luis Calvo Mackenna, Santiago, Chile.
³⁵ Immuno-reumatologia, Pediatria Specialistica Universitaria, Ospedale Infantile Regina Margherita, Torino, Italy.
³⁶ Facultad de Medicina, Universidad Autónoma del Estado de Morelos, Cuernavaca, Morelos, Mexico.
³⁷ Clinical Immunology and Vaccinology Unit, Children's Hospital "Bambino Gesu," Rome, Italy.
³⁸ Faculty of Medicine, Clínica Alemana Universidad del Desarrollo Roberto del Rio, Santiago, Chile.
³⁹ Department of Immunology, Sidra Medicine, Ar-Rayyan, Qatar.
⁴⁰ Department of Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
⁴¹ Catholic University of the Sacred Heart, Rome, Italy.
⁴² King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
⁴³ Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
⁴⁴ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
⁴⁵ Molecular and Cellular Immunology, UCL Great Ormond Street Institute of Child Health, London, UK.
⁴⁶ Hospital Pediátrico, Unidade Local de Saúde de Coimbra, Coimbra, Portugal.
⁴⁷ Clínica Universitária de Pediatria, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
⁴⁸ Institute of Immunity and Transplantation, University College London, London, UK.
⁴⁹ Department of Immunology, Royal Free London NHS Foundation Trust, London, UK.
⁵⁰ Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, University of California, Los Angeles, Los Angeles, CA, USA.
⁵¹ Division of Pediatric Pulmonology, Allergy-Immunology and Sleep Medicine, Riley Hospital for Children/Indiana University, Indianapolis, IN, USA.
⁵² Division of Immunology, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
⁵³ Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
⁵⁴ Center for Infectious Diseases Research (CIDR) and WHO Collaborating Center for Reference and Research on Bacterial Pathogens, American University of Beirut, Beirut, Lebanon.
⁵⁵ Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁵⁶ Division of Allergy and Immunology, Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
⁵⁷ Allergy and Immunology Section, Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, USA.
⁵⁸ Department of Clinical Immunology, Royal Free Hospital, London, UK.
⁵⁹ Section of Pathology, Department of Molecular and Translational Medicine, University of Brescia, Spedali Civili di Brescia, Brescia, Italy.
⁶⁰ Division of Allergy & Immunology, Columbia University Irving Medical Center, New York, NY, USA.
⁶¹ Division of Immunology, Boston Children's Hospital, Boston, MA, USA.
⁶² Primary Immunodeficiency Unit, Pediatrics, Hospital 12 Octubre, Madrid, Spain.
⁶³ Instituto de Investigation Hospital 12 Octubre (imas12), Madrid, Spain.
⁶⁴ School of Medicine Complutense University, Madrid, Spain.
⁶⁵ Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
⁶⁶ Division of Immunology, Allergy and Rheumatology, Joe DiMaggio Children's Hospital, Memorial Healthcare System, Hollywood, FL, USA.
⁶⁷ Florida International University Herbert Wertheim College of Medicine, Miami, FL, USA.
⁶⁸ Division of Infectious Diseases, Department of Pediatrics, Brown University and Rhode Island Hospital, Providence, RI, USA.
⁶⁹ Department of Pediatric Infectious Diseases and Pediatric Immunology, Shupyk National Healthcare University of Ukraine, Kiev, Ukraine.
⁷⁰ Division of Allergy, Asthma and Immunology, Cohen Children's Medical Center, Northwell Health, New Hyde Park, NY, USA.
⁷¹ Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
⁷² Children's Hospital of Los Angeles, Los Angeles, CA, USA.
⁷³ Division of Allergy and Immunology, Children's National Hospital, Washington, DC, USA.
⁷⁴ Division of Pediatric Allergy and Immunology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
⁷⁵ Department of Pediatric Immunology, Amsterdam UMC Locatie AMC, Amsterdam, Netherlands.
⁷⁶ Hematology Department, Regional Clinical Hospital, Orenburg, Russia.
⁷⁷ Immunopathology Department, NRC Institute of Immunology FMBA, Pigorov Russian National Research Medical University, Moscow, Russia.
⁷⁸ Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA.
⁷⁹ Institute for Clinical and Translational Research, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
⁸⁰ Cancer and Blood Disorders Institute, Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
⁸¹ Allergy and Immunology Division Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru.
⁸² Division of Allergy and Clinical Immunology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada.
⁸³ Immunology and Allergy Diseases, Saglık Bilimleri University, Antalya Training and Research Hospital Pediatric, Antalya, Turkey.
⁸⁴ Division of Allergy, Immunology and Transplantation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁸⁵ Infectious Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran.
⁸⁶ Department of Pediatric Immunology, Mother and Child Health Institute, Medical Faculty, University of Belgrade, Belgrade, Serbia.
⁸⁷ University of Brescia, Brescia, Italy.
⁸⁸ Department of Immunology, John Hunter Children's Hospital, Newcastle, NSW, Australia.
⁸⁹ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.
⁹⁰ Clinical Department, Regional Clinical Hospital No. 2, Orenburg, Russia.
⁹¹ Allen Institute for Immunology, Seattle, WA, USA.
⁹² Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin and Children's Wisconsin, Milwaukee, WI, USA.
⁹³ Division of Pediatric Allergy/Immunology, University of South Florida at Johns Hopkins All Children's Hospital, St. Petersburg, FL, USA.
⁹⁴ Division of Rheumatology, Allergy and Immunology, Virginia Commonwealth University, Richmond, VA, USA.
⁹⁵ Division of Allergy Immunology, Department of Pediatrics, Louisiana State University Health Sciences Center New Orleans, New Orleans, LA, USA.
⁹⁶ Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁹⁷ Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD, USA.
⁹⁸ Integrated Data Sciences Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁹⁹ Center for Genetic Errors of Immunity, Columbia University Medical Center, New York City, NY, USA.
¹⁰⁰ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰¹ Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy.
¹⁰² San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), IRCSS San Raffaele Scientific Institute, Milan 20132, Italy.

PMID: 39792639
PMCID: PMC12087669 (available on 2026-01-10)
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 (T_H2) 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.

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Competing interests: M.J.B. is a speaker for Grifols; consults for Pharming, Horizon/Amgen, and Grifols; receives sponsored research funding from the NIH, the Bill and Melinda Gates Foundation, and Pharming; and serves on the scientific advisory board for ADMA Biologics. H.C.S. has stock holdings in Amgen and Eli Lily. R.S.A. receives royalties from Elsevier for book publications, serves as deputy editor for the Journal of Immunology, is Committee Chair of Newborn Screening for SCID for the Clinical and Laboratory Standards Institute, and is a member of the Immunology Clinical Domain Working Group for ClinGen. B.J.D.S. is an ad hoc consultant for Sobi and a member of the Data Safety Monitoring Board for Orchard Therapeutics. I.M. is a senior Clinical Researcher at the FWO Flanders. R.L.F. has consulted for Takeda, Griffons, Horizon, and Pharming. B.W. serves as consultant for the Immunology Speakers Bureau, Takeda Pharmaceutocals. S. Prockop receives support for the conduct of clinical trials through Boston Children’s Hospital from AlloVir, Atara, and Jasper. She is an inventor of intellectual property related to development of third-party virus-specific T cells program with all rights assigned to Memorial Sloan Kettering Cancer Center; receives honoraria from Pierre Fabre, Regeneron; serves on the data safety monitoring board at Stanford University and New York Blood Center; and is consulting for Atara, Ensoma, Pierre Fabre, HEOR and VOR. J.S.T. serves on the scientific advisory board of CytoReason Inc. and Immunoscape Inc. and as the co–chief science officer (unpaid) of the Human Immunome Project (nonprofit). All other authors declare that they have no competing interests.

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References

1. Oettinger MA, Schatz DG, Gorka C, Baltimore D, RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248, 1517–1523 (1990). - PubMed
1. Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, Friedrich W, Seger RA, Hansen-Hagge TE, Desiderio S, Lieber MR, Bartram CR, RAG mutations in human B cell-negative SCID. Science 274, 97–99 (1996). - PubMed
1. Notarangelo LD, Kim MS, Walter JE, Lee YN, Human RAG mutations: Biochemistry and clinical implications. Nat. Rev. Immunol 16, 234–246 (2016). - PMC - PubMed
1. IJspeert H, Driessen GJ, Moorhouse MJ, Hartwig NG, Wolska-Kusnierz B, Kalwak K, Pituch-Noworolska A, Kondratenko I, van Montfrans JM, Mejstrikova E, Lankester AC, Langerak AW, van Gent DC, Stubbs AP, van Dongen JJM, van der Burg M, Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes. J. Allergy Clin. Immunol 133, 1124–1133 (2014). - PMC - PubMed
1. Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, Schneider DT, Manfras B, Pannicke U, Willemze R, Knuchel R, Gobel U, Schulz A, Borkhardt A, Friedrich W, Schwarz K, Niehues T, An immunodeficiency disease with RAG mutations and granulomas. N. Engl. J. Med 358, 2030–2038 (2008). - PubMed

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[1] Oettinger MA, Schatz DG, Gorka C, Baltimore D, RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248, 1517–1523 (1990). - PubMed

[2] Oettinger MA, Schatz DG, Gorka C, Baltimore D, RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination. Science 248, 1517–1523 (1990). - PubMed

[3] Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, Friedrich W, Seger RA, Hansen-Hagge TE, Desiderio S, Lieber MR, Bartram CR, RAG mutations in human B cell-negative SCID. Science 274, 97–99 (1996). - PubMed

[4] Schwarz K, Gauss GH, Ludwig L, Pannicke U, Li Z, Lindner D, Friedrich W, Seger RA, Hansen-Hagge TE, Desiderio S, Lieber MR, Bartram CR, RAG mutations in human B cell-negative SCID. Science 274, 97–99 (1996). - PubMed

[5] Notarangelo LD, Kim MS, Walter JE, Lee YN, Human RAG mutations: Biochemistry and clinical implications. Nat. Rev. Immunol 16, 234–246 (2016). - PMC - PubMed

[6] Notarangelo LD, Kim MS, Walter JE, Lee YN, Human RAG mutations: Biochemistry and clinical implications. Nat. Rev. Immunol 16, 234–246 (2016). - PMC - PubMed

[7] IJspeert H, Driessen GJ, Moorhouse MJ, Hartwig NG, Wolska-Kusnierz B, Kalwak K, Pituch-Noworolska A, Kondratenko I, van Montfrans JM, Mejstrikova E, Lankester AC, Langerak AW, van Gent DC, Stubbs AP, van Dongen JJM, van der Burg M, Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes. J. Allergy Clin. Immunol 133, 1124–1133 (2014). - PMC - PubMed

[8] IJspeert H, Driessen GJ, Moorhouse MJ, Hartwig NG, Wolska-Kusnierz B, Kalwak K, Pituch-Noworolska A, Kondratenko I, van Montfrans JM, Mejstrikova E, Lankester AC, Langerak AW, van Gent DC, Stubbs AP, van Dongen JJM, van der Burg M, Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes. J. Allergy Clin. Immunol 133, 1124–1133 (2014). - PMC - PubMed

[9] Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, Schneider DT, Manfras B, Pannicke U, Willemze R, Knuchel R, Gobel U, Schulz A, Borkhardt A, Friedrich W, Schwarz K, Niehues T, An immunodeficiency disease with RAG mutations and granulomas. N. Engl. J. Med 358, 2030–2038 (2008). - PubMed

[10] Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, Schneider DT, Manfras B, Pannicke U, Willemze R, Knuchel R, Gobel U, Schulz A, Borkhardt A, Friedrich W, Schwarz K, Niehues T, An immunodeficiency disease with RAG mutations and granulomas. N. Engl. J. Med 358, 2030–2038 (2008). - PubMed

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

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

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