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Multiomics Dissection of Human Rag Deficiency Reveals Distinctive Patterns of Immune Dysregulation But a Common Inflammatory Signature Publisher Pubmed



Bosticardo M1 ; Dobbs K1 ; Delmonte OM1 ; Martins AJ2 ; Pala F1 ; Kawai T1 ; Kenney H1 ; Magro G1 ; Rosen LB1 ; Yamazaki Y1 ; Yu HH1, 3 ; Calzoni E1 ; Lee YN4 ; Liu C2 Show All Authors
Authors
  1. Bosticardo M1
  2. Dobbs K1
  3. Delmonte OM1
  4. Martins AJ2
  5. Pala F1
  6. Kawai T1
  7. Kenney H1
  8. Magro G1
  9. Rosen LB1
  10. Yamazaki Y1
  11. Yu HH1, 3
  12. Calzoni E1
  13. Lee YN4
  14. Liu C2
  15. Stoddard J5
  16. Niemela J5
  17. Fink D6
  18. Castagnoli R1
  19. Ramba M7
  20. Cheng A1
  21. Riley D8
  22. Oikonomou V1
  23. Shaw E1
  24. Belaid B9
  25. Keles S10
  26. Alherz W11, 12
  27. Cancrini C13, 14
  28. Cifaldi C13
  29. Baris S15, 16
  30. Sharapova S17
  31. Schuetz C18
  32. Gennery AR19
  33. Freeman AF1
  34. Somech R4
  35. Choo S20
  36. Giliani SC21, 22, 23
  37. Gungor T24, 25
  38. Drozdov D24, 25, 26
  39. Meyts I27, 28
  40. Moshous D29, 30
  41. Neven B29, 30
  42. Abraham RS31
  43. Elmarsafy A32
  44. Kanariou M33
  45. King A34
  46. Licciardi F35
  47. Cruzmunoz ME36
  48. Palma P13, 37
  49. Poli C38
  50. Adeli M39
  51. Algeri M40, 41
  52. Alroqi FJ42
  53. Bastard P43, 44
  54. Bergerson JRE1
  55. Booth C45
  56. Brett A46, 47
  57. Burns SO48, 49
  58. Butte MJ50
  59. Padem N51
  60. De La Morena MT52
  61. Dbaibo G53, 54
  62. De Ravin SS1
  63. Dimitrova D55
  64. Djidjik R9
  65. Dorna MB56
  66. Dutmer CM57
  67. Elfeky R58
  68. Facchetti F59
  69. Fuleihan RL60
  70. Geha RS61
  71. Gonzalezgranado LI62, 63, 64
  72. Haljasmagi L65
  73. Ale H66, 67
  74. Hayward A68
  75. Hifanova AM69
  76. Ip W45
  77. Kaplan B70, 71
  78. Kapoor N72
  79. Karakocaydiner E15, 16
  80. Karner J65
  81. Keller MD73
  82. Davila Saldana BJ73
  83. Kiykim A74
  84. Kuijpers TW75
  85. Kuznetsova EE76
  86. Latysheva EA77
  87. Leiding JW78, 79, 80
  88. Locatelli F40, 41
  89. Alvalozada G81
  90. Mccusker C82
  91. Celmeli F83
  92. Morsheimer M84
  93. Ozen A15, 16
  94. Parvaneh N85
  95. Pasic S86
  96. Plebani A87
  97. Preece K88
  98. Prockop S89
  99. Sakovich IS17
  100. Starkova EE90
  101. Torgerson T91
  102. Verbsky J92
  103. Walter JE93
  104. Ward B94
  105. Wisner EL95
  106. Draper D1
  107. Myinthpu K1
  108. Truong PM1
  109. Lionakis MS1
  110. Similuk MB96
  111. Walkiewicz MA96
  112. Klion A97
  113. Holland SM1
  114. Oguz C98
  115. Bogunovic D99
  116. Kisand K65
  117. Su HC1, 100
  118. Tsang JS2
  119. Kuhns D6
  120. Villa A101, 102
  121. Rosenzweig SD5
  122. Pittaluga S8
  123. Notarangelo LD1
Show Affiliations
Authors Affiliations
  1. 1. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
  2. 2. Multiscale Systems Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, United States
  3. 3. Department of Pediatrics, National Taiwan University Children’s Hospital, Taipei, Taiwan
  4. 4. Pediatric Department A and the Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel HaShomer, 52621, Israel
  5. 5. Immunology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda, MD, United States
  6. 6. Neutrophil Monitoring Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, United States
  7. 7. Precision Immunology Institute, Icahn School of Medicine, New York City, NY, United States
  8. 8. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
  9. 9. Department of Medical Immunology, Beni Messous University Hospital Center, Faculty of Pharmacy, University of Algiers, Algiers, Algeria
  10. 10. Division of Pediatric Allergy and Immunology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
  11. 11. Department of Pediatrics, College of Medicine, Kuwait University, Safat, Kuwait City, Kuwait
  12. 12. Allergy and Clinical Immunology Unit, Pediatric Department, Al-Sabah Hospital, Kuwait City, Kuwait
  13. 13. Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
  14. 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. 15. Faculty of Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
  16. 16. Isil Berat Barlan Center for Translational Medicine, Istanbul Jeffrey Modell Foundation Diagnostic Center for Primary Immune Deficiencies, Istanbul, Turkey
  17. 17. Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
  18. 18. Department of Paediatrics, Universitatsklinikum Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany
  19. 19. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
  20. 20. Department of Allergy and Immunology, Royal Children’s Hospital, Melbourne, VIC, Australia
  21. 21. Angelo Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
  22. 22. Laboratory Department, Spedali Civili, Brescia, Italy
  23. 23. National Center for Gene Therapy and Drugs based on RNA Technology, CN3, Brescia, Italy
  24. 24. Division of Hematology/Oncology/Immunology, University Children’s Hospital Zurich, Zurich, Switzerland
  25. 25. Eleonore Foundation & Children’s Research Center (CRC), Zurich, Switzerland
  26. 26. Division of Pediatric Hematology and Oncology, Department of Pediatrics, Kantonsspital Aarau, Aarau, Switzerland
  27. 27. Department of Immunology and Microbiology, KU Leuven, Leuven, Belgium
  28. 28. University Hospitals Leuven, ERN-RITA Core Center, Leuven, Belgium
  29. 29. Hopital Necker Enfants Malades, Assistance Publique-Hopitaux de Paris, Universite Paris Cite, Paris, France
  30. 30. Institut Imagine, Universite Paris Cite, Paris, France
  31. 31. Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
  32. 32. Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
  33. 33. Department of Immunology—Histocompatibility, Specialized & Referral Center for Primary Immunodeficiencies—Paediatric Immunology, “Aghia Sophia” Children’s Hospital, Athens, Greece
  34. 34. Departamento de Pediatria, Hospital Luis Calvo Mackenna, Santiago, Chile
  35. 35. Pediatria Specialistica Universitaria, Ospedale Infantile Regina Margherita, Torino, Italy
  36. 36. Facultad de Medicina, Universidad Autonoma del Estado de Morelos, Morelos, Cuernavaca, Mexico
  37. 37. Clinical Immunology and Vaccinology Unit, Children’s Hospital “Bambino Gesu, Rome, Italy
  38. 38. Faculty of Medicine, Clinica Alemana Universidad del Desarrollo Roberto del Rio, Santiago, Chile
  39. 39. Department of Immunology, Sidra Medicine, Ar-Rayyan, Qatar
  40. 40. Department of Hematology/Oncology, IRCCS Bambino Gesu Children’s Hospital, Rome, Italy
  41. 41. Catholic University of the Sacred Heart, Rome, Italy
  42. 42. King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
  43. 43. Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, Assistance Publique-Hopitaux de Paris (AP-HP), Paris, France
  44. 44. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France
  45. 45. Molecular and Cellular Immunology, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
  46. 46. Hospital Pediatrico, Unidade Local de Saude de Coimbra, Coimbra, Portugal
  47. 47. Clinica Universitaria de Pediatria, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal
  48. 48. Institute of Immunity and Transplantation, University College London, London, United Kingdom
  49. 49. Department of Immunology, Royal Free London NHS Foundation Trust, London, United Kingdom
  50. 50. Department of Pediatrics, Division of Immunology, Allergy, and Rheumatology, University of California, Los Angeles, Los Angeles, CA, United States
  51. 51. Division of Pediatric Pulmonology, Allergy-Immunology and Sleep Medicine, Riley Hospital for Children, Indiana University, Indianapolis, IN, United States
  52. 52. Division of Immunology, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States
  53. 53. Department of Pediatrics and Adolescent Medicine, Faculty of Medicine, American University of Beirut Medical Center, Beirut, Lebanon
  54. 54. Center for Infectious Diseases Research (CIDR), WHO Collaborating Center for Reference and Research on Bacterial Pathogens, American University of Beirut, Beirut, Lebanon
  55. 55. Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
  56. 56. Division of Allergy and Immunology, Department of Pediatrics, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
  57. 57. Allergy and Immunology Section, Children’s Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, United States
  58. 58. Department of Clinical Immunology, Royal Free Hospital, London, United Kingdom
  59. 59. Section of Pathology, Department of Molecular and Translational Medicine, University of Brescia, Spedali Civili di Brescia, Brescia, Italy
  60. 60. Division of Allergy & Immunology, Columbia University Irving Medical Center, New York, NY, United States
  61. 61. Division of Immunology, Boston Children’s Hospital, Boston, MA, United States
  62. 62. Primary Immunodeficiency Unit, Pediatrics, Hospital 12 Octubre, Madrid, Spain
  63. 63. Instituto de Investigation Hospital 12 Octubre (imas12), Madrid, Spain
  64. 64. School of Medicine Complutense University, Madrid, Spain
  65. 65. Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
  66. 66. Division of Immunology, Allergy and Rheumatology, Joe DiMaggio Children’s Hospital, Memorial Healthcare System, Hollywood, FL, United States
  67. 67. Florida International University, Herbert Wertheim College of Medicine, Miami, FL, United States
  68. 68. Division of Infectious Diseases, Department of Pediatrics, Brown University, Rhode Island Hospital, Providence, RI, United States
  69. 69. Department of Pediatric Infectious Diseases and Pediatric Immunology, Shupyk National Healthcare University of Ukraine, Kiev, Ukraine
  70. 70. Division of Allergy, Asthma and Immunology, Cohen Children’s Medical Center, Northwell Health, New Hyde Park, NY, United States
  71. 71. Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
  72. 72. Children’s Hospital of Los Angeles, Los Angeles, CA, United States
  73. 73. Division of Allergy and Immunology, Children’s National Hospital, Washington, DC, United States
  74. 74. Division of Pediatric Allergy and Immunology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
  75. 75. Department of Pediatric Immunology, Amsterdam UMC Locatie AMC, Amsterdam, Netherlands
  76. 76. Hematology Department, Regional Clinical Hospital, Orenburg, Russian Federation
  77. 77. Immunopathology Department, NRC Institute of Immunology FMBA, Pigorov Russian National Research Medical University, Moscow, Russian Federation
  78. 78. Division of Allergy and Immunology, Department of Pediatrics, Johns Hopkins University, Baltimore, MD, United States
  79. 79. Institute for Clinical and Translational Research, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States
  80. 80. Cancer and Blood Disorders Institute, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States
  81. 81. Allergy and Immunology Division, Hospital Nacional Edgardo Rebagliati Martins, Lima, Peru
  82. 82. Division of Allergy and Clinical Immunology, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada
  83. 83. Immunology and Allergy Diseases, Saglik Bilimleri University, Antalya Training and Research Hospital Pediatric, Antalya, Turkey
  84. 84. Division of Allergy, Immunology and Transplantation, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
  85. 85. Infectious Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
  86. 86. Department of Pediatric Immunology, Mother and Child Health Institute, Medical Faculty, University of Belgrade, Belgrade, Serbia
  87. 87. University of Brescia, Brescia, Italy
  88. 88. Department of Immunology, John Hunter Children’s Hospital, Newcastle, NSW, Australia
  89. 89. Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, United States
  90. 90. Clinical Department, Regional Clinical Hospital, No. 2, Orenburg, Russian Federation
  91. 91. Allen Institute for Immunology, Seattle, WA, United States
  92. 92. Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Children’s Wisconsin, Milwaukee, WI, United States
  93. 93. Division of Pediatric Allergy/Immunology, University of South Florida, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States
  94. 94. Division of Rheumatology, Allergy and Immunology, Virginia Commonwealth University, Richmond, VA, United States
  95. 95. Division of Allergy Immunology, Department of Pediatrics, Louisiana State University Health Sciences Center New Orleans, New Orleans, LA, United States
  96. 96. Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
  97. 97. Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD, United States
  98. 98. Integrated Data Sciences Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
  99. 99. Center for Genetic Errors of Immunity, Columbia University Medical Center, New York City, NY, United States
  100. 100. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
  101. 101. Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy
  102. 102. San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), IRCSS San Raffaele Scientific Institute, Milan, 20132, Italy

Source: Science Immunology Published:2025


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. Copyright © 2025 The Authors, some rights reserved.
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