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Extended Clinical and Immunological Phenotype and Transplant Outcome in Cd27 and Cd70 Deficiency Publisher Pubmed



Ghosh S1 ; Bal SK2, 3, 4 ; Edwards ESJ5, 6 ; Pillay B5, 6 ; Heredia RJ2, 3, 4 ; Cipe FE7 ; Rao G5 ; Salzer E2, 3, 4, 8 ; Zoghi S2, 3, 4, 9 ; Abolhassani H9, 10 ; Momen T11 ; Gostick E12 ; Price DA12, 13 ; Zhang Y14, 15 Show All Authors
Authors
  1. Ghosh S1
  2. Bal SK2, 3, 4
  3. Edwards ESJ5, 6
  4. Pillay B5, 6
  5. Heredia RJ2, 3, 4
  6. Cipe FE7
  7. Rao G5
  8. Salzer E2, 3, 4, 8
  9. Zoghi S2, 3, 4, 9
  10. Abolhassani H9, 10
  11. Momen T11
  12. Gostick E12
  13. Price DA12, 13
  14. Zhang Y14, 15
  15. Oler AJ15
  16. Gonzagajauregui C16
  17. Erman B17, 18
  18. Metin A19
  19. Ilhan I20
  20. Haskologlu S21
  21. Islamoglu C21
  22. Baskin K21
  23. Ceylaner S22
  24. Yilmaz E23, 24
  25. Unal E23, 24
  26. Karakukcu M23, 24
  27. Berghuis D25
  28. Cole T26
  29. Gupta AK27
  30. Hauck F28
  31. Kogler H8
  32. Hoepelman AIM29
  33. Baris S30
  34. Karakocaydiner E30
  35. Ozen A30, 31, 32
  36. Kager L8
  37. Holzinger D33
  38. Paulussen M34
  39. Kruger R35
  40. Meisel R1
  41. Oommen PT1
  42. Morris E36
  43. Neven B37, 38
  44. Worth A39
  45. Van Montfrans J40
  46. Fraaij PLA41, 42
  47. Choo S26
  48. Dogu F21
  49. Graham Davies E39
  50. Burns S36, 43
  51. Duckers G44
  52. Becker RP44
  53. Von Bernuth H35, 45, 46
  54. Latour S47
  55. Faraci M48
  56. Gattorno M49
  57. Su HC14, 15
  58. Panhammarstrom Q50
  59. Hammarstrom L10, 51
  60. Lenardo MJ15, 52
  61. Ma CS5, 6
  62. Niehues T44
  63. Aghamohammadi A9, 53
  64. Rezaei N9, 53
  65. Ikinciogullari A21
  66. Tangye SG5, 6
  67. Lankester AC25
  68. Boztug K2, 3, 4, 8
Show Affiliations
Authors Affiliations
  1. 1. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Dusseldorf, Germany
  2. 2. Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
  3. 3. St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria
  4. 4. CeMM Research Center for Molecular Medicine, Austrian Academy of Sciences, Vienna, Austria
  5. 5. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  6. 6. St. Vincent’s Clinical School, UNSW Sydney, Randwick, NSW, Australia
  7. 7. Department of Pediatric Allergy and Immunology, Istinye University, Istanbul, Turkiye
  8. 8. St. Anna Children’s Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
  9. 9. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  10. 10. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden
  11. 11. Department of Allergy and Clinical Immunology, Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
  12. 12. Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom
  13. 13. Vaccine Research Center, United States
  14. 14. Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, United States
  15. 15. Clinical Genomics Program, and 16Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Bethesda, MD, United States
  16. 16. Regeneron Genetics Center, Tarrytown, NY, United States
  17. 17. Institute of Child Health, Hacettepe University, Ankara, Turkiye
  18. 18. Can Sucak Research Laboratory for Translational Immunology, Center for Genomics and Rare Diseases, Hacettepe University, Ankara, Turkiye
  19. 19. Division of Pediatric Allergy and Immunology, University of Health Sciences, Ankara City Hospital, Children’s Hospital, Ankara, Turkiye
  20. 20. Division of Pediatric Oncology, University of Health Sciences, Ankara City Hospital, Children’s Hospital, Ankara, Turkiye
  21. 21. Department of Pediatric Allergy and Immunology, School of Medicine, Ankara University, Ankara, Turkiye
  22. 22. Intergen Genetic Diagnosis and Research Center, Ankara, Turkiye
  23. 23. Department of Pediatrics, Division of Pediatric Hematology & Oncology & Molecular Biology and Genetic Department, Erciyes University, Kayseri, Turkiye
  24. 24. Gevher Nesibe Genom and Stem Cell Institution, GENKOK Genome and Stem Cell Center, Erciyes University, Kayseri, Turkiye
  25. 25. Willem-Alexander Children’s Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands
  26. 26. Department of Allergy and Immunology, Royal Children’s Hospital, Melbourne, VIC, Australia
  27. 27. Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
  28. 28. Dr von Hauner Children’s Hospital, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
  29. 29. Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, Netherlands
  30. 30. Division of Allergy and Immunology, Marmara University, Istanbul, Turkiye
  31. 31. Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkiye
  32. 32. Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkiye
  33. 33. Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany
  34. 34. Vestische Kinder-und Jugendklinik, Witten/Herdecke University, Datteln, Germany
  35. 35. Department of Pediatric Pulmonology, Immunology, and Intensive Care Medicine, Charite-Universitatsmedizin Berlin, Berlin, Germany
  36. 36. Institute of Immunity & Transplantation, University College London, Royal Free Hospital, London, United Kingdom
  37. 37. Unite d’Immuno-Hematologie et Rhumatologie, Departement de Pediatrie Necker-Enfants Malades Hospital, Assistance Publique-Hopitaux de Paris (APHP), Paris, France
  38. 38. INSERM U1163, Imagine Institute, Universite de Paris, Paris, France
  39. 39. UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
  40. 40. Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children’s Hospital, UMC Utrecht, Utrecht, Netherlands
  41. 41. Department of Viroscience, Erasmus MC, Rotterdam, Netherlands
  42. 42. Department of Pediatrics, Subdivision Infectious Diseases and Immunology, Erasmus MC-Sophia, Rotterdam, Netherlands
  43. 43. Department of Immunology, Royal Free London National Health Service (NHS) Foundation Trust, London, United Kingdom
  44. 44. Department of Pediatrics, Helios Children’s Hospital, Krefeld, Germany
  45. 45. Department of Immunology, Labor Berlin GmbH, Berlin, Germany
  46. 46. Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany
  47. 47. Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM U1163, Imagine Institute, Universite de Paris, Paris, France
  48. 48. Hematopoietic Stem Cell Transplantation Unit, Istituto di Ricovero e Cura Pediatrico a Carattere Scientifico (IRCSS), Istituto Giannina Gaslini Research Institute, Genova, Italy
  49. 49. Center for Autoinflammatory Diseases and Immunodeficiency, Istituto di Ricovero e Cura Pediatrico a Carattere Scientifico (IRCCS), Istituto Giannina Gaslini, Genova, Italy
  50. 50. Department of Biosciences and Nutrition (NEO), Karolinska Institutet, Karolinska, Sweden
  51. 51. Beijing Genomics Institute (BGI) Shenzhen, Shenzhen, China
  52. 52. Molecular Development of the Immune System Section, Laboratory of Immune System Biology, NIAID, National Institutes of Health, Bethesda, MD, United States
  53. 53. Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
  54. 54. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

Source: Blood Published:2020


Abstract

to lymphoma.; Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n 5 33; CD70, n 5 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV1 at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD81 T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma. © 2020 American Society of Hematology. All rights reserved.