Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency-Reference-Cited by-同舟云学术

Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency

Published:2020-12-03 Issue:23 Volume:136 Page:2638-2655
ISSN:0006-4971
Container-title:Blood
language:en
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Author:

Ghosh Sujal¹,Köstel Bal Sevgi²³⁴^ORCID,Edwards Emily S. J.⁵⁶^ORCID,Pillay Bethany⁵⁶,Jiménez Heredia Raúl²³⁴,Erol Cipe Funda⁷^ORCID,Rao Geetha⁵,Salzer Elisabeth²³⁴⁸,Zoghi Samaneh²³⁴⁹^ORCID,Abolhassani Hassan⁹¹⁰^ORCID,Momen Tooba¹¹,Gostick Emma¹²,Price David A.¹²¹³^ORCID,Zhang Yu¹⁴¹⁵,Oler Andrew J.¹⁵¹⁶^ORCID,Gonzaga-Jauregui Claudia¹⁷^ORCID,Erman Baran¹⁸¹⁹^ORCID,Metin Ayse²⁰^ORCID,Ilhan Inci²¹,Haskologlu Sule²²^ORCID,Islamoglu Candan²²^ORCID,Baskin Kubra²²,Ceylaner Serdar²³^ORCID,Yilmaz Ebru²⁴²⁵^ORCID,Unal Ekrem²⁴²⁵^ORCID,Karakukcu Musa²⁴²⁵^ORCID,Berghuis Dagmar²⁶,Cole Theresa²⁷,Gupta Aditya K.²⁸,Hauck Fabian²⁹^ORCID,Kogler Hubert⁸,Hoepelman Andy I. M.³⁰^ORCID,Baris Safa³¹³²³³,Karakoc-Aydiner Elif³¹³²³³,Ozen Ahmet³¹³²³³,Kager Leo⁸,Holzinger Dirk³⁴^ORCID,Paulussen Michael³⁵,Krüger Renate³⁶^ORCID,Meisel Roland¹,Oommen Prasad T.¹^ORCID,Morris Emma³⁷^ORCID,Neven Benedicte³⁸³⁹,Worth Austen⁴⁰^ORCID,van Montfrans Joris⁴¹,Fraaij Pieter L. A.⁴²⁴³,Choo Sharon²⁷,Dogu Figen²²,Davies E. Graham⁴⁰,Burns Siobhan³⁷⁴⁴,Dückers Gregor⁴⁵,Becker Ruy Perez⁴⁵,von Bernuth Horst³⁶⁴⁶⁴⁷,Latour Sylvain⁴⁸^ORCID,Faraci Maura⁴⁹,Gattorno Marco⁵⁰,Su Helen C.¹⁴¹⁵,Pan-Hammarström Qiang⁵¹^ORCID,Hammarström Lennart¹⁰⁵²,Lenardo Michael J.¹⁵⁵³^ORCID,Ma Cindy S.⁵⁶^ORCID,Niehues Tim⁴²,Aghamohammadi Asghar⁹⁵⁴,Rezaei Nima⁹⁵⁴^ORCID,Ikinciogullari Aydan²²^ORCID,Tangye Stuart G.⁵⁶^ORCID,Lankester Arjan C.²⁶,Boztug Kaan²³⁴⁸⁵⁵

Affiliation:

1. Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Center of Child and Adolescent Health, Heinrich-Heine-University, Düsseldorf, Germany;

2. Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria;

3. St. Anna Children’s Cancer Research Institute (CCRI), Vienna, Austria;

4. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria;

5. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia;

6. St. Vincent’s Clinical School, UNSW Sydney, Randwick, NSW, Australia;

7. Department of Pediatric Allergy and Immunology, Istinye University, Istanbul, Turkey;

8. St. Anna Children’s Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria;

9. Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran;

10. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden;

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. Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom;

13. Vaccine Research Center,

14. Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research,

15. Clinical Genomics Program, and

16. Bioinformatics 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;

17. Regeneron Genetics Center, Tarrytown, NY;

18. Institute of Child Health, Hacettepe University, Ankara, Turkey;

19. Can Sucak Research Laboratory for Translational Immunology, Center for Genomics and Rare Diseases, Hacettepe University, Ankara, Turkey;

20. Division of Pediatric Allergy and Immunology, University of Health Sciences/Ankara City Hospital/Children’s Hospital, Ankara, Turkey;

21. Division of Pediatric Oncology, University of Health Sciences/Ankara City Hospital/Children’s Hospital, Ankara, Turkey;

22. Department of Pediatric Allergy and Immunology, School of Medicine, Ankara University, Ankara, Turkey;

23. Intergen Genetic Diagnosis and Research Center, Ankara, Turkey;

24. Department of Pediatrics, Division of Pediatric Hematology & Oncology & Molecular Biology and Genetic Department, Erciyes University, Kayseri, Turkey;

25. Gevher Nesibe Genom and Stem Cell Institution, GENKOK Genome and Stem Cell Center, Erciyes University, Kayseri, Turkey;

26. Willem-Alexander Children’s Hospital, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands;

27. Department of Allergy and Immunology, The Royal Children’s Hospital, Melbourne, VIC, Australia;

28. Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India;

29. Dr von Hauner Children’s Hospital, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany;

30. Department of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht, The Netherlands;

31. Division of Allergy and Immunology, Marmara University, Istanbul, Turkey;

32. The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey;

33. Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey;

34. Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany;

35. Vestische Kinder-und Jugendklinik, Witten/Herdecke University, Datteln, Germany;

36. Department of Pediatric Pulmonology, Immunology, and Intensive Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany;

37. Institute of Immunity & Transplantation, University College London, Royal Free Hospital, London, United Kingdom;

38. Unité d’Immuno-Hematologie et Rhumatologie, Département de Pédiatrie Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France;

39. INSERM U1163, Imagine Institute, Université de Paris, Paris, France;

40. UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom;

41. Department of Pediatric Immunology and Infectious Diseases, Wilhelmina Children’s Hospital, UMC Utrecht, Utrecht, The Netherlands;

42. Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands;

43. Department of Pediatrics, Subdivision Infectious Diseases and Immunology, Erasmus MC-Sophia, Rotterdam, The Netherlands;

44. Department of Immunology, Royal Free London National Health Service (NHS) Foundation Trust, London, United Kingdom;

45. Department of Pediatrics, Helios Children’s Hospital, Krefeld, Germany;

46. Department of Immunology, Labor Berlin GmbH, Berlin, Germany;

47. Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany;

48. Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, INSERM U1163, Imagine Institute, Université de Paris, Paris, France;

49. Hematopoietic Stem Cell Transplantation Unit and Istituto di Ricovero e Cura Pediatrico a Carattere Scientifico (IRCSS) Istituto Giannina Gaslini Research Institute Genova, Italy;

50. Center for Autoinflammatory Diseases and Immunodeficiency, Istituto di Ricovero e Cura Pediatrico a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genova, Italy;

51. Department of Biosciences and Nutrition (NEO), Karolinska Institutet, Karolinska, Sweden;

52. Beijing Genomics Institute (BGI) Shenzhen, Shenzhen, China;

53. Molecular Development of the Immune System Section, Laboratory of Immune System Biology, NIAID, National Institutes of Health, Bethesda, MD;

54. Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran; and

55. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

Abstract

Abstract 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 = 33; CD70, n = 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 EBV+ 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 CD8+ 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Link

http://ashpublications.org/blood/article-pdf/136/23/2638/1791162/bloodbld2020006738.pdf

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