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


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Ghosh S., Bal S. K. , Edwards E. S. , Pillay B., Heredia R. J. , Cipe F. E. , ...More

Blood, vol.136, no.23, pp.2638-2655, 2020 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 136 Issue: 23
  • Publication Date: 2020
  • Doi Number: 10.1182/blood.2020006738
  • Journal Name: Blood
  • Journal Indexes: Science Citation Index Expanded, Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, Chemical Abstracts Core, EMBASE, International Pharmaceutical Abstracts, MEDLINE, Veterinary Science Database
  • Page Numbers: pp.2638-2655
  • Keywords: Deficiencies are IEIs characterized by EBV-associated immune dysregulation including HLH, Lymphoproliferation, Malignancy

Abstract

© 2020 American Society of Hematology. All rights reserved.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.