期刊
BLOOD
卷 136, 期 23, 页码 2638-2655出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020006738
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资金
- European Research Council (ERC) [820074]
- Austrian Science Fund (FWF) [P29951-B30]
- Susan and John Freeman Cancer Research Grant from Cancer Council NSW (Australia)
- National Health and Medical Research Council of Australia (NHMRC) [1127157]
- Wellcome Trust Senior Investigator Award [100326/Z/12/Z]
- Office of Health and Medical Research of the New South Wales Government of Australia
- NHMRC [104925, 176665]
- German Centre for Infection Research (DZIF) [TTU 07.909]
- Else Kroner-Fresenius Stiftung (EKFS) [2017_A110]
- German Federal Ministry of Education and Research (BMBF) [01GM1910C]
- UK National Institutes of Health Research
- Great Ormond Street Hospital Biomedical Research Centre
- Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health
- European Research Council (ERC) [820074] Funding Source: European Research Council (ERC)
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000566, ZIAAI001059] Funding Source: NIH RePORTER
- Wellcome Trust [100326/Z/12/Z] Funding Source: Wellcome Trust
- Austrian Science Fund (FWF) [P29951] Funding Source: Austrian Science Fund (FWF)
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 EBV1 at diagnosis, but only similar to 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.
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