Affiliation:
1. Department of Hematology, Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan China
Abstract
AbstractObjectivesIncreasing evidence indicates that some germline genetic mutations that impair pathways required for robust host immune surveillance against EBV infection may result in an extremely high susceptibility to EBV‐associated lymphoproliferative disease (EBV+ LPD). TNFRSF9 encodes a vital costimulatory molecule that enhances CD8+ T‐cell proliferation, survival and cytolytic activity. To date, no relevant case resulting from TNFRSF9 heterozygous mutations has been identified.MethodsHere, we report the first case of CD137 deficiency caused by two novel biallelic heterozygous TNFRSF9 mutations [NM_001561.5: c.208 + 1−>AT and c.452C>A (p.T151K)] in a patient presenting with severe EBV+ LPD. Immunophenotyping and in vitro assays of lymphocyte function and NK cell activity were performed.ResultsBiallelic TNFRSF9 mutations resulted in markedly reduced or abrogated expression of CD137 on activated T, B and NK cells. CD8+ T cells from the patient had impaired activation, reduced expression/release of interferon‐γ (IFN‐γ), tumor necrosis factor‐α (TNF‐α), perforin and granzyme B, and diminished cytotoxic activity. Functional experiments identified both variations were hypomorphic mutations and played a contributing role in CD137 deficiency and the development of EBV+ LPD.ConclusionOur study expands the genetic spectrum and clinical phenotype of patients with CD137 deficiency and provides additional evidence that the TNFRSF9 gene plays a critical role in host immune responses to EBV infection.
Funder
National Natural Science Foundation of China
Subject
General Nursing,Immunology,Immunology and Allergy