因两个新型双等位基因 TNFRSF9 突变导致的 CD137 缺陷，患者表现为严重的 EBV 相关淋巴增殖性疾病

Increasing 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.

Here, 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.

Biallelic 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.

Our 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.