Shen Kefeng, Wang Jiachen, Zhou Kuangguo, Mu Wei, Zhang Meilan, Deng Xinyue, Cai Haodong, Zhang Wei, Huang Wei, Xiao Min
Department of Hematology, Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan China.
Clin Transl Immunology. 2023 May 2;12(5):e1448. doi: 10.1002/cti2.1448. eCollection 2023.
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). encodes a vital costimulatory molecule that enhances CD8 T-cell proliferation, survival and cytolytic activity. To date, no relevant case resulting from heterozygous mutations has been identified.
Here, we report the first case of CD137 deficiency caused by two novel biallelic heterozygous mutations [NM_001561.5: c.208 + 1->AT and c.452C>A (p.T151K)] in a patient presenting with severe EBV LPD. Immunophenotyping and assays of lymphocyte function and NK cell activity were performed.
Biallelic 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 gene plays a critical role in host immune responses to EBV infection.
越来越多的证据表明，一些种系基因突变会损害宿主对EBV感染进行有效免疫监视所需的通路，可能导致对EBV相关淋巴增殖性疾病（EBV LPD）的极高易感性。CD137编码一种重要的共刺激分子，可增强CD8 T细胞的增殖、存活和细胞溶解活性。迄今为止，尚未发现由CD137杂合突变导致的相关病例。
在此，我们报告了首例由两个新的双等位基因杂合突变[NM_001561.5：c.208+1->AT和c.452C>A（p.T151K）]引起的CD137缺陷病例，该患者患有严重的EBV LPD。进行了免疫表型分析以及淋巴细胞功能和NK细胞活性检测。
双等位基因CD137突变导致活化的T、B和NK细胞上CD137的表达明显降低或缺失。患者的CD8 T细胞活化受损，干扰素-γ（IFN-γ）、肿瘤坏死因子-α（TNF-α）、穿孔素和颗粒酶B的表达/释放减少，细胞毒性活性减弱。功能实验确定这两种变异均为亚效突变，并在CD137缺陷和EBV LPD的发生中起作用。
我们的研究扩展了CD137缺陷患者的基因谱和临床表型，并提供了额外的证据表明CD137基因在宿主对EBV感染的免疫反应中起关键作用。
