High frequency of QPY allele and linkage disequilibrium of granzyme-B in Epstein-Barr-virus-associated hemophagocytic lymphohistiocytosis
High frequency of QPY allele and linkage disequilibrium of granzyme-B in Epstein-Barr-virus-associated hemophagocytic lymphohistiocytosis
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DOI：
10.1111/j.1399-0039.2004.00325.x
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发表时间：
2004-11-01
期刊：
影响因子：
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通讯作者：
Yasukawa, M
中科院分区：
文献类型：
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作者：
Zaitsu, M;Yamamoto, K;Yasukawa, M
已证实通过穿孔素/颗粒酶途径介导 T 淋巴细胞中 Epstein-Barr 病毒 (EBV) 特异性细胞毒性；因此，涉及溶细胞分子的研究对于阐明噬血细胞性淋巴组织细胞增多症（HLH）的发病机制至关重要。这项研究分析了 EBV-HLH 和传染性单核细胞增多症患者中颗粒酶 B 的三个等位基因突变（55Q/R、95P/A 和 247Y/H）的频率，发现与健康对照相比，EBV-HLH 患者中 QPY 单倍型的患病率较高。在内含子5中也检测到A>G多态性；此外，在这些多态性之间观察到几乎完全的连锁不平衡。颗粒酶-B QPY 单倍型的隐性作用可能与 EBV-HLH 的发病机制有关。在以 QPY/QPY、RAH/RAH 和 QPY/RAH 基因型为特征的患者中，细胞毒性 T 淋巴细胞的细胞毒性和 DNA 碎片没有差异。这一发现表明，靶细胞中的 DNA 片段化不仅由颗粒酶 B 介导，还由其他分子介导，包括其他颗粒酶或 Fas。
Mediation of Epstein-Barr virus (EBV)-specific cytotoxicity in T lymphocyte via the perforin/granzyme pathway has been demonstrated; therefore, a study involving cytolytic molecules was essential for the clarification of hemophagocytic lymphohistiocytosis (HLH) pathogenesis. This investigation, which analysed the frequency of three allelic mutations of granzyme-B (55Q/R, 95P/A and 247Y/H) in patients with EBV-HLH and infectious mononucleosis, identified the high prevalence of the QPY haplotype in EBV-HLH patients in comparison with healthy controls. A > G polymorphism was also detected in intron 5; furthermore, nearly complete linkage disequilibrium was observed among these polymorphisms. The recessive role of the QPY haplotype of granzyme-B might be responsible for the pathogenesis of EBV-HLH. Cytotoxicity and DNA fragmentation of cytotoxic T lymphocytes did not differ among patients characterized by the QPY/QPY, RAH/RAH and QPY/RAH genotypes. This finding suggested that DNA fragmentation in target cells is mediated not only by granzyme-B but also by other molecules, including other granzymes or Fas.