Kasahara Y, Wada T, Niida Y, Yachie A, Seki H, Ishida Y, Sakai T, Koizumi F, Koizumi S, Miyawaki T, Taniguchi N
Department of Pediatrics, School of Medicine, Kanazawa University, Ishikawa, Japan.
Int Immunol. 1998 Feb;10(2):195-202. doi: 10.1093/intimm/10.2.195.
Fas is an apoptosis-signaling receptor important for homeostasis of the immune system. In this study, Fas-mediated apoptosis and Fas mutations were analyzed in three Japanese children from two families with a lymphoproliferative disorder characterized by lymphadenopathy, hepatosplenomegaly, pancytopenia, hypergammaglobulinemia and an increase in TCR alphabeta+ CD4- CD8- T cells. Apoptosis induced by anti-Fas mAb was defective in both activated T cells and B cells, and granulocytes from these patients. Truncated Fas receptor lacking the cytoplasmic death domain caused by a point mutation in the splice region of intron 7 were demonstrated in two siblings. A homozygous point mutation in the splice acceptor of intron 3 was found in the Fas gene of the third patient, which resulted in the skipping of exon 4 and complete loss of Fas expression. Corresponding to these mutations, soluble Fas concentrations were decreased and reciprocally soluble Fas ligands were increased in patients' sera. Interestingly, co-stimulation by immobilized anti-Fas mAb in T cells from the two siblings was comparable to that seen in normal T cells. These results suggest that Fas-mediated apoptosis plays a pivotal role in immunological homeostasis in vivo, especially regarding clonal deletion of immune cells in humans.
Fas是一种对免疫系统稳态至关重要的凋亡信号受体。在本研究中，对来自两个家庭的三名日本儿童进行了Fas介导的凋亡和Fas突变分析，这些儿童患有以淋巴结病、肝脾肿大、全血细胞减少、高球蛋白血症以及TCRαβ+ CD4 - CD8 - T细胞增多为特征的淋巴增殖性疾病。抗Fas单克隆抗体诱导的凋亡在这些患者的活化T细胞、B细胞和粒细胞中均存在缺陷。在两名同胞中发现了由内含子7剪接区域的点突变导致的缺乏细胞质死亡结构域的截短Fas受体。在第三名患者的Fas基因中发现了内含子3剪接受体的纯合点突变，这导致外显子4跳跃并完全丧失Fas表达。与这些突变相对应，患者血清中可溶性Fas浓度降低，而可溶性Fas配体则相应增加。有趣的是，固定化抗Fas单克隆抗体对两名同胞T细胞的共刺激作用与正常T细胞相当。这些结果表明，Fas介导的凋亡在体内免疫稳态中起关键作用，尤其是在人类免疫细胞的克隆清除方面。
