Dysregulation of CD95/CD95 ligand apoptotic pathway in CD3+ large granular lymphocyte leukemia
Dysregulation of CD95/CD95 ligand apoptotic pathway in CD3+ large granular lymphocyte leukemia
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DOI：
10.1182/blood.v92.12.4771.424k32_4771_4777
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发表时间：
1998-12-15
期刊：
影响因子：
20.3
通讯作者：
Loughran, TP
中科院分区：
文献类型：
--
作者：
Lamy, T;Liu, JH;Loughran, TP
CD 95（Fas）诱导的细胞凋亡在清除活化的淋巴细胞和诱导外周耐受中起关键作用。CD 95/CD 95 L（Fas配体）-凋亡通路的缺陷已在自身免疫性淋巴组织增生性疾病（ALPS）和lpr或gld小鼠中被认识到，并分别归因于CD 95和CD 95 L基因突变。大颗粒淋巴细胞（LGL）白血病是一种以抗原激活的细胞毒性T淋巴细胞增殖为特征的慢性疾病。自身免疫特征如高丙种球蛋白血症、类风湿因子和循环免疫复合物是LGL白血病和ALPS的常见特征。因此，我们推测白血病LGL的扩大可能是继发于缺陷的CD 95凋亡途径。本研究检测了11例CD 3（+）LGL白血病患者CD 95和CD 95 L的表达，并探讨了CD 95单克隆抗体（MoAb）对白血病细胞凋亡的影响。我们发现，白血病LGL从每个病人表达组成性高水平的CD 95/CD 95 L，类似于在正常的活化T细胞。然而，来自这11名患者中的9名的细胞对抗CD 95诱导的细胞凋亡完全抵抗。类似地，细胞对抗CD 3-MoAb触发的细胞死亡具有抗性。抗CD 95诱导的细胞凋亡的缺乏不是由于CD 95抗原的突变。白血病LGL本身并不抵抗CD 95依赖性死亡，因为除了1例患者外，所有患者的LGL在植物血凝素/白细胞介素-1后均发生了凋亡。activation.白血病LGL对CD 95具有内在耐药性的患者具有对联合化疗具有耐药性的侵袭性LGL白血病。尽管表达高水平的CD 95，但白血病LGL对CD 95依赖性细胞凋亡具有抗性，这一发现与在CD 95 L转基因小鼠中进行的观察相似。这些数据表明，LGL白血病可能是一个有用的模型，失调的凋亡导致人类恶性肿瘤和自身免疫性疾病。(C)1998年，美国血液学会。
CD95 (Fas)-induced apoptosis plays a critical role in the elimination of activated lymphocytes and induction of peripheral tolerance. Defects in CD95/CD95L (Fas-Ligand)-apoptotic pathway have been recognized in autoimmune lymphoproliferative diseases (ALPS) and lpr or gld mice and attributed to CD95 and CD95L gene mutations, respectively. Large granular lymphocyte (LGL) leukemia is a chronic disease characterized by a proliferation of antigen-activated cytotoxic T lymphocytes. Autoimmune features such as hypergammaglobulinemia, rheumatoid factor, and circulating immune complexes are common features in LGL leukemia and ALPS. Therefore, we hypothesize that expansion of leukemic LGL may be secondary to a defective CD95 apoptotic pathway. In this study, we investigated expression of CD95 and CD95L in 11 patients with CD3(+) LGL leukemia and explored the apoptotic response to agonistic CD95 monoclonal antibody (MoAb). We found that leukemic LGL from each patient expressed constitutively high levels of CD95/CD95L, similar to those seen in normal activated T cells. However, cells from 9 of these 11 patients were totally resistant to anti-CD95-induced apoptosis. Similarly, cells were resistant to anti-CD3-MoAb-triggered cell death. Lack of anti-CD95-induced apoptosis was not due to mutations in the CD95 antigen. Leukemic LGL were not intrinsically resistant to CD95-dependent death, because LGL from all but 1 patient underwent apoptosis after phytohemagglutinin/interleukin-1. activation. The patient whose leukemic LGL were intrinsically resistant to CD95 had an aggressive form of LGL leukemia that was resistant to combination chemotherapy. These findings that leukemic LGL are resistant to CD95-dependent apoptosis despite expressing high levels of CD95 are similar to observations made in CD95L transgenic mice. These data suggest that LGL leukemia may be a useful model of dysregulated apoptosis causing human malignancy and autoimmune disease. (C) 1998 by The American Society of Hematology.