Defective T cell Fas function in patients with multiple sclerosis
Defective T cell Fas function in patients with multiple sclerosis
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DOI：
10.1212/wnl.55.7.921
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发表时间：
2000-10-10
期刊：
影响因子：
9.9
通讯作者：
Dianzani, U
中科院分区：
文献类型：
--
作者：
Comi, C;Leone, M;Dianzani, U
背景：Fas（CD 95）触发程序性细胞死亡，并参与关闭免疫反应。Fas或其信号通路的遗传性有害突变导致自身免疫/淋巴组织增生综合征（ALPS）。目的：评估Fas功能下降在MS发展中发挥作用的可能性。方法：作者通过评估单克隆抗体（Mab）触发Fas后的细胞存活率，评估了32名复发缓解型MS（RRMS）患者、15名继发性进展型MS（SPMS）患者和15名原发性进展型MS（PPMS）患者的长期T细胞系（培养21天）中的Fas功能。结果：Fas诱导的细胞死亡在所有患者组中均显著低于对照组，SPMS组低于RRMS组。此外，8/15例PPMS、10/15例SPMS和8/32例RRMS患者对Fas明显耐药。所有患者组对Fas诱导的细胞死亡的抵抗频率均显著高于对照组（2/75），SPMS组高于RRMS组。两名Fas耐药患者的父母是Fas耐药的，并且来自两名Fas耐药患者的T细胞与Fas敏感的HUT 78细胞的融合产生了Fas耐药的杂交系，这一发现表明，Fas耐药是由于Fas信号传导途径的遗传改变，分子的产生对正常的Fas系统产生了显性负效应。结论：免疫应答关闭系统的缺陷可能参与了MS的发病机制，尤其是其进行性演变。
Background; Fas (CD95) triggers programmed cell death and is involved in shutting off the immune response. Inherited deleterious mutations hitting Fas or its signaling pathway cause autoimmune/lymphoproliferative syndrome (ALPS). Objective: To assess the possibility that decreased Fas function plays a role in development of MS. Methods: The authors evaluated Fas function in long-term T cell lines (21 days of culture) from 32 patients with relapsing-remitting MS (RRMS), 15 with secondary progressive MS (SPMS), and 15 with primary progressive MS (PPMS) by assessing cell survival upon Fas triggering by monoclonal antibodies (Mab). Results: Fas-induced cell death was significantly lower in all patient groups than in controls, and lower in SPMS than in RRMS. Moreover, 8/15 patients with PPMS, 10/15 with SPMS, and 8/32 with RRMS were frankly resistant to Fas. Frequency of resistance to Fas-induced cell death was significantly higher in all patient groups than in controls (2/75), and higher in SPMS than in RRMS. The findings that the parents of two Fas-resistant patients were Fas-resistant and that fusion of T cells from two Fas-resistant patients with Fas-sensitive HUT78 cells gave rise to Fas-resistant hybrid lines suggest that Fas-resistance is due to inherited alterations of the Fas signaling pathway, with production of molecules exerting a dominant negative effect on a normal Fas system. Conclusions: Defects of the immune response shutting-off system may be involved in the pathogenesis of MS, particularly in its progressive evolution.