Caspase-mediated oligodendrocyte cell death in the pathogenesis of autoimmune demyelination
Caspase-mediated oligodendrocyte cell death in the pathogenesis of autoimmune demyelination
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DOI：
10.1016/s0168-0102(03)00127-5
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发表时间：
2003-08-01
影响因子：
2.9
通讯作者：
Miura, M
中科院分区：
文献类型：
--
作者：
Hisahara, S;Okano, H;Miura, M
多发性硬化（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）是中枢神经系统（CNS）的炎性疾病，其特征在于局部区域的脱髓鞘。NIS被认为是由活化的免疫细胞如T-和B-淋巴细胞和巨噬细胞/小胶质细胞介导的自身免疫性疾病。淋巴细胞在外周组织中由抗原引发，并且克隆扩增的细胞浸润CNS。它们产生大量的炎症和细胞因子，导致脱髓鞘和轴突变性。虽然一些研究表明，少突胶质细胞（OLG），髓鞘形成的神经胶质细胞在中枢神经系统中，是敏感的细胞死亡刺激，如细胞毒性细胞因子，抗髓鞘抗体，一氧化氮，和氧化应激，在体外，在MS/EAE的OLG损伤的机制仍然不清楚。在OLG和caspase-11缺陷小鼠中特异性表达抗凋亡蛋白的转基因小鼠对EAE诱导具有显著抗性。组织学分析显示，这些小鼠的CNS中半胱天冬酶激活的OLG和死亡的OLG的数量减少。浸润的免疫细胞的数量和细胞因子的量也显着减少在EAE病变。因此，半胱天冬酶介导的OLG死亡通过诱导局部炎症事件导致脱髓鞘加重和神经学表现恶化。(C)2003年Elsevier Science爱尔兰有限公司和日本神经科学学会。All rights reserved.
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. NIS is believed to be an autoimmune disorder mediated by activated immune cells such as T- and B-lymphocytes and macrophages/microglia. Lymphocytes are primed in the peripheral tissues by antigens, and clonally expanded cells infiltrate the CNS. They produce large amounts of inflammatory and cytokines that lead to demyelination and axonal degeneration. Although several studies have shown that oligodendrocytes (OLGs), the myelin-forming glial cells in the CNS, are sensitive to cell death stimuli, such as cytotoxic cytokines, anti-myelin antibodies, nitric oxide, and oxidative stress, in vitro, the mechanisms underlying injury to the OLGs in MS/EAE remain unclear. Transgenic mice that express the anti-apoptotic protein specifically in OLGs and caspase-11-deficient mice are significantly resistant to EAE induction. Histopathological analyses show that the number of caspase-activated OLGs and dead OLGs are reduced in the CNS of these mice. The numbers of infiltrating immune cells and the amounts of cytokines are also markedly reduced in EAE lesions. Therefore, caspase-mediated OLG death leads to the exacerbation of demyelination and the deterioration of neurological manifestations by inducing local inflammatory events. (C) 2003 Elsevier Science Ireland Ltd and Japan Neuroscience Society. All rights reserved.