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    【6h】 Mechanisms of demyelination and axonal damage in a CD8+ T cell-mediated model of spontaneous demyelinating disease.

    机译CD8 + T细胞介导的自发性脱髓鞘疾病模型中脱髓鞘和轴突损伤的机制。

    【摘要】Autoimmune demyelinating diseases of the nervous system are a major cause for neurological impairment in humans. Recent evidence indicates that CD8+ T cells may contribute significantly to pathogenesis in these conditions but the mechanisms by which CD8+ T cells induce damage remain to be established. To understand the mechanisms by which CD8+ T cells may induce nervous tissue injury in vivo, we study an animal model (referred to as L31) that spontaneously develops CD8+ T cell-mediated demyelination and axonal damage in the central nervous system (CNS).;We also determined the upregulation of the chemokines CCL5 and CXCL9 and the chemokine receptor CXCR3 in the CNS of L31 mice and established that absence of CXCR3 expression was sufficient to inhibit CD8+ T cell accumulation in the CNS, microglial activation, demyelination and disease development in the L31 model, although CXCR3 deficiency did not alter the functional phenotype of transgenic CD8+ T cells. In addition, no compensatory effect for CCR5 could be detected in L31 mice.;Finally, we established the presence of CD8+ T cells and tissue damage in the peripheral nervous system and obtained evidence suggesting that disease in the L31 mice may develop primarily in the CNS and spread into the peripheral nervous system as disease develops.;Our results support the relevance of CD8+ T cells in the pathogenesis of autoimmune disease of the nervous system and provide evidence implicating specific mechanisms in CD8+ T cell-mediated neuroinflammation in the L31 model.;In this project, we revealed that CD8+ T cells located in clusters at specific sites within the CNS of L31 mice and their location was associated with areas of demyelination. We showed that oligodendrocytes, but not neurons, from L31 mice up-regulated their expression of major histocompatibility complex class I (MHC I) molecules and had thus the potential to interact with CNS-infiltrating CD8+ T cells in a MHC I-dependent manner before clinical manifestations of disease. We reported that active caspase 3 was present in oligodendrocytes, suggesting that oligodendrocytes undergo apoptosis in L31 mice. We found that CNS-infiltrating CD8+ T cells from L31 mice were activated effector cells and we provided evidence showing that these cells degranulated in situ; nonetheless, we found that demyelination did not occur through either perforin- or Fas/FasL-dependent mechanisms.

    【摘要机译】神经系统的自身免疫性脱髓鞘疾病是人类神经系统损害的主要原因。最近的证据表明,在这些情况下,CD8 + T细胞可能显着促进了发病机理,但CD8 + T细胞诱导损伤的机制尚待建立。为了了解CD8 + T细胞在体内诱导神经组织损伤的机制,我们研究了一种动物模型(称为L31),该模型自发地发展CD8 + T细胞介导的脱髓鞘作用和中枢神经系统(CNS)的轴突损伤。我们还确定了L31小鼠中枢神经系统趋化因子CCL5和CXCL9以及趋化因子受体CXCR3的上调,并确定缺乏CXCR3表达足以抑制中枢神经系统CD8 + T细胞的积累,小胶质细胞活化,脱髓鞘和疾病的发展。 L31模型,尽管CXCR3缺乏并没有改变转基因CD8 + T细胞的功能表型。此外,在L31小鼠中未检测到对CCR5的补偿作用。最后,我们确定了CD8 + T细胞的存在和周围神经系统的组织损伤,并获得了表明L31小鼠疾病可能主要在中枢神经系统发展的证据。我们的研究结果支持了CD8 + T细胞在神经系统自身免疫性疾病发病机制中的相关性,并提供了证据证明L31模型中CD8 + T细胞介导的神经炎症的具体机制。在该项目中,我们揭示了CD8 + T细胞位于L31小鼠中枢神经系统内特定部位的簇中,其位置与脱髓鞘区域有关。我们显示L31小鼠的少突胶质细胞而非神经元上调了它们的主要组织相容性复合物I类(MHC I)分子的表达,因此具有在MHC I依赖方式下与CNS浸润CD8 + T细胞相互作用的潜力疾病的临床表现。我们报告说活跃的胱天蛋白酶3存在于少突胶质细胞中,这表明少突胶质细胞在L31小鼠中经历凋亡。我们发现,来自L31小鼠的CNS浸润CD8 + T细胞是激活的效应细胞,并且我们提供的证据表明这些细胞在原位脱颗粒。尽管如此,我们发现通过穿孔素依赖性或Fas / FasL依赖性机制均未发生脱髓鞘。

    【原文格式】PDF

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