脊髓多发性硬化斑块周围组织的重塑

摘要

Our knowledge of multiple sclerosis (MS) neuropathology has benefited from a number of studies that provided an in-depth description of plaques and, more recently, diffuse alterations of the normal-appearing white or grey matter. However, there have been few studies focusing on the periplaqueregions surrounding demyelinat-ed plaques, notably in MS spinal cords. In this context, the present study aimed to analyze the molecular im-munopathology of periplaque demyelinated lesions (PDLs) in the spinal cord of patients with a progressive form of MS. To achieve this goal, the neuropathological features of PDLs were analyzed in postmortem tissues derived from the cervical spinal cord of 21 patients with primary or secondary progressive MS. We found that PDLs cov-ered unexpectedly large areas of incomplete demyelination and were characterized by the superimposition of pro-and anti-inflammatory molecular signatures. Accordingly, macrophages/microglia accumulated in PDLs but ex-hibited a poor phagocytic activity toward myelin debris. Interestingly, while genes of the oligodendrocyte lineage were consistently down-regulated in PDLs, astrocyte-related molecules such as aquaporin 4, connexin 43 and the glutamate transporter EAAT1, were significantly upregulated in PDLs at the mRNA and protein levels. Overall, our work indicates that in the spinal cord of patients with a progressive form of MS, a tissue remodeling process that is temporally remote from plaque development takes place in PDLs. We propose that in spinal cord PDLs, this process is supported by subtle alterations of astrocyte functions and by low-grade inflammatory events that drive a slowly progressive loss of myelin and a failure of remyelination.%关于多发性硬化（multiple sclerosis，MS）斑块的病理以及MS患者灰白质的弥散性改变，目前已有相当多的深入研究报道。但对于脱髓鞘斑块周围组织的改变，尤其对是脊髓MS斑块周围组织的病理研究，目前几乎没有报道。本研究即对进展性脊髓MS患者的脊髓脱髓鞘病灶周围组织（periplaque demyelinated lesions，PDLs）进行分子免疫病理方面的研究。纳入初发或复发进展型脊髓MS患者21例，尸检得到其颈髓组织，对其PDLs的神经病理特征进行分析。结果显示，PDLs存在大面积的不完全性脱髓鞘现象，而且存在促炎症和抗炎症的叠加分子反应。巨噬细胞和小胶质细胞聚集在PDLs，但对脱髓鞘碎片的吞噬作用很弱。下调PDLs的少突胶质细胞基因，胶质细胞相关的分子标志物，如水通道蛋白（aquaporin）-4、缝隙连接蛋白（connexin）-43及谷氨酸转运子（glutamate transporter ）EAAT1的mRNA及蛋白表达水平均明显下调。本研究还显示，在进展型脊髓MS患者的脊髓组织中，伴随脱髓鞘斑块的形成，PDLs内的组织重塑早已开始并一直伴随着斑块的形成。笔者推测脊髓病灶PDLs内，组织重塑的过程一定伴随着星形胶质细胞功能的改变、较轻的炎症反应，共同促进了脱髓鞘的发生和进展。