Lieury Alice, Chanal Marie, Androdias Géraldine, Reynolds Richard, Cavagna Sylvie, Giraudon Pascale, Confavreux Christian, Nataf Serge
INSERM U1028, CNRS UMR 5292, Lyon Neuroscience Research Center, Neuro-Oncology and Neuro-Inflammation Team, Lyon, France; University Lyon 1, Lyon, France.
Glia. 2014 Oct;62(10):1645-58. doi: 10.1002/glia.22705. Epub 2014 Jun 7.
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 periplaque regions surrounding demyelinated plaques, notably in MS spinal cords. In this context, the present study aimed to analyze the molecular immunopathology 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 covered 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 exhibited 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.
我们对多发性硬化症（MS）神经病理学的认识受益于多项研究，这些研究深入描述了斑块，以及最近对外观正常的白质或灰质的弥漫性改变。然而，很少有研究关注脱髓鞘斑块周围的斑块周围区域，尤其是在MS脊髓中。在此背景下，本研究旨在分析进行性MS患者脊髓中斑块周围脱髓鞘病变（PDL）的分子免疫病理学。为实现这一目标，对21例原发性或继发性进行性MS患者颈髓的尸检组织中PDL的神经病理学特征进行了分析。我们发现，PDL覆盖了出乎意料的大面积不完全脱髓鞘区域，其特征是促炎和抗炎分子特征的叠加。相应地，巨噬细胞/小胶质细胞在PDL中积聚，但对髓磷脂碎片的吞噬活性较差。有趣的是，虽然少突胶质细胞谱系的基因在PDL中持续下调，但水通道蛋白4、连接蛋白43和谷氨酸转运体EAAT1等星形胶质细胞相关分子在PDL的mRNA和蛋白质水平上显著上调。总体而言，我们的研究表明，在进行性MS患者的脊髓中，PDL中发生了一个与斑块形成在时间上相隔较远的组织重塑过程。我们提出，在脊髓PDL中，这一过程由星形胶质细胞功能的细微改变和低度炎症事件支持，这些事件导致髓磷脂缓慢进行性丧失和髓鞘再生失败。
