Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg, Hannover, Germany.
J Cell Mol Med. 2010 Jan;14(1-2):434-48. doi: 10.1111/j.1582-4934.2008.00646.x. Epub 2009 Jan 14.
Theiler's murine encephalomyelitis is an experimentally virus-induced inflammatory demyelinating disease of the spinal cord, displaying clinical and pathological similarities to chronic progressive multiple sclerosis. The aim of this study was to identify pathways associated with chronic demyelination using an assumption-free combined microarray and immunohistology approach. Movement control as determined by rotarod assay significantly worsened in Theiler's murine encephalomyelitis -virus-infected SJL/J mice from 42 to 196 days after infection (dpi). In the spinal cords, inflammatory changes were detected 14 to 196 dpi, and demyelination progressively increased from 42 to 196 dpi. Microarray analysis revealed 1001 differentially expressed genes over the study period. The dominating changes as revealed by k-means and functional annotation clustering included up-regulations related to intrathecal antibody production and antigen processing and presentation via major histocompatibility class II molecules. A random forest machine learning algorithm revealed that down-regulated lipid and cholesterol biosynthesis, differentially expressed neurite morphogenesis and up-regulated toll-like receptor-4-induced pathways were intimately associated with demyelination as measured by immunohistology. Conclusively, although transcriptional changes were dominated by the adaptive immune response, the main pathways associated with demyelination included up-regulation of toll-like receptor 4 and down-regulation of cholesterol biosynthesis. Cholesterol biosynthesis is a rate limiting step of myelination and its down-regulation is suggested to be involved in chronic demyelination by an inhibition of remyelination.
Theiler 氏鼠脑脊髓炎是一种实验性病毒诱导的脊髓炎症性脱髓鞘疾病，其临床表现和病理学特征与慢性进行性多发性硬化症相似。本研究旨在使用无假设的组合微阵列和免疫组织化学方法，确定与慢性脱髓鞘相关的途径。从感染后的第 42 天到第 196 天，通过旋转棒试验测定的运动控制在 Theiler 氏鼠脑脊髓炎病毒感染的 SJL/J 小鼠中显著恶化。在脊髓中，炎症变化在 14 至 196 dpi 时被检测到，脱髓鞘从第 42 天到第 196 天逐渐增加。微阵列分析显示在整个研究期间有 1001 个差异表达的基因。通过 k-means 和功能注释聚类揭示的主要变化包括与鞘内抗体产生以及通过主要组织相容性复合体 II 分子进行抗原加工和呈递相关的上调。随机森林机器学习算法显示，下调的脂质和胆固醇生物合成、差异表达的神经突形态发生和上调的 Toll 样受体 4 诱导途径与免疫组织化学测定的脱髓鞘密切相关。总之，尽管转录变化主要由适应性免疫反应主导，但与脱髓鞘相关的主要途径包括 Toll 样受体 4 的上调和胆固醇生物合成的下调。胆固醇生物合成是髓鞘形成的限速步骤，其下调被认为通过抑制髓鞘再生而参与慢性脱髓鞘。
