Han May H, Hwang Sun-Il, Roy Dolly B, Lundgren Deborah H, Price Jordan V, Ousman Shalina S, Fernald Guy Haskin, Gerlitz Bruce, Robinson William H, Baranzini Sergio E, Grinnell Brian W, Raine Cedric S, Sobel Raymond A, Han David K, Steinman Lawrence
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature. 2008 Feb 28;451(7182):1076-81. doi: 10.1038/nature06559. Epub 2008 Feb 17.
Understanding the neuropathology of multiple sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits. Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque. Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation. In vivo administration of hirudin or recombinant activated protein C reduced disease severity in experimental autoimmune encephalomyelitis and suppressed Th1 and Th17 cytokines in astrocytes and immune cells. Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of experimental autoimmune encephalomyelitis. A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade.
了解多发性硬化症（MS）的神经病理学对于改进治疗方法至关重要。因此，识别MS病理类型特有的靶点可能具有治疗益处。在此，我们通过激光捕获显微切割和蛋白质组学，鉴定出MS三种主要病变类型（急性斑块、慢性活动性斑块和慢性斑块）特有的蛋白质。比较蛋白质组学图谱在慢性活动性斑块样本中鉴定出组织因子和蛋白C抑制剂，提示与凝血相关分子的失调。在实验性自身免疫性脑脊髓炎中，水蛭素或重组活化蛋白C的体内给药降低了疾病严重程度，并抑制了星形胶质细胞和免疫细胞中的Th1和Th17细胞因子。重组活化蛋白C突变形式的给药表明，其抗凝功能和信号传导功能对于实验性自身免疫性脑脊髓炎的最佳改善均至关重要。蛋白质组学方法揭示了针对MS特定病理阶段的潜在治疗靶点，并表明凝血级联反应参与其中。
