Deb Chandra, Lafrance-Corey Reghann G, Zoecklein Laurie, Papke Louisa, Rodriguez Moses, Howe Charles L
Departments of Neurology, Mayo Clinic, Rochester, Minnesota.
J Neuropathol Exp Neurol. 2009 Sep;68(9):1037-48. doi: 10.1097/NEN.0b013e3181b5417e.
Axon injury is a major determinant of the loss of neurological function in patients with multiple sclerosis. It is unclear, however, whether damage to axons is an obligatory consequence of demyelination or whether it is an independent process that occurs in the permissive environment of demyelinated lesions. Previous investigations into the role of CD8 T cells and perforin in the Theiler murine encephalomyelitis virus model of multiple sclerosis have used mouse strains resistant to Theiler murine encephalomyelitis virus infection. To test the role of CD8 T cells in axon injury, we established a perforin-deficient mouse model on the H-2 major histocompatibility complex background thereby removing confounding factors related to viral biology in this Theiler murine encephalomyelitis virus-susceptible strain. This permitted direct comparison of clinical and pathological parameters between perforin-competent and perforin-deficient mice. The extent of demyelination was indistinguishable between perforin-competent and perforin-deficient H-2 mice, but chronically infected perforin-deficient mice exhibited preservation of motor function and spinal axons despite the presence of spinal cord demyelination. Thus, demyelination is necessary but insufficient for axon injury in this model; the absence of perforin protects axons without impacting demyelination. These results suggest that perforin is a key mediator of axon injury and lend additional support to the hypothesis that CD8 T cells are primarily responsible for axon damage in multiple sclerosis.
轴突损伤是多发性硬化症患者神经功能丧失的主要决定因素。然而，目前尚不清楚轴突损伤是脱髓鞘的必然结果，还是在脱髓鞘病变的宽松环境中发生的独立过程。先前在多发性硬化症的泰勒氏鼠脑脊髓炎病毒模型中对CD8 T细胞和穿孔素作用的研究使用了对泰勒氏鼠脑脊髓炎病毒感染有抗性的小鼠品系。为了测试CD8 T细胞在轴突损伤中的作用，我们在H-2主要组织相容性复合体背景上建立了一个穿孔素缺陷小鼠模型，从而消除了与该泰勒氏鼠脑脊髓炎病毒易感品系中病毒生物学相关的混杂因素。这使得能够直接比较有穿孔素和无穿孔素小鼠之间的临床和病理参数。有穿孔素和无穿孔素的H-2小鼠之间的脱髓鞘程度没有区别，但尽管存在脊髓脱髓鞘，长期感染的无穿孔素小鼠仍表现出运动功能和脊髓轴突的保留。因此，在该模型中，脱髓鞘是轴突损伤的必要但不充分条件；穿孔素的缺失可保护轴突而不影响脱髓鞘。这些结果表明穿孔素是轴突损伤的关键介质，并为CD8 T细胞主要负责多发性硬化症中的轴突损伤这一假说提供了更多支持。
