Vogt Johannes, Paul Friedemann, Aktas Orhan, Müller-Wielsch Kathrin, Dörr Jan, Dörr Susanne, Bharathi B Suman, Glumm Robert, Schmitz Christoph, Steinbusch Harry, Raine Cedric S, Tsokos Michael, Nitsch Robert, Zipp Frauke
Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Ann Neurol. 2009 Sep;66(3):310-22. doi: 10.1002/ana.21719.
Multiple sclerosis (MS) is considered a chronic inflammatory and demyelinating disease of the central nervous system. Evidence that axonal and neuronal pathology contributes to the disease is accumulating, however, the distribution of neuronal injury as well as the underlying mechanisms have not yet been fully clarified. Here, we investigated the role of neuronal cell loss in MS and its animal model, experimental autoimmune encephalomyelitis (EAE).
We performed electrophysiological investigations in MS patients, including assessment of compound muscle action potentials and motor unit numbers and quantified neuronal cell loss in human MS samples and different EAE models by high-precision stereology.
Both electrophysiological and morphological analyses indicated a massive loss of lower motor neurons in MS patients. We regularly found dying spinal motor neurons surrounded by CD3+ (CD4+ as well as CD8+) T cells expressing tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We observed a similar degree of damage and immune attack in different variants of EAE; the lower motor neurons were preserved in adoptive transfer EAE induced with TRAIL-deficient T lymphocytes.
Our study indicates that damage to lower motor neurons and TRAIL-mediated inflammatory neurodegeneration in the spinal cord contribute to MS pathology.
多发性硬化症（MS）被认为是一种中枢神经系统的慢性炎症性脱髓鞘疾病。虽然越来越多的证据表明轴突和神经元病理改变与该疾病有关，然而，神经元损伤的分布及其潜在机制尚未完全阐明。在此，我们研究了神经元细胞丢失在MS及其动物模型实验性自身免疫性脑脊髓炎（EAE）中的作用。
我们对MS患者进行了电生理研究，包括复合肌肉动作电位和运动单位数量的评估，并通过高精度体视学方法对人类MS样本和不同EAE模型中的神经元细胞丢失进行了量化。
电生理和形态学分析均表明MS患者的下运动神经元大量丢失。我们经常发现垂死的脊髓运动神经元被表达肿瘤坏死因子相关凋亡诱导配体（TRAIL）的CD3 +（CD4 +以及CD8 +）T细胞包围。在不同变体的EAE中，我们观察到了相似程度的损伤和免疫攻击；在用缺乏TRAIL的T淋巴细胞诱导的过继转移EAE中，下运动神经元得以保留。
我们的研究表明，脊髓中下运动神经元的损伤以及TRAIL介导的炎性神经变性促成了MS的病理改变。
