【文献解读】程序性坏死， 免疫异常和运动神经元死亡在运动神经元病中是如何关联的？
2017/7/14 创新医学网

     文章来源：欧尔意 OAE 微信号

     作者：Sofina

    

     原文出处

     Liu JF, Zheng OX, Xin JG, Chen HH, Xin JJ. How are necroptosis, immune dysfunction, and motoneuron death connected in amyotrophic lateral sclerosis? Neuroimmunol Neuroinflammation 2017;4:109-16.

     DOI:10.20517/2347-8659.2017.12

     摘要

     运动神经元病(萎縮性脊髓側索硬化症，ALS)是一类神经系统的退化性疾病。ALS病人常常有异常的免疫反应/炎症，免疫异常可能在ALS病的发展过程中起重要的作用。但是，这些异常的免疫反应是如何开始的，又由哪些免疫细胞来介导的，目前仍然没有定论。现在，我们对这个病的认识非常有限，部分原因是诊断晚和积累性发展：这个疾病在得到诊断时，一般都已经有明显的神经系统症状，这个时候的异常免疫反应很难确定是疾病的结果还是原因；另外，因为发展过程有积累性，很难确定什么时候是检测异常免疫反应的最佳时间。所以，异常免疫反应在ALS的发病过程中的所作用还有待进一步阐明。为了克服诊断晚和积累性发展这两个研究的中的挑战，作者们给有遗传性运动神经元病的小鼠在表现出运动症状之前引入了运动神经损伤(面神经切断术)，并研究损伤之后的免疫反应。结果表明运动神经损伤引起的免疫反应很容易在3-14天检测到。从这个模型中，作者观察到总体活化的T细胞的和Th17细胞的数量在ALS小鼠高出野生型小鼠；面神经损伤后这一不同更加明显和容易检测。之前, 我们知道Th17细胞是一组促进炎症的发展的CD4 T细胞，但是不知道为什么运动神经损伤在ALS小鼠中会起这些促炎症的细胞发育，而不是诱导抑制炎症的细胞发育。最近的研究发现ALS疾病中存在着一种新的细胞死亡方式：程序性坏死(坏死性凋亡)。传统的凋亡不会引起免疫反应，但是程序性坏死过程中会释放出促进炎症发展的刺激因子并引起机体的免疫反应。我们猜想：在ALS发展的早期，基因突变或外伤(毒素)导致一小部分运动神经坏死、释放促炎症的刺激因子和运动神经元特异的抗原，引发机体针对运动神经的免疫反应。这种有针对性的免疫反应会在短期造成大量运动神经的损伤，导致病人表现为疾病的快速发展。在这篇文章中，作者回顾了ALS疾病的最新研究进展，讨论了免疫异常，细胞死亡的种类与疾病发展的关系，并提出来了一个新的ALS病理模型和治疗ALS的研究方向。

     关键词： 程序性坏死；Th17细胞；神经损伤；肌萎缩性脊髓侧索硬化症。

     Abnormal immune response/inflammation is present in patients of amyotrophic lateral sclerosis (ALS). Autoimmune-related inflammation has been thought to be involved in the pathogenesis of ALS. However, how the abnormal immune responses are initiated, what specific immune cells and how these immune cells are involved in this disease have not been well understood. This is partly owing to two facts of ALS: late diagnosis and chronic nature. The late diagnosis makes it difficult to conclude whether the abnormal immune responses/inflammation is the cause or result of the disease. The chronic nature makes it difficult to determine the best timing for the detection of such autoimmune responses. To resolve these two challenges for research, the authors introduced motor nerve injury (facial nerve axotomy, FNA) into a pre-symptomatic mouse ALS model (8-week-old SOD1G93A mice), which induces a readily detectable immune response in a predictable time period (3-14 days). The authors found that pre-symptomatic SOD1G93A mice showed a higher basal level of T cell activation and Th17 cells than WT mice, which can be further increased by FNA. However, why these pro-inflammatory Th lymphocyte subsets are preferentially elicited in ALS has been elusive. Recently, several studies support that the programmed necrosis (necroptosis), a new type of cell death, is present in ALS. Because necroptosis results in the release of pro-inflammatory stimuli, we speculate that initial motoneuron (MN) necroptosis may be the cause of abnormal immune responses in the development of ALS, and subsequently, inflammation/immune response serve as an amplifier to cause more MN death. Here, the authors reviewed recent studies concerning the type of MN death, the inflammation/immune responses and the research strategies for ALS. With the available evidences from the literature, the authors present a hypothesized working model to indicate the possible connections among necroptosis, immune responses and MN death in the development of ALS and suggest the future studies for searching the potential therapy for ALS.

     Key words: Necroptosis, Th17, nerve injury, amyotrophic lateral sclerosis.

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     本文摘要由通讯作者，芝加哥大学医学院病理学系辛军平博士(John J. Xin)提供。中文内容仅供参考，一切以英文原版为准。

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