Kipp Markus, van der Star Baukje, Vogel Daphne Y S, Puentes Fabìola, van der Valk Paul, Baker David, Amor Sandra
Department of Pathology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands; Institute of Neuroanatomy, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.
Department of Pathology, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
Mult Scler Relat Disord. 2012 Jan;1(1):15-28. doi: 10.1016/j.msard.2011.09.002. Epub 2011 Sep 16.
Although the primary cause of multiple sclerosis (MS) is unknown, the widely accepted view is that aberrant (auto)immune responses possibly arising following infection(s) are responsible for the destructive inflammatory demyelination and neurodegeneration in the central nervous system (CNS). This notion, and the limited access of human brain tissue early in the course of MS, has led to the development of autoimmune, viral and toxin-induced demyelination animal models as well as the development of human CNS cell and organotypic brain slice cultures in an attempt to understand events in MS. The autoimmune models, collectively known as experimental autoimmune encephalomyelitis (EAE), and viral models have shaped ideas of how environmental factors may trigger inflammation, demyelination and neurodegeneration in the CNS. Understandably, these models have also heavily influenced the development of therapies targeting the inflammatory aspect of MS. Demyelination and remyelination in the absence of overt inflammation are better studied in toxin-induced demyelination models using cuprizone and lysolecithin. The paradigm shift of MS as an autoimmune disease of myelin to a neurodegenerative disease has required more appropriate models reflecting the axonal and neuronal damage. Thus, secondary progressive EAE and spastic models have been crucial to develop neuroprotective approaches. In this review the current in vivo and in vitro experimental models to examine pathological mechanisms involved in inflammation, demyelination and neuronal degeneration, as well as remyelination and repair in MS are discussed. Since this knowledge is the basis for the development of new therapeutic approaches for MS, we particularly address whether the currently available models truly reflect the human disease, and discuss perspectives to further optimise and develop more suitable experimental models to study MS.
虽然多发性硬化症（MS）的主要病因尚不清楚，但被广泛接受的观点是，感染后可能出现的异常（自身）免疫反应是导致中枢神经系统（CNS）发生破坏性炎症性脱髓鞘和神经退行性变的原因。这一观点，以及在MS病程早期获取人脑组织的机会有限，导致了自身免疫、病毒和毒素诱导的脱髓鞘动物模型的开发，以及人类CNS细胞和脑器官型切片培养物的开发，以试图了解MS中的相关事件。统称为实验性自身免疫性脑脊髓炎（EAE）的自身免疫模型和病毒模型，塑造了关于环境因素如何触发CNS炎症、脱髓鞘和神经退行性变的观念。可以理解的是，这些模型也对针对MS炎症方面的治疗方法的发展产生了重大影响。在使用铜离子螯合剂和溶血卵磷脂的毒素诱导脱髓鞘模型中，可以更好地研究在无明显炎症情况下的脱髓鞘和再髓鞘化过程。MS从一种髓鞘自身免疫性疾病向神经退行性疾病的范式转变，需要更合适的模型来反映轴突和神经元损伤。因此，继发性进行性EAE和痉挛模型对于开发神经保护方法至关重要。在这篇综述中，讨论了目前用于研究MS中炎症、脱髓鞘、神经元变性以及再髓鞘化和修复所涉及病理机制的体内和体外实验模型。由于这些知识是开发MS新治疗方法的基础，我们特别探讨了当前可用模型是否真的能反映人类疾病，并讨论了进一步优化和开发更合适的实验模型以研究MS的前景。
