Stinissen P, Raus J, Zhang J
Multiple Sclerosis and Immunology Unit, Dr. L. Willems-Instituut, Diepenbeek, Belgium.
Crit Rev Immunol. 1997;17(1):33-75. doi: 10.1615/critrevimmunol.v17.i1.20.
Accumulating evidence indicates that multiple sclerosis (MS) is an autoimmune disease mediated by autoreactive T lymphocytes with specificity for myelin antigens. Initially, the evidence to support this hypothesis was based mainly on experiments performed in experimental allergic encephalomyelitis (EAE), the animal model of MS. In this model it was demonstrated that T cells reactive to several myelin antigens are encephalitogenic. Many recent immunological and immunohistochemical studies in MS have yielded further data to support this view. For instance, it was demonstrated that activated myelin basic protein (MBP) and proteolipid protein (PLP)-specific T cells accumulate in the central nervous system (CNS), and that clonally expanded MBP-specific T cells persist for several years in the blood of patients with MS. Furthermore, T cells with specificity for MBP were identified in the brain lesions of the patients. It is not yet clear how these autoreactive T cells are activated in the periphery, but several studies have suggested that viral antigens mimicking the myelin epitopes, or superantigens may be involved. Furthermore, we and others have provided evidence showing that the regulatory mechanisms that control autoreactive T cells in healthy subjects are potentially defective in MS patients. In addition to myelin reactive T cells, B cells producing myelin-specific antibodies and gamma delta T cells may also play an important role in the autoimmune cascade. Based on the recent insights in the disease mechanisms, new experimental therapies were developed to target specifically the pathogenic lymphocytes in MS. Some therapies yielded encouraging data in pilot studies, whereas phase III trials of other drugs showed beneficial effects on the disease course. In this article, we overview the most recent data on the role of autoreactive lymphocytes in the pathogenesis of the disease, and discuss some of the recently developed immunotherapeutical strategies in MS.
越来越多的证据表明，多发性硬化症（MS）是一种由对髓鞘抗原有特异性的自身反应性T淋巴细胞介导的自身免疫性疾病。最初，支持这一假说的证据主要基于在实验性变态反应性脑脊髓炎（EAE）（MS的动物模型）中进行的实验。在这个模型中，已证明对几种髓鞘抗原有反应的T细胞具有致脑炎作用。最近在MS中进行的许多免疫学和免疫组织化学研究产生了更多数据来支持这一观点。例如，已证明活化的髓鞘碱性蛋白（MBP）和蛋白脂蛋白（PLP）特异性T细胞在中枢神经系统（CNS）中积聚，并且克隆扩增的MBP特异性T细胞在MS患者的血液中持续存在数年。此外，在患者的脑损伤中鉴定出了对MBP有特异性的T细胞。目前尚不清楚这些自身反应性T细胞在外周如何被激活，但一些研究表明，模仿髓鞘表位的病毒抗原或超抗原可能参与其中。此外，我们和其他人提供的证据表明，健康受试者中控制自身反应性T细胞的调节机制在MS患者中可能存在缺陷。除了髓鞘反应性T细胞外，产生髓鞘特异性抗体的B细胞和γδT细胞也可能在自身免疫级联反应中起重要作用。基于对疾病机制的最新认识，已开发出新的实验性疗法来特异性靶向MS中的致病性淋巴细胞。一些疗法在试点研究中产生了令人鼓舞的数据，而其他药物的III期试验显示对病程有有益影响。在本文中，我们概述了自身反应性淋巴细胞在该疾病发病机制中作用的最新数据，并讨论了MS中一些最近开发的免疫治疗策略。
