Neuromyelitis optica and opticospinal multiple sclerosis: Mechanisms and pathogenesis.
Neuromyelitis optica and opticospinal multiple sclerosis: Mechanisms and pathogenesis.
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DOI：
10.1016/j.pathophys.2010.04.008
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发表时间：
2011-02-01
期刊：
影响因子：
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通讯作者：
Kira, Jun-Ichi
中科院分区：
文献类型：
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作者：
Kira, Jun-Ichi
多发性硬化症（MS）是中枢神经系统（CNS）的脱髓鞘疾病，而视神经肌萎缩症（NMO）是选择性影响视神经和脊髓的CNS炎性疾病。在亚洲人中，MS是罕见的;然而，当它出现时，视神经和脊髓的选择性和严重参与是特征。这种形式，称为opticosporinal MS（OSMS），具有类似的功能，复发形式的NMO在西方人群。最近，发现了一种针对NMO的特异性IgG，命名为NMO-IgG，并且发现相关抗原是水通道蛋白4（AQP 4），其是CNS中的主要水通道蛋白之一。因为据报道，在30-60%的OSMS患者中存在NMO-IgG，所以亚洲人的OSMS被认为是与NMO相同的实体。NMO-IgG/抗AQP 4抗体对NMO的敏感性为30%至80%，特异性为90- 100%。NMO的病理学研究表明，血管周围免疫复合物（IgM，IgG和C9 neo）沉积和AQP 4在活动性病变中的广泛损失，其中髓鞘碱性蛋白（MBP）染色相对保留。来自NMO-IgG血清阳性NMO患者的IgG在补体存在下诱导培养物中的星形胶质细胞死亡，并且当MBP特异性T细胞共转移以引起实验性自身免疫性脑脊髓炎时，在体内再现星形胶质细胞损失。因此，假设补体激活抗AQP 4抗体在通过星形胶质细胞坏死的NMO病变的发展中发挥关键作用，而脱髓鞘是次要事件。然而，在NMO的尸检病例中，我们和其他人发现，有些表现出选择性AQP 4丢失，而另一些则表现出AQP 4的保留，即使在急性病变中。我们还发现，在一些MS病变中，AQP 4的丢失范围远远超出髓鞘丢失的区域。在CSF中，促炎细胞因子如IL-17、IL-8、IFN γ和G-CSF在OSMS患者中显著升高，而不管是否存在抗AQP 4抗体。在OSMS和NMO患者中，对髓磷脂蛋白具有反应性的T细胞显示分子内和分子间表位扩散，表明T细胞已经在体内被髓磷脂抗原刺激。这些结果表明，NMO和OSMS在亚洲人的机制是异质性的，抗AQP 4抗体相关和不相关的，不仅抗AQP 4抗体，而且髓鞘自身反应性Th 17或Th 1细胞也可能在触发CNS炎症中发挥作用。本文讨论了动校正和OSMS的可能机制。
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) while neuromyelitis optica (NMO) is an inflammatory disease of the CNS that selectively affects the optic nerves and spinal cord. In Asians, MS is rare; however, when it appears, the selective and severe involvement of the optic nerves and spinal cord is characteristic. This form, termed opticospinal MS (OSMS), has similar features to the relapsing form of NMO in Western populations. Recently, a specific IgG against NMO, designated NMO-IgG, was discovered, and the relevant antigen was found to be aquaporin-4 (AQP4), one of the major water channel proteins in the CNS. Because NMO-IgG has been reported to be present in 30-60% of OSMS patients, OSMS in Asians has been suggested to be the same entity as NMO. The sensitivity of NMO-IgG/anti-AQP4 antibody for NMO varies from 30% to 80%, while the specificity is 90-100%. Pathological studies on NMO have revealed perivascular immune complex (IgM, IgG and C9neo) deposition and extensive loss of AQP4 in active lesions, where myelin basic protein (MBP) staining was relatively preserved. IgG from NMO-IgG-seropositive NMO patients induces astrocyte death in culture in the presence of complements, and reproduces astrocyte loss in vivo when MBP-specific T cells are co-transferred to cause experimental autoimmune encephalomyelitis. It is thus postulated that the complement-activating anti-AQP4 antibody plays a pivotal role in the development of NMO lesions through astrocyte necrosis, and that demyelination is a secondary event. However, in autopsied cases of NMO, we and others found that some demonstrated selective AQP4 loss while others showed preservation of AQP4, even in the acute lesions. We also found that, in some MS lesions, AQP4 was lost extensively far beyond the areas of myelin loss. In the CSF, proinflammatory cytokines such as IL-17, IL-8, IFNgamma, and G-CSF are markedly elevated in OSMS patients, irrespective of the presence or absence of anti-AQP4 antibody. In OSMS and NMO patients, T cells reactive to myelin proteins show intra- and inter-molecular epitope spreading, suggesting that T cells are already stimulated with myelin antigens in vivo. These findings suggest that mechanism of NMO and OSMS in Asians is heterogeneous, anti-AQP4 antibody-related and -unrelated, and that not only anti-AQP4 antibody but also myelin-autoreactive Th17 or Th1 cells may also play a role in triggering CNS inflammation. Possible mechanisms for NMO and OSMS are discussed in this review.