Department of Neurology, Mayo Clinic, Rochester, MN.
Brain Pathol. 2014 Jan;24(1):83-97. doi: 10.1111/bpa.12099.
Neuromyelitis optica (NMO) is a disabling autoimmune astrocytopathy characterized by typically severe and recurrent attacks of optic neuritis and longitudinally extensive myelitis. Until recently, NMO was considered an acute aggressive variant of multiple sclerosis (MS), despite the fact that early studies postulated that NMO and MS may be two distinct diseases with a common clinical picture. With the discovery of a highly specific serum autoantibody (NMO-IgG), Lennon and colleagues provided the first unequivocal evidence distinguishing NMO from MS and other central nervous system (CNS) inflammatory demyelinating disorders. The target antigen of NMO-IgG was confirmed to be aquaporin-4 (AQP4), the most abundant water channel protein in the CNS, mainly expressed on astrocytic foot processes at the blood-brain barrier, subpial and subependymal regions. Pathological studies demonstrated that astrocytes were selectively targeted in NMO as evidenced by the extensive loss of immunoreactivities for the astrocytic proteins, AQP4 and glial fibrillary acidic protein (GFAP), as well as perivascular deposition of immunoglobulins and activation of complement even within lesions with a relative preservation of myelin. In support of these pathological findings, GFAP levels in the cerebrospinal fluid (CSF) during acute NMO exacerbations were found to be remarkably elevated in contrast to MS where CSF-GFAP levels did not substantially differ from controls. Additionally, recent experimental studies showed that AQP4 antibody is pathogenic, resulting in selective astrocyte destruction and dysfunction in vitro, ex vivo and in vivo. These findings strongly suggest that NMO is an autoimmune astrocytopathy where damage to astrocytes exceeds both myelin and neuronal damage. This chapter will review recent neuropathological studies that have provided novel insights into the pathogenic mechanisms, cellular targets, as well as the spectrum of tissue damage in NMO.
视神经脊髓炎（NMO）是一种致残性自身免疫性星形胶质细胞病，其特征为典型的严重且反复的视神经炎和长节段性脊髓炎发作。直到最近，NMO 被认为是多发性硬化症（MS）的一种急性侵袭性变异，尽管早期研究表明 NMO 和 MS 可能是两种具有共同临床表现的不同疾病。随着高度特异性血清自身抗体（NMO-IgG）的发现，Lennon 及其同事首次提供了明确的证据，将 NMO 与 MS 和其他中枢神经系统（CNS）炎症性脱髓鞘疾病区分开来。NMO-IgG 的靶抗原被确认为水通道蛋白-4（AQP4），这是中枢神经系统中最丰富的水通道蛋白，主要表达在血脑屏障、软脑膜和室管膜下区的星形胶质细胞足突上。病理学研究表明，星形胶质细胞是 NMO 的特异性靶细胞，这一点可以从星形胶质细胞蛋白 AQP4 和胶质纤维酸性蛋白（GFAP）的免疫反应性广泛丧失以及免疫球蛋白在血管周围沉积和补体激活得到证明，甚至在相对保留髓鞘的病变中也是如此。支持这些病理学发现的是，在急性 NMO 恶化期间，脑脊液（CSF）中的 GFAP 水平显著升高，而在 MS 中，CSF-GFAP 水平与对照组没有实质性差异。此外，最近的实验研究表明，AQP4 抗体具有致病性，导致体外、离体和体内选择性星形胶质细胞破坏和功能障碍。这些发现强烈表明，NMO 是一种自身免疫性星形胶质细胞病，其中星形胶质细胞的损伤超过了髓鞘和神经元的损伤。本章将回顾最近的神经病理学研究，这些研究为 NMO 的发病机制、细胞靶点以及组织损伤谱提供了新的见解。
