A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica
A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica
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DOI：
10.1093/brain/awf151
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发表时间：
2002-07-01
期刊：
影响因子：
14.5
通讯作者：
Lassmann, H
中科院分区：
文献类型：
--
作者：
Lucchinetti, CF;Mandler, RN;Lassmann, H
Devic病[视神经肌萎缩症（NMO）]是一种中枢神经系统的特发性炎性脱髓鞘疾病，其特征在于视神经炎和肌萎缩的发作。导致炎性脱髓鞘病变选择性定位于视神经和脊髓的机制尚不清楚。在高比例的NMO患者中观察到B细胞自身免疫的血清学和临床证据。本研究的目的是调查体液机制的重要性，包括补体激活，在产生脊髓和视神经的坏死性脱髓鞘。从9例临床确诊的Devic病尸检病例中检查了82处病变。通过检查巨噬细胞内髓鞘降解产物的抗原谱，将病变中的脱髓鞘活性免疫细胞化学分类为早期活性（21个病变）、晚期活性（18个病变）、非活性（35个病变）或髓鞘再生（8个病变）。病变的病理学进行了分析，使用广泛的免疫学和神经生物学标志物，和病变的髓鞘蛋白损失的基础上定义，斑块的地理和扩展，少突胶质细胞破坏的模式和补体激活的免疫病理学证据。所有9名患者的病理学均相同。广泛的脱髓鞘存在于多个脊髓水平，与空洞，坏死和急性轴突病理（球状体），在灰色和白色物质。病变内少突胶质细胞明显丢失。活动性病变中的炎性浸润以广泛的巨噬细胞浸润为特征，伴有大量的血管周围粒细胞和嗜酸性粒细胞以及罕见的CD 3（+）和CD 8（+）T细胞。活动性病变中存在明显的免疫球蛋白（主要是IgM）和补体C9 neo抗原血管周围沉积，与活动性和非活动性病变中的显著血管纤维化和玻璃样变性相关。在Devic NMO病例中观察到的补体激活、嗜酸性粒细胞浸润和血管纤维化的程度与原型多发性硬化相比更为突出，并支持体液免疫在NMO发病机制中的作用。基于这项研究，未来的治疗策略，旨在限制补体激活，嗜酸性粒细胞脱粒和中性粒细胞/巨噬细胞/小胶质细胞激活的有害影响是值得进一步研究。
Devic's disease [neuromyelitis optica (NMO)] is an idiopathic inflammatory demyelinating disease of the CNS, characterized by attacks of optic neuritis and myelitis. The mechanisms that result in selective localization of inflammatory demyelinating lesions to the optic nerves and spinal cord are unknown. Serological and clinical evidence of B cell autoimmunity has been observed in a high proportion of patients with NMO. The purpose of this study was to investigate the importance of humoral mechanisms, including complement activation, in producing the necrotizing demyelination seen in the spinal cord and optic nerves. Eighty-two lesions were examined from nine autopsy cases of clinically confirmed Devic's disease. Demyelinating activity in the lesions was immunocytochemically classified as early active (21 lesions), late active (18 lesions), inactive (35 lesions) or remyelinating (eight lesions) by examining the antigenic profile of myelin degradation products within macrophages. The pathology of the lesions was analysed using a broad spectrum of immunological and neurobiological markers, and lesions were defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction and the immunopathological evidence of complement activation. The pathology was identical in all nine patients. Extensive demyelination was present across multiple spinal cord levels, associated with cavitation, necrosis and acute axonal pathology (spheroids), in both grey and white matter. There was a pronounced loss of oligodendrocytes within the lesions. The inflammatory infiltrates in active lesions were characterized by extensive macrophage infiltration associated with large numbers of perivascular granulocytes and eosinophils and rare CD3(+) and CD8(+) T cells. There was a pronounced perivascular deposition of immunoglobulins (mainly IgM) and complement C9neo antigen in active lesions associated with prominent vascular fibrosis and hyalinization in both active and inactive lesions. The extent of complement activation, eosinophilic infiltration and vascular fibrosis observed in the Devic NMO cases is more prominent compared with that in prototypic multiple sclerosis, and supports a role for humoral immunity in the pathogenesis of NMO. Based on this study, future therapeutic strategies designed to limit the deleterious effects of complement activation, eosinophil degranulation and neutrophil/macrophage/microglial activation are worthy of further investigation.