背景:纯合子CD59缺陷型患者表现为复发性周围神经病变,类似于格林-巴利综合征(GBS),溶血性贫血和复发性中风。已经描述了导致功能丧失的CD59中的可变突变,总的来说,17/18有任何突变的患者出现复发性GBS。在这里,我们确定了膜结合补体调节因子的定位和可能的作用,包括CD59,在小鼠和人类的外周神经系统(PNS)中。
方法:我们检查了健康人和CD59缺乏患者周围神经中膜结合补体调节因子的定位,以及野生型(WT)和CD59a缺陷型小鼠。通过共聚焦和电子显微镜检查了坐骨神经和髓鞘化背根神经节(DRG)神经元/雪旺氏细胞培养物的横截面。
结果:我们证明CD59a缺陷小鼠表现出正常的周围神经形态,但在年龄较大时出现髓鞘异常。它们通常表达髓鞘蛋白零(P0),ankyrinG(AnkG),Caspr,营养不良聚糖,和神经原素。使用针对CD59和髓磷脂碱性蛋白(MBP)的抗体对WT神经进行免疫标记,P0和AnkG显示CD59沿节间定位,但在Ranvier的节点中不存在。在神经内的血管中也检测到CD59。最后,我们表明Ranvier的节点缺乏其他补体膜调节蛋白,包括CD46、CD55、CD35和CR1相关基因-y(Crry),使该区域高度暴露于互补攻击。
结论:Ranvier的节点缺乏CD59,因此不受补体终末攻击的保护。人PNS中的髓磷脂单位受CD59和CD55保护,但不受CD46或CD35保护。这使得PNS中的节点和髓鞘在自身炎症性格林-巴利综合征中容易受到补体攻击和脱髓鞘的影响。如CD59缺乏中所见。
BACKGROUND: Homozygous CD59-deficient patients manifest with recurrent peripheral neuropathy resembling Guillain-Barré syndrome (GBS), hemolytic anemia and recurrent strokes. Variable mutations in CD59 leading to loss of function have been described and, overall, 17/18 of patients with any mutation presented with recurrent GBS. Here we determine the localization and possible role of membrane-bound complement regulators, including CD59, in the peripheral nervous systems (PNS) of mice and humans.
METHODS: We examined the localization of membrane-bound complement regulators in the peripheral nerves of healthy humans and a CD59-deficient patient, as well as in wild-type (WT) and CD59a-deficient mice. Cross sections of teased sciatic nerves and myelinating dorsal root ganglia (DRG) neuron/Schwann cell cultures were examined by confocal and electron microscopy.
RESULTS: We demonstrate that CD59a-deficient mice display normal peripheral nerve morphology but develop myelin abnormalities in older age. They normally express myelin protein zero (P0), ankyrin G (AnkG), Caspr, dystroglycan, and neurofascin. Immunolabeling of WT nerves using antibodies to CD59 and myelin basic protein (MBP), P0, and AnkG revealed that CD59 was localized along the internode but was absent from the nodes of Ranvier. CD59 was also detected in blood vessels within the nerve. Finally, we show that the nodes of Ranvier lack other complement-membrane regulatory proteins, including CD46, CD55, CD35, and CR1-related gene-y (Crry), rendering this area highly exposed to complement attack.
CONCLUSIONS: The Nodes of Ranvier lack CD59 and are hence not protected from complement terminal attack. The myelin unit in human PNS is protected by CD59 and CD55, but not by CD46 or CD35. This renders the nodes and myelin in the PNS vulnerable to complement attack and demyelination in autoinflammatory Guillain-Barré syndrome, as seen in CD59 deficiency.