Amsterdam UMC, Vrije Universiteit, Department of Anatomy and Neurosciences, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam, The Netherlands.
Department Biomedical Sciences of Cells and Systems, University Medical Center Groningen, Groningen, The Netherlands.
Ann Neurol. 2021 Apr;89(4):711-725. doi: 10.1002/ana.26014. Epub 2021 Jan 27.
Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease of unknown etiology. Although the prevalent view regards a CD4 -lymphocyte autoimmune reaction against myelin at the root of the disease, recent studies propose autoimmunity as a secondary reaction to idiopathic brain damage. To gain knowledge about this possibility we investigated the presence of axonal and myelinic morphological alterations, which could implicate imbalance of axon-myelin units as primary event in MS pathogenesis.
Using high resolution imaging histological brain specimens from patients with MS and non-neurological/non-MS controls, we explored molecular changes underpinning imbalanced interaction between axon and myelin in normal appearing white matter (NAWM), a region characterized by normal myelination and absent inflammatory activity.
In MS brains, we detected blister-like swellings formed by myelin detachment from axons, which were substantially less frequently retrieved in non-neurological/non-MS controls. Swellings in MS NAWM presented altered glutamate receptor expression, myelin associated glycoprotein (MAG) distribution, and lipid biochemical composition of myelin sheaths. Changes in tethering protein expression, widening of nodes of Ranvier and altered distribution of sodium channels in nodal regions of otherwise normally myelinated axons were also present in MS NAWM. Finally, we demonstrate a significant increase, compared with controls, in citrullinated proteins in myelin of MS cases, pointing toward biochemical modifications that may amplify the immunogenicity of MS myelin.
Collectively, the impaired interaction of myelin and axons potentially leads to myelin disintegration. Conceptually, the ensuing release of (post-translationally modified) myelin antigens may elicit a subsequent immune attack in MS. ANN NEUROL 2021;89:711-725.
多发性硬化症（MS）是一种病因不明的慢性神经炎症和神经退行性疾病。尽管目前普遍认为 CD4 淋巴细胞针对疾病根源处髓鞘的自身免疫反应是疾病的主要原因，但最近的研究提出，自身免疫是对特发性脑损伤的继发反应。为了了解这种可能性，我们研究了轴突和髓鞘形态学改变的存在，这可能意味着轴突-髓鞘单位的失衡是 MS 发病机制中的主要事件。
使用来自 MS 患者和非神经/非-MS 对照者的高分辨率成像组织学脑标本，我们探索了正常髓鞘化和无炎症活性的正常外观白质（NAWM）中，支撑轴突与髓鞘之间失衡相互作用的分子变化。
在 MS 大脑中，我们检测到了由髓鞘从轴突上脱离形成的泡状肿胀，这些肿胀在非神经/非-MS 对照者中明显较少见。MS NAWM 中的肿胀表现出谷氨酸受体表达、髓鞘相关糖蛋白（MAG）分布以及髓鞘鞘脂质生化组成的改变。在正常髓鞘化轴突的节结区域，连接蛋白表达的改变、节结宽度的增加以及钠通道的分布改变也存在于 MS NAWM 中。最后，与对照组相比，我们在 MS 病例的髓鞘中发现了显著增加的瓜氨酸化蛋白，表明可能存在使 MS 髓鞘免疫原性增强的生化修饰。
髓鞘和轴突之间的相互作用受损可能导致髓鞘解体。从概念上讲，随后释放（翻译后修饰的）髓鞘抗原可能会在 MS 中引发后续的免疫攻击。ANN NEUROL 2021；89：711-725。
