Rehabilitation Centre Meidling AUVA, Koeglergasse 2a, A-1120 Vienna, Austria.
Med Hypotheses. 2010 Aug;75(2):229-34. doi: 10.1016/j.mehy.2010.02.028. Epub 2010 Mar 12.
This paper summarizes neuroendocrine effects on myelination and their possible relevance for the pathogenesis of multiple sclerosis (MS). Steroid hormones known as neurosteroids are synthesized in the human central nervous system (CNS) and exert local effects on glial and neuronal tissue. Progesterone derivatives seem to act as promyelinating factors in the slow but continuous process of myelin maintenance in the adult human brain. Diminished production of these myelin-promoting factors may lead to the formation of structurally altered and less stable myelin, resulting in the observed pathology of the normal-appearing white matter (NAWM) in MS. Dysmyelination, characterized by an altered myelin protein composition, reduced myelin content and increased vulnerability of the myelin sheath, precedes the formation of inflammatory lesions and the clinical onset of disease. Defects in the myelin sheath first occur in mechanically strained areas of the brain, where myelin turnover is physiologically increased. The continuous exposure of myelin proteins, normally sheltered from immunosurveillance, will lead to microglia activation and phagocytosis of myelin. Phagocytic cells from the brain and myelin material may drain to cervical lymph nodes with subsequent priming of T-cells. Finally, heterogenous focal auto-inflammatory reactions contribute to the clinical symptoms of the disease. Neurosteroids influence the biochemical composition of myelin proteins and promote myelin renewal. These promyelinating neurosteroidal functions seem to be impaired in the MS brain. Contrary to the view of auto-inflammatory demyelination being a causative factor in MS pathogenesis, it is argued here that widespread dysmyelination in the adult human brain precedes and induces a focal immune response to various myelin compounds.
本文总结了神经内分泌对髓鞘形成的影响及其在多发性硬化症（MS）发病机制中的可能相关性。作为神经甾体的类固醇激素在人体中枢神经系统（CNS）中合成，并对神经胶质和神经元组织发挥局部作用。孕激素衍生物似乎在成人大脑中髓鞘持续缓慢形成过程中发挥着促进髓鞘形成的作用。这些促进髓鞘形成的因子产生减少可能导致髓鞘结构改变和稳定性降低，从而导致 MS 正常外观白质（NAWM）的观察到的病理学改变。脱髓鞘的特征是髓鞘蛋白组成改变、髓鞘含量减少和髓鞘鞘脆弱性增加，发生在炎症病变形成和疾病临床发作之前。髓鞘鞘的缺陷首先发生在大脑中机械应变区域，那里的髓鞘周转率生理性增加。正常情况下受到免疫监视保护的髓鞘蛋白的持续暴露将导致小胶质细胞激活和髓鞘吞噬。来自大脑和髓鞘物质的吞噬细胞可能会流入颈部淋巴结，随后 T 细胞被激活。最后，异质局灶性自身炎症反应导致疾病的临床症状。神经甾体影响髓鞘蛋白的生化组成并促进髓鞘更新。这些促进髓鞘形成的神经甾体功能似乎在 MS 大脑中受损。与自身炎症性脱髓鞘被认为是 MS 发病机制中的一个因果因素的观点相反，本文认为，成人大脑中的广泛脱髓鞘先于并诱导对各种髓鞘化合物的局灶性免疫反应。
