Davalos Dimitrios, Mahajan Kedar R, Trapp Bruce D
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
Mult Scler. 2019 Oct;25(11):1434-1435. doi: 10.1177/1352458519852723. Epub 2019 Jul 18.
Blood-brain barrier (BBB) disruption, perivascular inflammation, demyelination, and axonal damage are key histopathological hallmarks of multiple sclerosis (MS). The vast majority of MS lesions develop around disrupted blood vessels. This is often attributed to active inflammation and the infiltration of immune cells into the central nervous system (CNS). Indeed, evidence of BBB disruption by gadolinium enhancement on magnetic resonance imaging (MRI) constitutes the most reliable indication of active inflammatory MS lesions. However, increasing evidence highlights a more central role for the leakage of blood factors into the CNS -an inevitable consequence of BBB disruption- whose entry precedes and promotes new lesion formation. Fibrinogen is a soluble blood protein known for its role in coagulation, through its rapid conversion to fibrin, the foundation of blood clots. Analyses in human MS tissue and in several animal models identified fibrinogen in the CNS prior to leukocyte infiltration, and the onset of demyelination, or clinical symptoms. Moreover, extensive preclinical studies demonstrated that fibrinogen is unique among other blood proteins or coagulation factors that may also enter the CNS, as it promotes inflammatory processes within perivascular lesions, and thereby contributes to neuronal damage, and inhibits tissue repair processes.
血脑屏障（BBB）破坏、血管周围炎症、脱髓鞘和轴突损伤是多发性硬化症（MS）的关键组织病理学特征。绝大多数MS病变发生在受损血管周围。这通常归因于活跃的炎症以及免疫细胞浸润到中枢神经系统（CNS）。事实上，磁共振成像（MRI）上钆增强显示血脑屏障破坏的证据是活动性炎症性MS病变最可靠的指标。然而，越来越多的证据表明，血液因子渗漏到中枢神经系统中起着更核心的作用——这是血脑屏障破坏的必然结果——其进入先于并促进新病变的形成。纤维蛋白原是一种可溶性血液蛋白，因其在凝血过程中的作用而闻名，它能迅速转化为纤维蛋白，即血凝块的基础。对人类MS组织和几种动物模型的分析发现在白细胞浸润、脱髓鞘或临床症状出现之前，中枢神经系统中就存在纤维蛋白原。此外，广泛的临床前研究表明，纤维蛋白原在其他可能也进入中枢神经系统的血液蛋白或凝血因子中是独特的，因为它促进血管周围病变内的炎症过程，从而导致神经元损伤，并抑制组织修复过程。
