DellaValle Brian, Manresa-Arraut Alba, Hasseldam Henrik, Stensballe Allan, Rungby Jørgen, Larsen Agnete, Hempel Casper
Department of Biomedicine/Pharmacology, Aarhus University, Aarhus, Denmark.
Department of Clinical Microbiology, Copenhagen University Hospital, Copenhagen, Denmark.
Front Immunol. 2018 Jun 4;9:1254. doi: 10.3389/fimmu.2018.01254. eCollection 2018.
Multiple sclerosis (MS) is a devastating autoimmune disease, afflicting people in the prime of their lives. Presently, after initial clinical presentation, there are no reliable markers for whether a patient will develop MS, or whether their prognosis will be aggressive or relapsing-remitting. Furthermore, many MS patients do not respond to treatment. Thus, markers for diagnosis, prognosis, and treatment-responsiveness are lacking for a disease, where a precision medicine approach would be valuable. The glycocalyx (GLX) is the carbohydrate-rich outer surface of the blood vessel wall and is the first interaction between the blood and the vessel. We hypothesized that cleavage of the GLX may be an early stage predictor of immune attack, blood-brain barrier (BBB) breakdown, and disease severity in MS.
Two experimental models of MS, experimental autoimmune encephalitis (EAE), were included in this study. EAE was induced in C57BL/6J mice and Lewis rats, which were monitored for weight loss and clinical presentation in comparison to healthy controls. Plasma samples were obtained longitudinally from mice until peak disease severity and at peak disease severity in rats. Soluble GLX-associated glycosaminoglycans (GAG) and proteoglycans (PG) were detected in plasma samples.
All animals receiving EAE emulsion developed fulminant EAE (100% penetrance). Increased plasma levels of chondroitin sulfate were detected before the onset of clinical symptoms and remained elevated at peak disease severity. Hyaluronic acid was increased at the height of the disease, whereas heparan sulfate was transiently increased during early stages only. By contrast, syndecans 1, 3, and 4 were detected in EAE samples as well as healthy controls, with no significant differences between the two groups.
In this study, we present data supporting the shedding of the GLX as a new class of biomarker for MS. In particular, soluble, sugar-based GLX components are associated with disease severity in two models of MS, molecules that would not be detected in proteomics-based screens of MS patient samples. Patient studies are presently underway.
多发性硬化症（MS）是一种具有破坏性的自身免疫性疾病，折磨着正值壮年的人群。目前，在初次临床表现后，对于患者是否会发展为MS，或者其预后是侵袭性的还是复发缓解型的，尚无可靠的标志物。此外，许多MS患者对治疗无反应。因此，对于一种采用精准医学方法会很有价值的疾病，缺乏诊断、预后和治疗反应性的标志物。糖萼（GLX）是血管壁富含碳水化合物的外表面，是血液与血管之间的首次相互作用。我们假设GLX的裂解可能是MS中免疫攻击、血脑屏障（BBB）破坏和疾病严重程度的早期预测指标。
本研究纳入了两种MS实验模型，即实验性自身免疫性脑脊髓炎（EAE）。在C57BL/6J小鼠和Lewis大鼠中诱导EAE，并与健康对照相比监测体重减轻和临床表现。从小鼠纵向采集血浆样本直至疾病严重程度达到峰值，在大鼠疾病严重程度达到峰值时也采集血浆样本。检测血浆样本中可溶性GLX相关的糖胺聚糖（GAG）和蛋白聚糖（PG）。
所有接受EAE乳剂的动物均发生暴发性EAE（100%发病率）。在临床症状出现前检测到硫酸软骨素的血浆水平升高，并在疾病严重程度达到峰值时仍保持升高。透明质酸在疾病高峰期增加，而硫酸乙酰肝素仅在早期短暂增加。相比之下，在EAE样本以及健康对照中均检测到多配体蛋白聚糖1、3和4，两组之间无显著差异。
在本研究中，我们提供的数据支持GLX的脱落作为MS的一类新的生物标志物。特别是，可溶性的、基于糖的GLX成分与两种MS模型中的疾病严重程度相关，这些分子在基于蛋白质组学的MS患者样本筛查中无法检测到。目前正在进行患者研究。
