Neurolymphatic biomarkers of brain endothelial inflammatory activation: Implications for multiple sclerosis diagnosis
Neurolymphatic biomarkers of brain endothelial inflammatory activation: Implications for multiple sclerosis diagnosis
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DOI：
10.1016/j.lfs.2019.05.021
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发表时间：
2019-07-15
期刊：
影响因子：
6.1
通讯作者：
Alexander, J. S.
中科院分区：
文献类型：
--
作者：
Yun, J. W.;Cvek, U.;Alexander, J. S.
目的：多发性硬化症（MS）是年轻人非创伤性神经功能障碍的主要原因，由于缺乏诊断标志物，其诊断常常被推迟。在多发性硬化症的早期阶段开始疾病改善治疗尤其重要，因为目前可用的治疗主要针对复发缓解型多发性硬化症，并且随着疾病进展为更慢性的继发性进展型多发性硬化症而效果较差。因此，探索特异性和敏感的生物标志物将有助于快速和更准确的诊断，使现有的治疗更有效。主要方法：采用Western blotting法检测培养的人脑内皮细胞中神经淋巴蛋白的表达。此外，使用150例复发缓解型MS患者，26例继发性进展型MS患者和60例健康对照样本，使用点印迹分析检测血清样本中的神经淋巴蛋白表达。主要发现：人脑微血管内皮细胞表达神经淋巴标志物。神经淋巴蛋白丰度在肿瘤坏死因子(TNF)- α刺激时增加，但在干扰素(IFN)- γ或TNF + IFN联合治疗时减少。多发性硬化症患者的循环神经淋巴蛋白水平明显降低。此外，其中一种标志物FOXC2与多发性硬化的临床分期有关，与复发缓解型多发性硬化相比，FOXC2在继发性进展型多发性硬化中的表达显著降低。意义：我们的研究结果描述了神经淋巴蛋白在炎症应激下改变的脑内皮表达，并提供了使用循环神经淋巴蛋白集体池作为多发性硬化诊断和预后生物标志物的可能性。
Aims: Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in young adults, and its diagnosis is often delayed due to the lack of diagnostic markers. Initiation of disease-modifying therapy in the early stages of MS is especially critical because currently available therapy mostly target relapsing-remitting MS, and is less effective as disease progresses into the more chronic form of secondary-progressive MS. Therefore, exploring specific and sensitive biomarkers will facilitate an expedited and more accurate diagnosis to allow currently available therapies to be more effective.Main methods: Western blotting was conducted to detect the expression of neurolymphatic proteins in human brain endothelial cells in culture. Additionally, using a cohort of 150 patients with relapsing remitting MS, 26 with secondary progressive MS, and 60 healthy control samples, neurolymphatic protein expression was detected in serum samples using dot blot analysis.Key findings: Human brain microvascular endothelial cells express neurolymphatic markers. Neurolymphatic protein abundance increases with tumor necrosis factor (TNF)-alpha stimulation but decreases with interferon (IFN)-gamma or combined (TNF + IFN) treatment. Circulating neurolymphatic protein levels is significantly lower in MS patients. Further, one of the markers, FOXC2, is associated with the clinical stages of MS, with significantly lower expression in secondary progressive MS compared to relapsing remitting MS.Significance: Our findings describe brain endothelial expression of neurolymphatic proteins, which is altered under inflammatory stress, and provide a possibility of using a collective pool of circulating neurolymphatic proteins as a diagnostic and prognostic biomarker of MS.