Study of the autoimmune mechanism in narcolepsy using gene expressional profiling

发作性睡病是一种常见的睡眠障碍，以白天过度嗜睡、猝倒(情绪引发的肌肉张力突然丧失)和其他异常快速眼动睡眠的表现为特征。发作性睡病的病理生理学涉及人类白细胞抗原和下丘脑肌醇的神经传递。几乎所有发作性睡病患者都有一个共同的HLA等位基因DQB1^*0602，这表明这种疾病是基于自身免疫的。超过90%的发作性睡病病例与脑脊液中下丘脑肌素-1(HCRT1)的急剧下降有关。免疫组织化学研究还显示发作性睡病患者下丘脑中的HCRT细胞计数减少了90%以上。在这项研究中，我们使用死后的人脑样本来比较发作性睡病患者和对照组受试者的转录组。我们的主要目标是确定发作性睡病患者下丘脑后部可能存在的其他失调基因。我们还开发了一种新的放射性配基结合分析系统来解决…是否与发作性睡病相关的基因中，有11个基因表达上调，35个基因表达下调，其中9个基因表达下调。亚克汀类基因是下调最多的基因。在这9个基因中，胰岛素样生长因子结合蛋白(IGFBP)被证实在下丘脑神经元中高表达。研究人员比较了发作性睡病患者和对照组的血清中是否存在针对下丘脑肌醇及其受体和IGFBP的自身抗体。我们检测到3例患者的自身抗体，1例患者的hcrtr1抗体，5例患者的hcrtr2自身抗体，但该发现不具有疾病特异性。我们找不到抗IGFBP的自身抗体。我们的结果不支持自身抗体介导的下丘脑系统功能障碍是发作性睡病的病理生理学基础的假说。然而，已知IGFBP具有促凋亡特性，并可能参与发作性睡病的发病机制。较少

Narcolepsy is a common sleep disorder characterized by excessive daytime sleepiness, cataplexy (sudden loss of muscle tone triggered by emotion) and other manifestations of abnormal REM sleep. The pathophysiology of narcolepsy involves the HLA and hypocretin neurotransmission. Almost all cases with narcolepsy share a common HLA allele, DQB1^*0602 suggesting an autoimmune basis for the disorder. Over 90% of narcolepsy cases are associated with a dramatic decrease in hypocretin-1 (HCRT1) in the cerebrospinal fluid. Immunohistochemical studies also revealed a more than 90% decrease in HCRT cell count in the hypothalamus of narcoleptic subjects. In this study, we have used postmortem human brain samples to compare the transcriptome of narcoleptic versus control subjects. Our primary goal was to identify other genes that may be dysregulated in the posterior hypothalamus of narcoleptic patients. We have also developed a novel radioligand binding assay system to address the question whether a … More utoantibodies against hypocretin and hypocretin receptors and other identified narcolepsy-related genes were involved in narcolepsy pathophysiology or not.Out of 11 upregulated and 35 downregulated genes in narcolepsy, 9 downregulated genes were verified with quantitative RT-PCR. Hypocretin was the most downregulated gene. One of these 9 genes, insulin-like growth factor binding protein(IGFBP), was confirmed to be highly expressed in hypocretin neurons. Sera from narcolepsy and control subjects were compared for the presence of autoantibodies against hypocretin, its receptors, and IGFBP. We detected autoantibodies against hypocretin in 3 patients, hcrtr1 in 1 patient, and hcrtr2 in 5 patients, but the finding was not disease specific. We were unable to find autoantibodies against IGFBP. Our results do not support the hypothesis that autoantibody-mediated dysfunction in the hypocretin system underlies the pathophysiology of narcolepsy. However IGFBP is known to have proapoptotic properties and may be involved in the pathogenesis of narcolepsy. Less