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，其特征是白天过度嗜睡、紧张症（由情绪触发的肌肉张力突然丧失）和其他异常REM睡眠的表现。发作性睡病的病理生理学涉及HLA和下丘脑泌素神经传递。几乎所有的发作性睡病患者都有一个共同的HLA等位基因DQB 1 ^*0602，这表明该疾病是自身免疫性疾病。超过90%的发作性睡病病例与脑脊液中下丘脑泌素-1（HCRT 1）的急剧减少有关。免疫组织化学研究还显示，发作性睡眠受试者下丘脑中HCRT细胞计数减少90%以上。在这项研究中，我们使用死后人脑样本比较发作性睡眠与对照组的转录组。我们的主要目标是确定其他基因，可能是在后下丘脑的发作性睡眠患者失调。我们还开发了一种新的放射性配体结合测定系统，以解决是否存在放射性配体结合的问题。 关于我们 定量RT-PCR检测到11个基因在发作性睡病中表达上调，35个基因表达下调，9个基因表达下调。下丘脑分泌素是下调最多的基因。其中胰岛素样生长因子结合蛋白（IGFBP）基因在下丘脑泌素神经元中高表达。从嗜睡症和对照组受试者的血清进行了比较的存在下丘脑泌素，其受体，IGFBP的自身抗体。我们在3例患者中检测到抗下丘脑泌素的自身抗体，在1例患者中检测到hcrtr 1，在5例患者中检测到hcrtr 2，但发现不是疾病特异性的。我们无法找到针对IGFBP的自身抗体。我们的研究结果不支持下丘脑泌素系统中自身抗体介导的功能障碍是发作性睡病病理生理学基础的假设。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。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