Centre de Physiopathologie Toulouse Purpan, INSERM UMR1043, CNRS UMR5282, Université de Toulouse III, Toulouse, France.
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Lancet Neurol. 2015 Mar;14(3):318-28. doi: 10.1016/S1474-4422(14)70218-2. Epub 2015 Feb 16.
The discovery of hypocretins (orexins) and their causal implication in narcolepsy is the most important advance in sleep research and sleep medicine since the discovery of rapid eye movement sleep. Narcolepsy with cataplexy is caused by hypocretin deficiency owing to destruction of most of the hypocretin-producing neurons in the hypothalamus. Ablation of hypocretin or hypocretin receptors also leads to narcolepsy phenotypes in animal models. Although the exact mechanism of hypocretin deficiency is unknown, evidence from the past 20 years strongly favours an immune-mediated or autoimmune attack, targeting specifically hypocretin neurons in genetically predisposed individuals. These neurons form an extensive network of projections throughout the brain and show activity linked to motivational behaviours. The hypothesis that a targeted immune-mediated or autoimmune attack causes the specific degeneration of hypocretin neurons arose mainly through the discovery of genetic associations, first with the HLA-DQB1*06:02 allele and then with the T-cell receptor α locus. Guided by these genetic findings and now awaiting experimental testing are models of the possible immune mechanisms by which a specific and localised brain cell population could become targeted by T-cell subsets. Great hopes for the identification of new targets for therapeutic intervention in narcolepsy also reside in the development of patient-derived induced pluripotent stem cell systems.
下丘脑泌素（食欲素）的发现及其在嗜睡症中的因果关系是自快速眼动睡眠发现以来睡眠研究和睡眠医学最重要的进展。伴有猝倒的嗜睡症是由于下丘脑大多数产生下丘脑泌素的神经元被破坏，导致下丘脑泌素缺乏引起的。在动物模型中，敲除下丘脑泌素或下丘脑泌素受体也会导致嗜睡症表型。尽管下丘脑泌素缺乏的确切机制尚不清楚，但过去 20 年的证据强烈支持免疫介导或自身免疫攻击，针对特定的遗传易感性个体中的下丘脑泌素神经元。这些神经元在整个大脑中形成了一个广泛的投射网络，并显示出与动机行为相关的活动。靶向免疫介导或自身免疫攻击导致下丘脑泌素神经元特异性退化的假设主要是通过发现与 HLA-DQB1*06:02 等位基因的遗传关联以及随后与 T 细胞受体α基因座的遗传关联而产生的。受这些遗传发现的指导，现在正在等待实验验证的是可能的免疫机制模型，这些机制可以使特定的局部脑细胞群体成为 T 细胞亚群的靶向目标。在嗜睡症中识别新的治疗靶点的巨大希望也存在于患者衍生的诱导多能干细胞系统的发展中。
