Freeman Sean A, Ayoub Ikram, Dauvilliers Yves, Liblau Roland S
Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University of Toulouse, CNRS, INSERM, UPS, Toulouse, France; Department of Neurology, Toulouse University Hospitals, Toulouse, France.
Department of Neurosciences, Mayo Clinic, Jacksonville, FL 32224, USA.
Semin Immunol. 2025 Jun;78:101962. doi: 10.1016/j.smim.2025.101962. Epub 2025 May 14.
Narcolepsy type 1 (NT1) is a chronic orphan neurological sleep disorder characterized by the loss of hypocretin-producing neurons in the lateral hypothalamus, which play a crucial role in wakefulness. Given the genetic association with the HLA-DQB1 * 06:02 allele and environmental links with the 2009 influenza pandemic, many lines of evidence point towards an immune mechanism, notably autoimmunity, underlying the disease pathophysiology. Autoreactive T cells are found in the blood of NT1 patients, and mouse models demonstrate their migratory capacity and contribution in the selective destruction of hypocretin-producing neurons. However, direct evidence for their role in human NT1 pathophysiology remains elusive. In complementing these findings, hypothesis-generating approaches-including multiparametric immune profiling, transcriptomic sequencing and large-scale proteomic of blood and cerebrospinal fluid-have uncovered promising new avenues into the immune system's involvement in NT1. In this review, we explore the mechanisms driving NT1 pathogenesis, emphasizing both hypothesis-driven and hypothesis-generating approaches, and discuss potential future directions that could pave the way for targeted immunotherapies.
1型发作性睡病（NT1）是一种慢性罕见神经睡眠障碍，其特征是下丘脑外侧产生食欲素的神经元丧失，这些神经元在清醒中起关键作用。鉴于与HLA-DQB1 * 06:02等位基因的遗传关联以及与2009年流感大流行的环境联系，许多证据表明免疫机制，尤其是自身免疫，是该疾病病理生理学的基础。在NT1患者血液中发现了自身反应性T细胞，小鼠模型证明了它们的迁移能力以及在选择性破坏产生食欲素的神经元中的作用。然而，它们在人类NT1病理生理学中作用的直接证据仍然难以捉摸。作为对这些发现的补充，包括多参数免疫分析、转录组测序以及血液和脑脊液的大规模蛋白质组学在内的假设生成方法，揭示了免疫系统参与NT1的有前景的新途径。在本综述中，我们探讨驱动NT1发病机制的机制，强调假设驱动和假设生成方法，并讨论可能为靶向免疫疗法铺平道路的潜在未来方向。
