Narcoimmunomics

Narcolepsy type 1 (NT1) is a rare, chronic neurological disorder characterized by excessive daytime sleepiness and cataplexy, caused by a selective loss of hypothalamic orexin-producing neurons, leading to reduced cerebrospinal fluid (CSF) orexin-A levels. Strong evidence suggests an autoimmune etiology, with NT1 showing a remarkable association with the HLA-DQB1*06:02 allele and certain triggers like the 2009 H1N1 influenza vaccine. Recent studies in animal models have identified T cell involvement in NT1 pathogenesis, with CD4+ T cells initiating hypothalamic inflammation and CD8+ T cells contributing to orexin neuron destruction. In humans, increased frequencies of orexin-specific CD4+ T cells in NT1 patients further support an autoimmune basis. However, it remains unclear if these immune disturbances are primary or secondary to the disease. Our research focuses on elucidating the immune pathways responsible for the destruction of orexin neurons. Specifically, we aim to (i) identify the immune mechanisms involved, and (ii) isolate and profile clonally expanded T cells to pinpoint key autoantigens and effector mechanisms. At our reference center, NT1 patients undergo a comprehensive clinical and biological evaluation, including HLA typing and CSF orexin measurement, with biobanking of serum, CSF, and PBMCs. Control subjects are also recruited for comparative studies. We will employ large-scale aptamer-based proteomics and single-cell transcriptomics to assess neuroimmune alterations in CSF, as well as TCR repertoire analysis using 10X Genomics to compare NT1 patients with controls. In addition, we will investigate the antigen specificity of expanded CSF CD4+ T cells and validate these findings in peripheral blood, particularly near disease onset. Our overarching goal is to refine our understanding of the neuro-immunological mechanisms underlying orexin neuron destruction in NT1 and to identify potential immune-targeting therapeutic strategies.