Cellular auto-immune mechanisms of narcolepsy

发作性睡病的细胞自身免疫机制

• 批准号: 9335997
• 负责人: Igor J Koralnik
• 金额: $ 20.42万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335997
• 关键词: Acquired Immunodeficiency Syndrome; Adolescence; Alleles; Anxiety; Autoimmune Diseases; Biological Assay; Blood Tests; CD8-Positive T-Lymphocytes; Cataplexy; Cause of Death; Cell Culture Techniques; Cellular Immunity; Child; Chronic; Clinical Management; Data; Diagnosis; Diagnostic; Diagnostic tests; Drowsiness; Early Diagnosis; Emotions; Epitopes; Future; Goals; Histocompatibility Antigens Class II; Hypothalamic structure; Immune; Immune response; Immunologics; Immunologist; Immunology; Incidence; Individual; Investigation; Knowledge; Laughter; Life; Link; Maps; Mass Vaccinations; Measures; Messenger RNA; Mission; Molecular Mimicry; Multiple Sclerosis; Muscle Weakness; Narcolepsy; National Institute of Neurological Disorders and Stroke; Neuronal Injury; Neurons; Neuropeptides; Outcome; Paper; Paralysed; Pathogenicity; Patients; Peptides; Prevention strategy; Preventive Intervention; Public Health; Publications; RNA; Research; Role; Scandinavia; Severities; Severity of illness; Sleep; Sleep Disorders; Specimen; Staining method; Stains; Symptoms; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Vaccination; Vaccines; clinical Diagnosis; cytokine; hypocretin; immunosuppressed; influenza virus vaccine; innovation; nervous system disorder; neuroimmunology; novel diagnostics; response; screening; targeted treatment; vaccination strategy; vaccine development

Narcolepsy with Cataplexy (N/C) is a common sleep disorder, but very little is understood about the underlying mechanism that causes N/C and why symptoms are severe in some patients but not in others. N/C is caused by selective loss of the hypothalamic neurons that produce the orexin neuropeptides and is strongly associated with the Major Histocompatibility Complex (MHC) class II allele DQB1 *0602. We hypothesize that N/C is caused by CD4+ or CD8+ T cells response directed against the hypothalamic neurons producing the orexin neuropeptides, and that a more aggressive immune response results in increased severity of N/C. This hypothesis is supported by a number of publications suggesting a causal role of the cellular immune response in N/C as well as our own preliminary data. Our long term goal is to understand the cause of N/C and the determinants of disease severity. In doing so, we will also devise a much needed blood test for the early diagnosis of NC and prediction of disease severity. Our objectives are to determine whether N/C patients mount a cellular immune response to orexin peptides and whether this response is associated with more severe symptoms. The rationale is that these proposed studies will enable us to develop a blood test for early diagnosis of N/C and predictor of disease severity. To test these hypotheses, we will pursue the following set of Specific Aims: Aim 1) Correlate disease severity with the cellular immune response to orexin neuropeptides in DQB1 *0602+ Narcolepsy with Cataplexy patients. We will measure narcolepsy symptoms severity using well- validated scales and correlate symptom severity with the reactivity of CD4+ or CD8+ T cells to orexin peptides using three different assays: 1) Intracellular Cytokine Staining (ICS) assay 2) Luminex xMAP bead array on cell culture supernatant and 3) RT-qPCR for cytokine mRNA on cellular RNA . Aim 2) Identify immunodominant orexin epitopes recognized by CD4+ or CD8+ T cells in DQB1 *0602+ Narcolepsy with Cataplexy patients. We will map orexin epitopes in N/C patients using ICS and devise a diagnostic blood test and predictor of disease severity for N/C. The approach is innovative, because it departs significantly from the status quo by focusing on the cellular mechanisms leading to N/C. The proposed research is significant because it will allow us to identify the immunopathogenic mechanisms leading to N/C, develop a blood test for early diagnosis of N/C and predict disease severity. The knowledge gained from these studies will also have far reaching implications in advancing the fields of Sleep Disorders and Neuro-Immunology.

发作性睡病伴猝倒 (N/C) 是一种常见的睡眠障碍，但对其潜在的原因知之甚少 导致 N/C 的机制以及为什么某些患者的症状较严重而其他患者则不然。 N/C 引起 通过选择性丧失产生食欲素神经肽并与之密切相关的下丘脑神经元 具有主要组织相容性复合物 (MHC) II 类等位基因 DQB1 *0602。我们假设 N/C 是 由 CD4+ 或 CD8+ T 细胞针对产生食欲素的下丘脑神经元的反应引起 神经肽，更积极的免疫反应会导致 N/C 严重程度增加。这 该假设得到了许多出版物的支持，表明细胞免疫反应的因果作用 N/C 以及我们自己的初步数据。我们的长期目标是了解 N/C 的原因以及 疾病严重程度的决定因素。在此过程中，我们还将为早期患者设计急需的血液测试。 NC 的诊断和疾病严重程度的预测。我们的目标是确定 N/C 患者是否 对食欲素肽产生细胞免疫反应，以及这种反应是否与更多相关 严重的症状。理由是，这些拟议的研究将使我们能够开发一种血液测试来早期诊断 N/C 的诊断和疾病严重程度的预测。 为了检验这些假设，我们将追求以下一组具体目标： 目标 1) 将疾病严重程度与 DQB1 中食欲素神经肽的细胞免疫反应相关联 *0602+ 猝倒患者发作性睡病。我们将使用良好的方法来测量发作性睡病症状的严重程度 经过验证的量表并将症状严重程度与 CD4+ 或 CD8+ T 细胞对食欲素肽的反应性相关联 使用三种不同的测定：1) 细胞内细胞因子染色 (ICS) 测定 2) 细胞上的 Luminex xMAP 珠阵列 培养上清液和 3) RT-qPCR 检测细胞 RNA 上的细胞因子 mRNA。 目标 2) 鉴定 DQB1 *0602+ 中 CD4+ 或 CD8+ T 细胞识别的免疫显性食欲素表位 发作性睡病与猝倒患者。我们将使用 ICS 绘制 N/C 患者的食欲素表位图并设计一个 N/C 的诊断性血液检测和疾病严重程度的预测。 该方法是创新的，因为它通过专注于蜂窝技术而显着偏离现状。 导致 N/C 的机制。拟议的研究意义重大，因为它将使我们能够确定 导致 N/C 的免疫致病机制，开发血液检测以早期诊断 N/C 并预测 疾病的严重程度。从这些研究中获得的知识也将产生深远的影响 推进睡眠障碍和神经免疫学领域的发展。