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.

发作性睡病合并猝倒(N/C)是一种常见的睡眠障碍，但对其潜在原因了解甚少 导致N/C的机制，以及为什么一些患者症状严重，而另一些患者症状不严重。导致N/C 通过选择性地丧失产生食欲素神经肽的下丘脑神经元，并与 具有主要组织相容性复合体(MHC)II类等位基因DQB1*0602。我们假设N/C是 由CD4+或CD8+T细胞对产生增食欲素的下丘脑神经元的反应引起 神经肽，更具侵袭性的免疫反应导致N/C严重程度增加。 这一假说得到了一些出版物的支持，这些出版物表明细胞免疫反应具有因果关系。 以及我们自己的初步数据。我们的长期目标是了解N/C的原因和 疾病严重程度的决定因素。在这样做的同时，我们还将为早期患者设计一种亟需的血液测试 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 启动对增食欲素肽的细胞免疫反应，以及这种反应是否与更多 严重的症状。理由是这些拟议的研究将使我们能够开发出一种早期的血液测试 N/C的诊断和疾病严重程度的预测。 为了验证这些假设，我们将追求以下一套具体目标： 目的1)DQB1的疾病严重程度与增食欲素神经肽的细胞免疫应答相关 *0602+发作性睡病患者。我们将使用Well-来测量嗜睡症症状的严重程度- 验证量表和症状严重程度与CD4+或CD8+T细胞对食欲素肽的反应性相关 使用三种不同的检测方法：1)细胞内细胞因子染色(ICS)检测2)细胞上Luminex xMAP微珠阵列 培养上清液；3)RT-qPCR检测细胞RNA上的细胞因子mRNA。 目的2)确定DQB1*0602+中CD4+或CD8+T细胞识别的免疫优势增食欲素表位 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，并设计一种 诊断血液测试和N/C疾病严重程度的预测因子 这种方法是创新的，因为它通过专注于细胞 导致N/C的机制这项拟议的研究具有重要意义，因为它将使我们能够确定 导致N/C的免疫病理机制，开发一种用于N/C早期诊断和预测的血液检测方法 疾病的严重性。从这些研究中获得的知识也将对 推进睡眠障碍和神经免疫学领域。