Pandemrix and T Cell Immunology in Narcolepsy

Pandemrix 和 T 细胞免疫学在发作性睡病中的应用

基本信息

批准号：
10618986
负责人：
Emmanuel J Mignot
金额：
$ 71.77万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-13 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10618986
关键词：
Adjuvant Affect Animal Model Antigen Presentation Antigen-Presenting Cells Antigens Autoantigens Autoimmune Autoimmune Diseases Autoimmune Process Autoimmune Responses Binding Biological Assay Blood Blood Tests Brain C-terminal CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Death Cell model Cells Cessation of life Chemicals Child China Code Data Dendritic cell activation Diagnostic Diagnostic tests Disease Environmental Risk Factor Epitope spreading Epitopes Europe Flu virus Frequencies Genes Genetic Polymorphism Genetic Risk Genetic study Genome Genomics Genotype Goals HLA-A gene HLA-DP Antigens HLA-DQA1 HLA-DR Antigens Human IFNAR1 gene Immune Immune response Immune system Immunization Programs Immunology Incidence Individual Influenza Influenza A Virus, H1N1 Subtype Influenza Hemagglutinin Jurkat Cells Knowledge Laboratories Ligands Maps Mediating Modeling Molecular Mimicry Narcolepsy Neurons Pathogenicity Patients Peptides Persons Phenotype Post-Translational Protein Processing Predisposition Prevention strategy Preventive measure Process Publishing REM Sleep Reagent Receptor Cell Research Research Personnel Risk Role Safety Sequence Homology Sorting Symptoms T cell receptor repertoire sequencing T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Technology Transfection United States Vaccination Vaccines Virus alpha-beta T-Cell Receptor amidation antigen processing autoreactivity cross reactivity design flu genetic association high risk population hypocretin improved influenza virus vaccine influenzavirus novel therapeutics pandemic disease pandemic influenza receptor response single cell sequencing single-cell RNA sequencing

项目摘要

ABSTRACT: Genetic studies indicate a strong (97%) association of narcolepsy with HLA-DQA1*01:02/DQB1*06:02 (DQ0602), weaker associations with HLA-DP and class I HLA- A*11:01, and effects in other immune related genes such as the TCR αβ loci. The disease is caused by the loss of hypocretin (HCRT)/orexin neurons, as loss of HCRT or HCRT receptors recapitulates symptoms in animal models. Results from our laboratory and from others indicate that a critical step in the disease process is a CD4+ T cell autoimmune response targeting HCRT itself, notably a DQ0602 restricted response to the amidated, C-terminal end of secreted HCRT peptides (HCRTNH2). Indeed, increased T cell response to HCRTNH2 presented by DQ0602 is observed in narcolepsy (our observation), followed by a broader CD4+ T cell responses to other HCRT fragments presented by other HLA class II molecules (other investigators), a result of epitope spreading. This is likely followed by a CD8+ T cell response to HLA class I presented antigens that results in hypocretin cell death and life-long narcolepsy. Unique to narcolepsy, a known environmental factor, the flu, has been associated with initiation of the autoimmune process. Indeed, an increased incidence of narcolepsy in children has been observed following the 2009-2010 pH1N1 Influenza pandemic in China and following vaccination with Pandemrix (GSK), an AS03 adjuvanted pandemic H1N1 2009 (pH1N1) vaccine, but not other vaccines. These observations indicate that epitopes within the pH1N1 virus and vaccine can precipitate narcolepsy in some individuals, findings substantiated by the fact narcolepsy patients have increased T cells binding NP17-31 and pHA273-287, a flu hemagglutinin fragment with significant HCRTNH2 sequence homology. This mechanism is also supported by our preliminary data suggesting TRAJ24 and TRBVB4-2 involvement in pHA273-287, NP17-31 and HCRTNH2 TCR responses, as these TCR segments are modulated by SNPs associated with narcolepsy. In this application, we will further characterize antigenic differences in Pandemrix, Arepanrix and Focetria, vaccines used in the 2009-2010 pH1N1 vaccination campaign, capitalizing on the observation that they have differential risk for precipitating narcolepsy. Our hypothesis, supported by preliminary data, is that Pandemrix contains more pHA273-287 peptide, the main mimic of HCRTNH2 autoimmune responses. In addition, we will continue isolation and characterization of Pandemrix/H1N1 reactive and HCRTNH2 DQ0602 restricted CD4+ T cells. Our hypothesis is that we will ultimately discover pHA273-287/HCRTNH2 and other flu/HCRT cross-reactive cells that use TRAJ24 and TRBVB4-2 segments. Finally, we aim to characterize the phenotype of the corresponding pathogenic cells through single cell sequencing. This high impact study is expected to eventually lead to a) demonstration of molecular mimicry in narcolepsy and b) improved safety of influenza vaccines.

抽象的：遗传学研究表明发作性睡病与 HLA-DQA1*01:02/DQB1*06:02 存在很强的关联性 (97%) (DQ0602)，与 HLA-DP 和 I 类 HLA-A*11:01 的关联较弱，以及对其他免疫相关的影响基因，如 TCR αβ 基因座该疾病是由下丘脑分泌素 (HCRT)/食欲素神经元的缺失引起的。 HCRT 或 HCRT 受体的丧失概括了我们实验室和动物模型中的症状。其他人的研究表明，疾病过程中的一个关键步骤是针对 CD4+ T 细胞的自身免疫反应 HCRT 本身，尤其是 DQ0602 对分泌 HCRT 酰胺化 C 末端的限制性反应事实上，在 DQ0602 中观察到 T 细胞对 HCRTNH2 的反应增加。发作性睡病（我们的观察），随后是对其他 HCRT 片段出现更广泛的 CD4+ T 细胞反应由其他 HLA II 类分子（其他研究人员）识别，这是表位扩散的结果。 CD8+ T 细胞对 HLA I 类呈递抗原作出反应，导致下丘脑分泌素细胞死亡并终身死亡发作性睡病是一种已知的环境因素，流感与发作性睡病的发生有关。事实上，已经观察到儿童发作性睡病的发病率有所增加。 2009-2010 年中国发生 pH1N1 流感大流行并接种 Pandemrix (GSK) 疫苗后， AS03 佐剂大流行 H1N1 2009 (pH1N1) 疫苗，但不是其他疫苗这些观察结果。表明 pH1N1 病毒和疫苗内的表位可以在某些个体中引发发作性睡病，嗜睡病患者 T 细胞结合 NP17-31 和 pHA273-287 增加这一事实证实了这一发现，流感血凝素片段具有显着的 HCRTNH2 序列同源性，这一机制也得到了支持。我们的初步数据表明 TRAJ24 和 TRBVB4-2 参与 pHA273-287、NP17-31 和 HCRTNH2 TCR 反应，因为这些 TCR 片段是由与发作性睡病相关的 SNP 调节的。我们将进一步描述 Pandemrix、Arepanrix 和 Focetria 的抗原差异，这些疫苗用于 2009 年至 2010 年 pH1N1 疫苗接种活动，利用观察到他们有不同的风险初步数据支持，我们的假设是 Pandemrix 含有更多的成分。 pHA273-287 肽，HCRTNH2 自身免疫反应的主要模拟物此外，我们将继续分离。 Pandemrix/H1N1 反应性和 HCRTNH2 DQ0602 限制性 CD4+ T 细胞的表征。假设我们最终会发现 pHA273-287/HCRTNH2 和其他流感/HCRT 交叉反应细胞最后，我们的目标是表征相应的表型。这项高影响力的研究预计最终会导致：证明发作性睡病的分子拟态；b) 提高流感疫苗的安全性。