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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：
10405047
负责人：
Emmanuel J Mignot
金额：
$ 77.84万
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/10405047
关键词：
Adjuvant Affect Animal Model 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 H1N1 vaccine 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 Lead Life 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 Symptoms T cell receptor repertoire sequencing T cell response T-Cell Activation T-Cell Receptor T-Lymphocyte Technology United States Vaccination Vaccines alpha-beta T-Cell Receptor antigen processing autoreactivity case control 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.

摘要：遗传研究表明发作性睡病与HLA-DQA 1 *01：02/DQB 1 *06：02有很强的相关性（97%）（DQ 0602），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。这种疾病是由下丘脑泌素（HCRT）/食欲素神经元的丢失引起的， HCRT或HCRT受体的丧失再现了动物模型中的症状。我们实验室的结果和表明疾病过程中的关键步骤是CD 4 + T细胞自身免疫应答， HCRT本身，特别是DQ 0602对分泌的HCRT的酰胺化C末端的限制性应答肽（HCRTNH 2）。事实上，在小鼠中观察到增加的T细胞对DQ 0602呈递的HCRTNH 2的应答。嗜睡症（我们的观察），其次是更广泛的CD 4 + T细胞对其他HCRT片段的反应，其他HLA II类分子（其他研究者），表位扩散的结果。这很可能是一个 CD 8 + T细胞对HLA I类呈递抗原的应答导致下丘脑泌素细胞死亡和寿命延长嗜睡症发作性睡病所特有的一种已知的环境因素--流感，自身免疫过程事实上，已经观察到儿童嗜睡症的发病率增加在2009-2010年中国pH 1 N1流感大流行和Pandemrix（GSK）疫苗接种后， AS 03佐剂化的2009年H1N1大流行性流感（pH 1 N1）疫苗，而不是其他疫苗。这些观察结果表明pH 1 N1病毒和疫苗内表位可在某些个体中诱发发作性睡病，发作性睡病患者结合NP 17 -31和pHA 273 -287的T细胞增加，流感血凝素片段与HCRTNH 2序列具有显著同源性。这一机制也得到了我们的初步数据表明TRAJ 24和TRBVB 4 -2参与pHA 273 -287、NP 17 -31和HCRTNH 2 TCR 这些TCR片段受到与嗜睡症相关的SNP的调节。在本申请中，我们将进一步描述Pandemrix、Arepanrix和Focetria疫苗的抗原差异， 2009-2010年pH 1 N1疫苗接种运动，利用观察结果，诱发嗜睡症我们的假设得到了初步数据的支持， pHA 273 -287肽，HCRTNH 2自身免疫应答的主要模拟物。另外，我们将继续隔离和Pandemrix/H1N1反应性和HCRTNH 2 DQ 0602限制性CD 4 + T细胞的表征。我们假设我们最终将发现pHA 273 -287/HCRTNH 2和其他流感/HCRT交叉反应细胞，使用TRAJ 24和TRBVB 4 -2段。最后，我们的目标是表征相应的表型病原体细胞通过单细胞测序。这项高影响力的研究预计最终将导致a）发作性睡病中分子模拟的证明和B）改进流感疫苗的安全性。