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:
- 金额:$ 77.84万
- 依托单位:
- 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:
- 关键词:AdjuvantAffectAnimal ModelAntigen-Presenting CellsAntigensAutoantigensAutoimmuneAutoimmune DiseasesAutoimmune ProcessAutoimmune ResponsesBindingBiological AssayBloodBlood TestsBrainC-terminalCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell DeathCell modelCellsCessation of lifeChemicalsChildChinaCodeDataDendritic cell activationDiagnosticDiagnostic testsDiseaseEnvironmental Risk FactorEpitope spreadingEpitopesEuropeFlu virusFrequenciesGenesGenetic PolymorphismGenetic RiskGenetic studyGenomeGenomicsGenotypeGoalsH1N1 vaccineHLA-A geneHLA-DP AntigensHLA-DQA1HLA-DR AntigensHumanIFNAR1 geneImmuneImmune responseImmune systemImmunization ProgramsImmunologyIncidenceIndividualInfluenzaInfluenza A Virus, H1N1 SubtypeInfluenza HemagglutininJurkat CellsKnowledgeLaboratoriesLeadLifeLigandsMapsMediatingModelingMolecular MimicryNarcolepsyNeuronsPathogenicityPatientsPeptidesPersonsPhenotypePost-Translational Protein ProcessingPredispositionPrevention strategyPreventive measureProcessPublishingREM SleepReagentReceptor CellResearchResearch PersonnelRiskRoleSafetySequence HomologySymptomsT cell receptor repertoire sequencingT cell responseT-Cell ActivationT-Cell ReceptorT-LymphocyteTechnologyUnited StatesVaccinationVaccinesalpha-beta T-Cell Receptorantigen processingautoreactivitycase controlcross reactivitydesignflugenetic associationhigh risk populationhypocretinimprovedinfluenza virus vaccineinfluenzavirusnovel therapeuticspandemic diseasepandemic influenzareceptorresponsesingle cell sequencingsingle-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.
文摘:
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Emmanuel J Mignot其他文献
Emmanuel J Mignot的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Emmanuel J Mignot', 18)}}的其他基金
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
- 批准号:
10618986 - 财政年份:2021
- 资助金额:
$ 77.84万 - 项目类别:
KIR and HLA effects in CNS paraneoplastic syndromes and related neuroimmune conditions
KIR 和 HLA 对 CNS 副肿瘤综合征和相关神经免疫性疾病的影响
- 批准号:
10266033 - 财政年份:2020
- 资助金额:
$ 77.84万 - 项目类别:
KIR and HLA effects in CNS paraneoplastic syndromes and related neuroimmune conditions
KIR 和 HLA 对 CNS 副肿瘤综合征和相关神经免疫性疾病的影响
- 批准号:
10680363 - 财政年份:2020
- 资助金额:
$ 77.84万 - 项目类别:
Center for Narcolepsy and Related Disorders (P50)
发作性睡病及相关疾病中心 (P50)
- 批准号:
9245340 - 财政年份:2016
- 资助金额:
$ 77.84万 - 项目类别:
HLA-DQ Sequencing Studies in Narcolepsy/Hypocretin Deficiency
发作性睡病/下丘脑分泌素缺乏症的 HLA-DQ 测序研究
- 批准号:
8129460 - 财政年份:2010
- 资助金额:
$ 77.84万 - 项目类别:
HLA-DQ Sequencing Studies in Narcolepsy/Hypocretin Deficiency
发作性睡病/下丘脑分泌素缺乏症的 HLA-DQ 测序研究
- 批准号:
8259851 - 财政年份:2010
- 资助金额:
$ 77.84万 - 项目类别:
HLA-DQ Sequencing Studies in Narcolepsy/Hypocretin Deficiency
发作性睡病/下丘脑分泌素缺乏症的 HLA-DQ 测序研究
- 批准号:
7991554 - 财政年份:2010
- 资助金额:
$ 77.84万 - 项目类别:
Sleep promotion in zebrafish by hypocretin neuronal networks
下丘脑分泌素神经元网络促进斑马鱼的睡眠
- 批准号:
7506836 - 财政年份:2008
- 资助金额:
$ 77.84万 - 项目类别:
Sleep promotion in zebrafish by hypocretin neuronal networks
下丘脑分泌素神经元网络促进斑马鱼的睡眠
- 批准号:
7620945 - 财政年份:2008
- 资助金额:
$ 77.84万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 77.84万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 77.84万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 77.84万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 77.84万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 77.84万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 77.84万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 77.84万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 77.84万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 77.84万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 77.84万 - 项目类别:
Grant-in-Aid for Early-Career Scientists