Pandemrix and T Cell Immunology in Narcolepsy

摘要： 遗传学研究表明，发作性睡病与人类白细胞抗原DQA1*01：02/DQB1*06：02有很强的相关性(97%) (DQ0602)，与人类白细胞抗原-DP和I类人类白细胞抗原-A*11：01的相关性较弱，以及对其他免疫相关的影响 TcRαβ基因座等基因。这种疾病是由下丘脑皮质激素(Hcrt)/增食欲素神经元的丢失引起的，如 HCRT或HCRT受体的缺失重现了动物模型中的症状。我们实验室的结果和 来自其他人的研究表明，疾病过程中的关键步骤是以CD4+T细胞自身免疫反应为靶点 HCRT本身，特别是DQ0602对分泌型HCRT的酰胺化C末端的限制性反应 多肽(HCRTNH2)。事实上，由DQ0602呈现的对HCRTNH2的T细胞应答增加在 发作性睡病(我们的观察)，随后出现更广泛的CD4+T细胞对其他HCRT片段的反应 其他人类白细胞抗原II类分子(其他研究人员)，这是表位扩散的结果。这之后可能会有一个 CD8+T细胞对人类白细胞抗原I类抗原的反应可导致下丘脑细胞死亡和终生 嗜睡症。发作性睡病独有的一种已知环境因素，即流感，与发作性睡病有关。 自体免疫过程。事实上，已经观察到儿童发作性睡病的发病率有所增加。 在2009-2010年中国发生H1N1流感大流行和接种潘德姆利克斯疫苗后， 一种AS03佐剂的2009年大流行H1N1(PH1N1)疫苗，但不是其他疫苗。这些观察结果 表明H1N1病毒和疫苗中的表位可能会导致一些人发作性睡病， 发作性睡病患者与NP17-31和PHA273-287结合的T细胞增加，这一事实证实了这一发现 流感血凝素片段具有显著的HCRTNH2序列同源性。这一机制也得到了 我们的初步数据表明TRAJ24和TRBVB4-2参与了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调制的。在此应用程序中， 我们将进一步表征Pandemrix，Arepanrix和Focetria疫苗的抗原差异，这三种疫苗用于 2009-2010年H1N1疫苗接种活动，利用观察到他们对 发作性发作性睡病。我们的假设得到了初步数据的支持，即Pandemrix含有更多 PHA273-287肽，主要模拟HCRTNH2自身免疫反应。此外，我们将继续隔离 以及Pandemrix/H1N1反应性和HCRTNH2 DQ0602限制性CD4+T细胞的特征。我们的 假设我们最终会发现PHA273-287/HCRTNH2和其他Flu/HCRT交叉反应细胞 使用TRAJ24和TRBVB4-2数据段。最后，我们的目标是表征相应的表型 通过单细胞测序获得致病细胞。这项影响很大的研究预计最终将导致) 分子模仿在发作性睡病中的演示以及b)提高了流感疫苗的安全性。

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.