Peripheral Adaptive Immune System Changes Associated with Alzhiemer's Disease

项目总结/摘要 阿尔茨海默病（AD）是人类最常见的与年龄相关的认知功能障碍。进步 B-淀粉样蛋白（Ab）的积累和大脑某些部位的神经炎症是主要的病理学 AD 1的特点衰老是AD发展的最大风险。就像人类的大脑， 与外周适应性免疫的许多变化有关。AD中的大多数遗传关联 指出基因参与先天性炎症和小胶质细胞活化，适应性免疫及其在 认知能力下降和AD几乎被忽视。然而，在AD中已经注意到Ab特异性T细胞的存在， 患者，并显示随着年龄的增长。最近，通过采用无偏见的方法，我们探讨了 多个AD患者队列以及年龄和性别匹配的健康对照中的T细胞。我们的研究表明 外周血和脑脊液中效应记忆CD 8 T细胞的频率增加 AD患者的促炎潜能增强。此外，我们发现这些CD 8效应T细胞 与认知呈负相关。此外，外周血中的T细胞受体（TCR）测序和 脑脊液显示克隆扩增增加。我们的研究还将T细胞免疫特征与 在AD中具有更高的克隆扩增。然而，无论这些T细胞在AD中是有益的还是有害的， 这些克隆性T细胞对Ab有特异性反应，它们在AD中的实际TCR库和表型是什么？ 仍然未知。因此，需要更多的研究来深入了解CD 4和CD 8 T细胞在肿瘤中的作用。 AD中的Ab反应性。随着越来越多的证据表明T细胞在AD中的作用，我们的中心假设是， 失调的淀粉样蛋白特异性T细胞应答有助于AD发病机制。我们将讨论这一假设 通过测定1）健康对照和AD患者中的Ab特异性T细胞应答和2）AD患者中的Ab特异性T细胞应答， 细胞受体（TCR）库中的健康对照和AD患者。拟议的研究将奠定基础， 增强我们对Ab介导的T细胞应答和独特的细胞和分子编程的理解 途径。此外，在提供基于Ab的治疗之前，测试AD患者中固有的CD 4和CD 8 T细胞对Ab的活性。 基于AD的免疫治疗将有助于对患者进行分层，并对未来的Ab定向免疫治疗具有重要意义。 治疗

PROJECT SUMMARY/ABSTRACT Alzheimer disease (AD) is the most common form of age-related cognitive failure in humans. Progressive accumulation of b-amyloid (Ab) and neuroinflammation of certain parts of the brain are dominant pathological features of AD 1. Aging represents the greatest risk for development of AD. As like in the brain, aging in humans is associated with many changes in the peripheral adaptive immunity. Most of the genetic association in AD points to genes involved in innate inflammation and microglial cell activation, adaptive immunity and its role in cognitive decline and AD is almost ignored. However, the presence of Ab specific T cells has been noted in AD patients and shown to increase with age. Recently, by employing unbiased approaches we explored the role of T cells in multiple cohorts of AD patients as well as age and sex matched healthy controls. Our study showed that there is increased frequency of effector memory CD8 T cells in the peripheral blood and cerebrospinal fluid of AD patients with enhanced proinflammatory potential. In addition, we found that these CD8 effector T cells were negatively correlated with cognition. Further, T cell receptor (TCR) sequencing in the peripheral blood and cerebrospinal fluid showed increased clonal expansion. Our study also associated a T cell immune signature with higher clonal expansion in AD. However, whether these T cells are beneficial or detrimental in AD, whether these clonal T cells respond specifically to Ab, and what their actual TCR repertoire and phenotypes are in AD remain unknown. Therefore, additional studies are required to gain insight into the role of CD4 and CD8 T cell reactivity to Ab in AD. With increasing evidence for T cell effects in AD, our central hypothesis is that the dysregulated amyloid specific T cell responses contribute to AD pathogenesis. We will address this hypothesis by determining 1) the Ab specific T cell responses in healthy controls and AD patients and 2) the Ab specific T cell receptor (TCR) repertoire in healthy controls and AD patients. The proposed studies will lay the groundwork to enhance our understanding of Ab mediated T cell response and unique cellular and molecular programming pathways. Further, testing intrinsic CD4 and CD8 T cell activity in AD patients to Ab before offering Ab-based immunotherapy based in AD will help stratify patients and have major implications for future Ab-directed therapies.