Peripheral Adaptive Immune System Changes Associated with Alzhiemer's Disease

与阿尔茨海默病相关的外周适应性免疫系统变化

• 批准号: 10194864
• 负责人: Naresha Saligrama
• 金额: $ 43.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194864
• 关键词: AN-1792; Active Immunization; Adaptive Immune System; Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Antibodies; Antigens; B-Lymphocytes; Blood Vessels; Brain; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cerebrospinal Fluid; Clinical; Clinical Trials; Clonal Expansion; Clonality; Cognition; Cognitive; Cytometry; Development; Disease; Early Diagnosis; Excision; Failure; Frequencies; Future; Gene Expression Profile; Genes; Human; Immune; Immune response; Immunization; Immunotherapeutic agent; Immunotherapy; Impaired cognition; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Investigation; Length; Measures; Mediating; Mediator of activation protein; Memory; Meningoencephalitis; Microglia; Molecular; Mus; Neurodegenerative Disorders; Participant; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptides; Peripheral; Peripheral Blood Lymphocyte; Phenotype; Play; Receptor Signaling; Risk; Role; Senile Plaques; Severity of illness; Surface; T cell receptor repertoire sequencing; T cell response; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Transcript; Universities; Washington; abeta accumulation; adaptive immunity; age related; antigen-specific T cells; base; biomarker development; cohort; cytokine; effector T cell; genetic association; individual patient; insight; mouse model; neuroinflammation; patient stratification; peripheral blood; response; sex; single-cell RNA sequencing; synthetic peptide

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.

项目摘要/摘要 阿尔茨海默病(AD)是人类最常见的与年龄相关的认知衰竭形式。渐进式 脑部某些部位的b-淀粉样蛋白积聚和神经炎是主要的病理性病变。 AD的特点1.衰老是AD发展的最大风险。就像在大脑中一样，人类的衰老 与外周获得性免疫的许多变化有关。阿尔茨海默病的大多数遗传关联 指出参与先天炎症和小胶质细胞激活、获得性免疫及其作用的基因 认知功能减退和AD几乎被忽视。然而，在AD中已经注意到抗体特异性T细胞的存在 患者，并显示随着年龄的增长而增加。最近，通过使用公正的方法，我们探索了 AD患者多个队列中的T细胞以及年龄和性别与健康对照组匹配。我们的研究表明 外周血液和脑脊液中效应记忆CD8 T细胞的频率增加 阿尔茨海默病患者的促炎潜能增强。此外，我们发现这些CD8效应T细胞 与认知呈负相关。此外，外周血中T细胞受体(TCR)的测序和 脑脊液呈克隆性扩张。我们的研究还发现了T细胞免疫信号 AD的克隆性扩张程度较高。然而，无论这些T细胞在AD中是有益的还是有害的，无论 这些克隆性T细胞对抗体有特异性反应，以及它们在AD中的实际TCR谱系和表型是什么 仍然不为人所知。因此，需要更多的研究来深入了解CD4和CD8 T细胞的作用 AD患者对抗体的反应性。随着越来越多的证据表明T细胞在阿尔茨海默病中的作用，我们的中心假设是 调节失调的淀粉样特异性T细胞反应参与了AD的发病。我们将解决这一假设 通过测定1)正常人和AD患者的抗体特异性T细胞反应和2)抗体特异性T细胞 健康对照组和AD患者的细胞受体(TCR)谱。拟议的研究将奠定基础 为了加深我们对抗体介导的T细胞反应和独特的细胞和分子编程的理解 小路。此外，在提供基于抗体的抗体之前，检测AD患者固有的CD4和CD8 T细胞对抗体的活性 以AD为基础的免疫治疗将有助于对患者进行分层，并对未来的抗体导向具有重大意义 治疗。