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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要/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 的特点 1. 衰老是 AD 发生的最大风险。就像大脑一样，人类的衰老与外周适应性免疫的许多变化有关。 AD 的大部分遗传关联指出与先天性炎症和小胶质细胞激活、适应性免疫及其作用有关的基因认知能力下降和AD几乎被忽视。然而，AD 中存在 Ab 特异性 T 细胞患者，并且随着年龄的增长而增加。最近，通过采用公正的方法，我们探索了多组 AD 患者以及年龄和性别的 T 细胞与健康对照相匹配。我们的研究表明外周血和脑脊液中效应记忆 CD8 T 细胞的频率增加 AD 患者的促炎潜力增强。此外，我们发现这些CD8效应T细胞与认知呈负相关。此外，外周血中的 T 细胞受体 (TCR) 测序和脑脊液显示克隆扩张增加。我们的研究还与 T 细胞免疫特征相关 AD 中克隆扩增较高。然而，这些 T 细胞对于 AD 是有益还是有害，是否这些克隆 T 细胞对抗体有特异性反应，以及它们在 AD 中的实际 TCR 库和表型仍然未知。因此，需要进行更多研究来深入了解 CD4 和 CD8 T 细胞的作用 AD 中抗体的反应性。随着 T 细胞对 AD 影响的证据越来越多，我们的中心假设是淀粉样蛋白特异性 T 细胞反应失调导致 AD 发病机制。我们将解决这个假设通过确定 1) 健康对照和 AD 患者中的 Ab 特异性 T 细胞反应和 2) Ab 特异性 T 健康对照和 AD 患者的细胞受体 (TCR) 库。拟议的研究将为增强我们对 Ab 介导的 T 细胞反应以及独特的细胞和分子编程的理解途径。此外，在提供基于 Ab 的药物之前，测试 AD 患者对 Ab 的内在 CD4 和 CD8 T 细胞活性基于 AD 的免疫疗法将有助于对患者进行分层，并对未来的抗体导向产生重大影响疗法。