Microglia antigen presentation in the CNS of Alzheimer's disease

阿尔茨海默病中枢神经系统中小胶质细胞抗原呈递

• 批准号: 10162474
• 负责人: Elizabeth M Bradshaw
• 金额: $ 67.43万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10162474
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Autoimmune Diseases; Autopsy; B-Lymphocytes; Bar Codes; Binding; Blood; Brain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Clone Cells; Complex; DNA; Dementia; Dendritic Cells; Doctor of Philosophy; Effector Cell; Etiology; Event; Extracellular Protein; Genes; Genetic Predisposition to Disease; Genetic study; Goals; HLA Antigens; Hippocampus (Brain); Histocompatibility Antigens Class II; Human; Immune; Immune response; Immune system; Impaired cognition; Individual; Infectious Agent; Innate Immune System; Label; Late Onset Alzheimer Disease; Late-Onset Disorder; Libraries; Link; Major Histocompatibility Complex; Microglia; Mind; Morphology; Names; Natural Killer Cells; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenicity; Pathology; Patients; Peptides; Peripheral; Phase; Phenotype; Play; Population; Predisposition; Prefrontal Cortex; Process; Proteins; Public Health; Regulatory T-Lymphocyte; Reporting; Resolution; Risk Factors; Role; Senile Plaques; Specificity; Stains; Susceptibility Gene; System; T cell receptor repertoire sequencing; T-Lymphocyte; Techniques; Technology; Tumor-infiltrating immune cells; Validation; Viral; age related neurodegeneration; antigen binding; antigen-specific T cells; cytokine; cytotoxic; genetic association; genome wide association study; in vivo; insight; macrophage; neuron loss; neuropathology; novel; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic virus; response

PIs: Bradshaw, Elizabeth M., Ph.D. and Wassim Elyaman, Ph.D. Title: Microglia antigen presentation in the CNS of Alzheimer's disease Project Summary/Abstract Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia. Genome-wide association studies have identified novel AD susceptibility loci. Interestingly the associated genes at several of these loci implicate the immune system in late-onset AD (LOAD), specifically the innate immune system, including the human leukocyte antigen (HLA) region. The finding of the HLA region being genetically associated with LOAD further emphasizes the question of how microglia, the antigen-presenting cells of the central nervous system (CNS), interact with infiltrating T cells, which have been observed in the hippocampus of AD patients, and specifically what antigens are being presented. In parallel, the pathogen hypothesis has garnered more support for a possible pathogenic etiology of AD. We propose to leverage our understanding of the immune system combined with cutting-edge technology and access to AD patient blood and brain autopsies to determine if these neuroinvasive pathogens are neurovirulent in AD. For this application, we propose a multifaceted approach to: 1) identify the peptides being presented by the MHC of microglia in the AD brain in regions of high T cell infiltration and areas of low T cell infiltration; 2) examine the antigen reactivity and phenotype of T cells infiltrating the hippocampus in AD, and 3) determine how microglia function as antigen-presenting cells of pathogens to infiltrating T cells.

PIS：Bradshaw，Elizabeth M.，博士和Wassim Elyaman博士 标题：阿尔茨海默氏病中枢神经系统中的小胶质细胞抗原表现 项目摘要/摘要 阿尔茨海默氏病（AD）是一种与年龄有关的神经退行性疾病，其特征是进行性认知 衰落和痴呆。全基因组关联研究已经确定了新型的AD敏感性基因座。 有趣的是，其中几个基因座的相关基因牵涉到后期AD中的免疫系统 （负载），特别是先天免疫系统，包括人类白细胞抗原（HLA）区域。这 发现HLA区域与负载相关的发现进一步强调了如何 小胶质细胞是中枢神经系统（CNS）的抗原呈递细胞，与浸润的T细胞相互作用， 在AD患者的海马中观察到的，尤其是哪些抗原 提出。同时，病原体假设获得了对可能的致病性病因的更多支持 广告。我们建议利用对免疫系统和前沿结合的理解 技术并获得广告患者的血液和大脑尸检，以确定这些神经侵袭性病原体是否是否 在AD中是神经性肺部的。对于此应用，我们提出了一种多面方法：1）确定肽 由高T细胞浸润区域的AD大脑中的小胶质细胞MHC呈现 细胞浸润； 2）检查T细胞的抗原反应性和表型 3）确定小胶质细胞如何充当病原体的抗原呈递细胞对浸润T细胞的作用。