Immunoglobulin Genes and Immunity to HSV1 in Alzheimer's Disease

阿尔茨海默病中的免疫球蛋白基因和 HSV1 免疫

• 批准号: 10576613
• 负责人: JANARDAN P PANDEY
• 金额: $ 37.75万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10576613
• 关键词: Address; Affinity; African American; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Antibodies; Antibody Response; Antigen-Antibody Complex; Apolipoprotein E; Brain Diseases; Candidate Disease Gene; Cells; Chromosome 14; Chromosomes; Complex; Cystic Fibrosis; DNA; Dementia; Development; Disease; Elderly; Environmental Risk Factor; Etiology; European; Exclusion; Fc domain; Frequencies; Gene Modified; Genes; Genetic; Genetic Variation; Genotype; Glycoproteins; Haplotypes; Heavy-Chain Immunoglobulins; Herpesviridae; Herpesvirus 1; Humoral Immunities; IgG1; Immune system; Immunity; Immunobiology; Immunoglobulin G; Immunoglobulin Genes; Immunoglobulins; Immunologic Surveillance; Immunologics; Immunotherapy; Infection; International; Investigation; Late Onset Alzheimer Disease; Ligation; Link; Literature; Mediating; Meta-Analysis; Neurons; Pathogenesis; Pathway interactions; Patients; Persons; Phagocytes; Population; Population Group; Prevalence; Proteins; Receptor Gene; Recurrence; Reporting; Risk; Role; Simplexvirus; Susceptibility Gene; Testing; Viral; Virus; Waxes; aged; antibody-dependent cell cytotoxicity; antibody-dependent cellular phagocytosis; apolipoprotein E-4; cohort; genome wide association study; genotyping technology; interest; novel; pathogen; receptor; response; risk variant; study population; vaccine candidate; virtual

Alzheimer’s disease (AD) is a heterogeneous and complex disorder and both genetic and environmental factors are likely to be involved in its etiology. Hundreds of putative susceptibility genes for late-onset AD have been reported, but the majority of these claims—with the exception of the e4 allele of the apolipoprotein E gene—have not been consistently replicated. Furthermore, the functional significance of the majority of the positional candidate genes in AD pathogenesis is not clear. One putative environmental (viral) factor that has been implicated in AD etiology is herpes simplex virus type 1 (HSV1). An infectious etiology for AD would suggest that the genes of the host immune system might also mediate the putative pathways towards the development of this disorder. Indeed, the genome-wide association studies (GWAS) and meta-analyses of AD have reported many risk-conferring genes that are enriched in the immune system pathways. The GWAS of AD, however, do not evaluate a major gene complex of the immune system—GM (g marker) allotypes encoded by immunoglobulin heavy chain G (IGHG) genes on chromosome 14. HSV1 is a ubiquitous herpesvirus. Not all HSV1-infected people are equally likely to develop AD-related complications, suggesting the involvement of host genetic factors in the HSV1-spurred dementia. Immunoglobulin GM allotypes are excellent candidate genes for modifying the HSV1-AD association, because they modulate the HSV1 immunoevasion strategies and, epistatically with Fcg receptor (FcgR) genes, contribute to the magnitude of antibody-dependent cellular cytotoxicity of HSV1-infected cells. In a recent study, we have shown that a GM genotype was associated with a 4-fold increased risk of AD. This association was independent of apolipoprotein e4 genotype and other AD risk genes. Based on these observations, we hypothesize that GM genes are risk factors for AD, and the underlying mechanisms include their influence on the magnitude of humoral immunity to HSV1 proteins and antibody-dependent cellular phagocytosis (ADCP) of neuronal cells. The following specific aims will test our hypothesis: 1) Determine if GM genotypes are risk factors for Alzheimer’s disease. DNA from a large study population of AD patients and controls will be characterized for several GM alleles to confirm our preliminary findings; 2) Determine if the magnitude of antibody responsiveness to particular HSV1 proteins is associated with GM alleles. We will quantitate antibody responses to HSV1-gD (a major glycoprotein and vaccine candidate) in the sera of AD patients and controls and determine if the magnitude of antibody responsiveness is associated with GM allotypes; 3) Determine if particular allelic combinations of Fc (GM) and cellular FcgR alleles influence the level of ADCP. Using HSV-gD as target, we will determine whether the level of anti-HSV1- gD-mediated ADCP is associated with particular combinations of Fcg (GM) and FcgRIIa alleles. Results of this investigation may begin to address the recurrent criticism of studies documenting the HSV1-AD association: Why the prevalence of HSV1 infection does not correlate with the prevalence of AD in the population?

阿尔茨海默病（Alzheimer's disease，AD）是一种异质性的复杂疾病，既有遗传因素，也有环境因素 因素可能参与其病因。数百种晚发性AD的推定易感基因， 但大多数这些索赔-除了载脂蛋白E的e4等位基因 基因并没有被持续复制。此外，大多数人的功能意义 候选基因在AD发病机制中的位置尚不清楚。一个假定的环境（病毒）因素， 与AD病因学有关的是单纯疱疹病毒1型（HSV 1）。AD的感染性病因学将 这表明宿主免疫系统的基因也可能介导通往免疫系统的假定途径。 这种疾病的发展。事实上，全基因组关联研究（GWAS）和AD的荟萃分析 已经报道了许多在免疫系统途径中富集的风险基因。GWAS 然而，AD不评估免疫系统的主要基因复合物-GM（g标记）同种异型编码 免疫球蛋白重链G（IGHG）基因在染色体14。HSV 1是一种普遍存在的疱疹病毒。不是所有 HSV 1感染者同样有可能发生AD相关并发症，这表明 HSV 1型痴呆症的宿主遗传因素。免疫球蛋白GM同种异型是绝佳的候选者 用于修饰HSV 1-AD关联的基因，因为它们调节HSV 1免疫逃避策略 并且，与Fcg受体（FcgR）基因上位性地，有助于抗体依赖性细胞凋亡的大小。 HSV 1感染细胞的细胞毒性。在最近的一项研究中，我们已经表明，GM基因型与 AD风险增加4倍这种关联独立于载脂蛋白e4基因型和其他AD 风险基因基于这些观察，我们假设GM基因是AD的危险因素， 潜在的机制包括它们对HSV 1蛋白的体液免疫强度的影响， 神经元细胞的抗体依赖性细胞吞噬作用（ADCP）。以下具体目标将考验我们的 假设：1）确定GM基因型是否是阿尔茨海默病的危险因素。一项大型研究的DNA AD患者和对照人群的几个GM等位基因将被表征，以证实我们的初步研究结果。 2）确定抗体对特定HSV 1蛋白的反应性的大小是否与 转基因等位基因我们将定量对HSV 1-gD（一种主要的糖蛋白和疫苗）的抗体应答 候选者），并确定抗体反应性的大小是否 3）确定Fc（GM）和细胞FcgR的特定等位基因组合 等位基因影响ADCP水平。使用HSV-gD作为靶标，我们将确定抗HSV 1-gD的水平是否与HSV 1-gD的水平相关。 gD介导的ADCP与Fcg（GM）和FcgRIIa等位基因的特定组合相关。成果 调查可能会开始，以解决对记录HSV 1-AD关联的研究的反复批评： 为什么HSV 1感染的患病率与人群中AD的患病率无关？