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 (AD) 是一种异质且复杂的疾病，与遗传和环境因素有关 其病因可能涉及多种因素。数百个推定的迟发性 AD 易感基因 已被报道，但大多数这些说法——载脂蛋白 E 的 e4 等位基因除外 基因——没有被一致地复制。此外，大多数的功能意义 候选基因在AD发病机制中的位置尚不清楚。一种假定的环境（病毒）因素 AD 的病因是 1 型单纯疱疹病毒 (HSV1)。 AD 的传染性病因 表明宿主免疫系统的基因也可能介导通往 这种疾病的发展。事实上，AD 的全基因组关联研究 (GWAS) 和荟萃分析 已经报道了许多在免疫系统途径中富集的赋予风险的基因。的 GWAS 然而，AD 并不评估免疫系统的主要基因复合体——编码的 GM（g 标记）同种异型 由 14 号染色体上的免疫球蛋白重链 G (IGHG) 基因产生。HSV1 是一种普遍存在的疱疹病毒。不是全部 HSV1 感染者同样有可能出现 AD 相关并发症，这表明 HSV1 引发的痴呆症的宿主遗传因素。免疫球蛋白 GM 同种异型是极好的候选者 修饰 HSV1-AD 关联的基因，因为它们调节 HSV1 免疫逃避策略 并且，与 Fcg 受体 (FcgR) 基因上位，有助于抗体依赖性细胞的大小 HSV1 感染细胞的细胞毒性。在最近的一项研究中，我们表明转基因基因型与 AD 风险增加 4 倍。这种关联与载脂蛋白 e4 基因型和其他 AD 无关 风险基因。基于这些观察，我们假设 GM 基因是 AD 的危险因素，并且 潜在的机制包括它们对 HSV1 蛋白体液免疫程度的影响以及 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 假设：1）确定转基因基因型是否是阿尔茨海默病的危险因素。来自大型研究的 DNA AD 患者和对照群体将针对几个 GM 等位基因进行表征，以确认我们的初步结果 发现; 2) 确定抗体对特定 HSV1 蛋白的反应程度是否相关 带有转基因等位基因。我们将定量对 HSV1-gD（一种主要糖蛋白和疫苗）的抗体反应 候选者）在 AD 患者和对照的血清中，并确定抗体反应性的大小 与 GM 同种异型相关； 3) 确定 Fc (GM) 和细胞 FcgR 的特定等位基因组合是否 等位基因影响 ADCP 水平。以HSV-gD为靶标，我们将确定抗HSV1-的水平是否 gD 介导的 ADCP 与 Fcg (GM) 和 FcgRIIa 等位基因的特定组合相关。结果 调查可能会开始解决对记录 HSV1-AD 关联的研究反复出现的批评： 为什么人群中 HSV1 感染的患病率与 AD 的患病率不相关？