Immunoglobulin GM (γ marker) Allotypes and Immunity to HSV1 in Alzheimer’s Disease

阿尔茨海默病中免疫球蛋白 GM（γ 标记）同种异型和对 HSV1 的免疫

基本信息

批准号：
10464940
负责人：
JANARDAN P PANDEY
金额：
$ 36.7万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
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：
2021-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10464940
关键词：
Affinity African American Alleles Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos 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 Disease Progression Elderly Environmental Risk Factor Etiology European Exclusion Fc domain Frequencies GTP-Binding Protein alpha Subunits, Gs Gene-Modified Genes Genetic Genetic Variation Genotype Glycoproteins Haplotypes Heavy-Chain Immunoglobulins Herpesviridae Herpesvirus 1 Humoral Immunities IgG1 Immune Immune system Immunity Immunobiology Immunoglobulin G Immunoglobulins Immunologic Surveillance Immunologics Immunotherapy Infection International Investigation Late Onset Alzheimer Disease Ligation Link Literature Mediating Meta-Analysis Neurons Pathogenesis Pathway interactions Patients Phagocytes Population Population Group Predisposition Prevalence Proteins Receptor Gene Reporting Risk Role Simplexvirus Susceptibility Gene Testing United States National Institutes of Health Viral Virus Waxes aged antibody-dependent cell cytotoxicity antibody-dependent cellular phagocytosis apolipoprotein E-4 base cohort genome wide association study genotyping technology interest novel pathogen receptor response risk variant study population vaccine candidate virtual

项目摘要

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. Clearly, 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 biotinylated HSV-gD as target, we will determine whether the level of ADCP is associated with particular combinations of Fcg (GM) and FcgRIIa alleles. Results of this investigation may begin to answer the question: 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数以百计的迟发性 AD 的假定易感基因可能与该病有关。已有报道，但大多数这些说法——载脂蛋白 E 的 e4 等位基因除外此外，大多数基因的功能意义尚未得到一致的复制。 AD 发病机制中的候选基因位置尚不清楚，其中一种可能的环境（病毒）因素。 AD 的病因是 1 型单纯疱疹病毒 (HSV1)。表明宿主免疫系统的基因也可能介导通往事实上，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风险基因。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。显然，并非所有 HSV1 感染者都同样可能出现 AD 相关并发症，这表明宿主遗传因素在 HSV1 引发的痴呆中的作用非常好。修饰 HSV1-AD 关联的候选基因，因为它们调节 HSV1 免疫逃避策略，并与 Fcg 受体 (FcgR) 基因上位，有助于抗体依赖性的程度 HSV1 感染细胞的细胞毒性在最近的一项研究中，我们表明 GM 基因型是与 AD 风险增加 4 倍相关，这种关联与载脂蛋白 e4 基因型无关。和其他 AD 风险基因根据这些观察，我们发现转基因基因是 AD 的危险因素，其潜在机制包括对 HSV1 体液免疫程度的影响蛋白质和神经元细胞的抗体依赖性细胞吞噬作用（ADCP）的具体目标如下。将检验我们的假设：1) 确定 GM 基因型是否是阿尔茨海默病 DNA 的危险因素。 AD 患者和对照的大型研究群体将针对多个 GM 等位基因进行表征，以证实我们的研究初步发现；2) 确定抗体对特定 HSV1 蛋白的反应程度是否为我们将定量对 HSV1-gD（一种主要糖蛋白）的抗体反应。候选疫苗）在 AD 患者和对照者的血清中，并确定抗体的大小是否反应性与 GM 同种异型相关；3) 确定 Fc (GM) 和我们将使用生物素化的 HSV-gD 作为目标，确定细胞 FcgR 等位基因影响 ADCP 的水平。 ADCP 水平是否与 Fcg (GM) 和 FcgRIIa 等位基因的特定组合相关。这项调查的进展可能会开始回答这个问题：为什么 HSV1 感染的流行率不高？与人群中 AD 的患病率相关吗？