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

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赋予风险的基因。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。 显然，并非所有的HSV 1感染者都同样有可能发生AD相关并发症，这表明， 宿主遗传因素参与HSV 1刺激的痴呆。免疫球蛋白GM同种异型是优秀的 用于修饰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）基因上位性，有助于抗体依赖性的大小， 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，转基因型是 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。基于这些观察，我们假设GM基因是AD的危险因素， 其作用机制包括影响HSV1的体液免疫强度 蛋白质和神经元细胞的抗体依赖性细胞吞噬作用（ADCP）。以下具体目标 将测试我们的假设：1）确定GM基因型是否是阿尔茨海默病的危险因素。的dna 将对AD患者和对照的大型研究人群进行几种GM等位基因的表征，以证实我们的研究结果。 初步发现; 2）确定抗体对特定HSV 1蛋白的反应性的大小是否是 与转基因等位基因相关我们将定量对HSV1-gD（一种主要的糖蛋白， 候选疫苗），并确定抗体的大小 3）确定Fc（GM）和Fc（GM）的特定等位基因组合是否与GM同种异型相关; 细胞FcgR等位基因影响ADCP水平。使用生物素化的HSV-gD作为靶标，我们将确定 ADCP水平是否与Fcg（GM）和FcgRIIa等位基因的特定组合相关。结果 这项研究的结果可能开始回答这个问题：为什么HSV 1感染的流行不 与人群中AD的患病率相关吗

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?