Genetic Markers of IgG and Cytomegalovirus Immunoevasion in Alzheimer Disease

阿尔茨海默病(AD)是一种异质性的复杂疾病，既有遗传因素，也有环境因素 很可能与其病因学有关。数百个可能的晚发性阿尔茨海默病易感基因 但这些说法中的大多数--除了载脂蛋白E基因的e4等位基因-- 没有被一致地复制。此外，大多数位置词的功能意义也是如此 AD发病机制中的候选基因尚不清楚。一个假定的环境(病毒)因素一直是 涉案的是人类巨细胞病毒(CMV)。最近的研究证实，巨细胞病毒感染与 AD的风险增加，而且CMV感染的几个免疫学和病毒学特征相关 与本病的临床和病理措施相一致。然而，很明显，并不是所有受影响的人都是一样的。 同样有可能发生CMV刺激的AD，这表明宿主遗传因素可能参与其中 修改对该病毒的免疫力。巨细胞病毒已经进化出一大批免疫逃避策略。一种策略 涉及产生具有Fcγ受体(FcγR)功能特性的蛋白质，这可能使 病毒通过逃避抗CMV抗体结合的效应后果来逃避宿主免疫监视， 例如抗体依赖的细胞毒性。我们已经证明了一个主要基因复合体的等位基因 免疫系统--GM(γ标记物)异型--调节着这一病毒策略。我们还展示了特定的 GM基因对CMV糖蛋白B(GB)的抗体反应性大小有贡献，这是 在疱疹病毒中保守，因为它在传染性、病毒附着和进入中发挥重要作用。基于 这些观察结果，我们假设GM基因是CMV-AD关联的效应修饰物，并且 潜在的机制包括它们对抗CMV免疫的贡献以及它们对 病毒免疫逃避策略。以下具体目标将检验我们的假设：1)确定GM等位基因 调节与CMV感染相关的AD风险：来自3个大型纵向老龄化队列的DNA-大多数 已被鉴定为抗CMV抗体的-将被分型为几个GM等位基因。我们会 确定GM等位基因是否是AD的危险因素，影响抗CMV抗体的反应性，从而 作为巨细胞病毒-AD关联的效应修饰物；2)确定巨细胞病毒编码的FcγR蛋白是否有差异结合 阿尔茨海默病患者抗巨细胞病毒免疫球蛋白抗体Fcγ(GM)区基因差异研究 TRL11/IRL11、RL-13和UL119-UL118FcγR的胞外区将被克隆并在哺乳动物中表达 用标准方法进行细胞培养。利用AD患者的血清和免疫球蛋白亚类特异性亲和层析，我们 将提纯针对CMV gB的抗体。同种异型免疫球蛋白的亲和力比较 分子到巨细胞病毒FcγRs将通过表面等离子体共振进行监测。这项提议开启了一个新的 探索我们对宿主免疫遗传因子参与的研究途径 阿尔茨海默病的发病机制。这项研究的结果可能会导致针对AD的新的免疫疗法。

Alzheimer 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 is human cytomegalovirus (CMV). Recent studies have established that CMV infection is associated with an increased risk of AD, and that several immunological and virological features of CMV infection correlate with clinical and pathological measures of this disease. It is clear, however, that not all equally exposed people are equally likely to develop CMV-spurred AD, suggesting the involvement of host genetic factors that could modify immunity to this virus. CMV has evolved a large repertoire of immunoevasion strategies. One strategy involves generating proteins that have functional properties of the Fcγ receptor (FcγR), which may enable the virus to evade host immunosurveillance by evading the effector consequences of anti-CMV antibody binding, such as antibody-dependent cellular cytotoxicity. We have shown that alleles of a major gene complex of the immune system—GM (γ marker) allotypes—modulate this viral strategy. We have also shown that particular GM genotypes contribute to the magnitude of antibody responsiveness to CMV glycoprotein B (gB), which is conserved in herpesviruses because of its important role in infectivity, viral attachment and entry. Based on these observations, we hypothesize that GM genes are effect modifiers of CMV-AD association, and the underlying mechanisms include their contribution to anti-CMV immunity and their modulating influence on the viral immunoevasion strategies. The following specific aims will test our hypothesis: 1) Determine if GM alleles modulate the AD risk associated with CMV infection: DNA from 3 large longitudinal aging cohorts—most of which have been characterized for anti-CMV antibodies—will be genotyped for several GM alleles. We will determine whether GM alleles are risk factors for AD, influence anti-CMV antibody responsiveness, and thus act as effect modifiers of CMV-AD association; 2) Determine if CMV-encoded FcγR proteins bind differentially to genetically disparate Fcγ (GM) regions of anti-CMV IgG antibodies in AD patients: DNA encoding the ectodomains of TRL11/IRL11, RL-13, and UL119-UL118 FcγRs will be cloned and expressed in mammalian cells by standard methods. Using IgG subclass-specific affinity chromatography and sera from AD patients, we will purify IgG antibodies directed against CMV gB. Comparative affinities of allotypically disparate IgG molecules to the CMV FcγRs will be monitored by surface plasmon resonance. This proposal opens a new avenue of investigation towards our understanding of the host immunogenetic factors involved in the etiopathogenesis of AD. Results from this investigation could lead to novel immunotherapies against AD.