Genetic Polymorphisms in Rhesus Macaque FcRn and Association with IgG Levels

描述：新生儿Fc受体(FcRN)在体内调节免疫球蛋白稳态方面起着重要作用，在转基因小鼠模型中其表达水平与疫苗诱导的抗体水平相关[1，2]。FcRN与抗体Fc部分的亲和力决定了抗体的血清半衰期。因此，保护性抗体的持久性会受到宿主FcRN功能的影响。FcRN的遗传多态可以影响Fc结合[3]，并可能影响免疫球蛋白的半衰期。因此，我们假设宿主基因组FcRN的多态影响灵长类动物的抗体水平，并可能解释抗体的个体间差异。 被动免疫或接种疫苗时的水平。我们在这个建议中的目标是确定FcRN基因中影响FcRN表达和功能的功能性宿主基因组多态性。特别是，我们想要测试基因组FcRN多态影响血清免疫球蛋白水平的可能性。FcRN的这种功能将影响疫苗诱导抗体的持久性。FcRN基因组变异的影响还没有在任何疫苗研究中得到评估。我们的努力将在一项使用猕猴包膜糖蛋白的疫苗研究中测试FcRN的功能。使用恒河猴的样本(作为一项资助的临床前疫苗研究的一部分)，我们识别了这种受体的基因组变异，并测试了FcRN的多态形式对FcRN表达的影响。我们研究了FcRN等位基因变异与总免疫球蛋白水平和疫苗诱导的免疫球蛋白水平的关系。建议的研究有可能确定FcRN的基因组变异在调节免疫球蛋白水平中的作用，这对未来的疫苗研究具有相关性。这些知识将来可以用于选择免疫原和动物群体，特别是当需要少量动物来评估策略时，如Fc融合蛋白或被动抗体转移。

DESCRIPTION: Neonatal Fc receptor (FcRn) plays important role in regulating IgG homeostasis in vivo and it's expression level is shown to correlate with vaccine induced antibody levels in transgenic mouse model [1, 2]. The affinity of FcRn to Fc portion of IgG determines serum half-life of antibodies. Durability of protective antibodies can thus, be influenced by host FcRn function. Genetic polymorphisms in FcRn can affect Fc binding [3] and possibly half-life of IgG. Therefore, we hypothesize that host genomic polymorphisms in FcRn influence antibody levels in primates and might account for inter-individual variations in antibody levels upon passive immunization or vaccination. Our goal in this proposal is to identify functional host genomic polymorphisms in the FcRn gene that influence FcRn expression and function. In particular, we want to test the possibility that genomic FcRn polymorphisms influence levels of serum IgG. Such function of FcRn will influence the durability of vaccine-induced antibodies. An effect of FcRn genomic variations has not been evaluated in any vaccine study. Our efforts will test FcRn function in a vaccination study that uses envelope glycoprotein in rhesus macaques. Using samples from rhesus macaques (as part of a funded preclinical vaccine study), we identify genomic variations in this receptor and test the polymorphic forms of FcRn for their influence on FcRn expression. We study association of variant allelic forms of FcRn with levels of total and vaccine induced IgG. The proposed studies have the potential to identify role of genomic variations in FcRn in regulating IgG levels, which have relevance for future vaccine studies. The knowledge can be applied in future to select immunogens and animal groups, especially when small numbers of animals are needed for evaluating strategies such as Fc-fusion proteins or passive antibody transfers.