Genetic Polymorphisms in Rhesus Macaque FcRn and Association with IgG Levels

描述：新生Fc受体（Neonatal Fc receptor, FcRn）在体内调节IgG稳态中起重要作用，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对IgG 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可能受到宿主FcRn功能的影响。FcRn的遗传多态性可以影响Fc结合[3]和IgG的半衰期。因此，我们假设宿主FcRn基因组多态性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

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.