Regulation of the IgG Fc domain repertoire

项目总结/摘要 IgG抗体是人体免疫的中心介质，既可以保护免受感染，又具有免疫原性。 可能介导自身免疫性疾病。虽然抗体介导的免疫已经研究了几十年， 人与人之间IgG介导的效应子能力的异质性， 赞赏.这种异质性源于IgG Fc结构域的结构决定簇的差异;这， 进而影响介导抗体效应子功能的Fc-Fc受体相互作用。我们正在进行的 实验已经确定了免疫功能和对由Fc引起的疾病的易感性的区别， 域多样性具体地，我们已经发现特异性Fc结构域库可以增强疫苗免疫。 在登革热感染过程中，免疫反应和对疾病的易感性增加。鉴于这些发现，一个关键的 问题出现了：Fc结构域库是如何调节的？本提案中的研究旨在确定 IgG Fc结构域库的调节剂。我们将定义遗传的影响，年龄和性别如何影响 保留曲目。此外，我们还将研究基础Fc结构域库如何影响持久的B和T细胞应答， 预防针调节Fc结构域库的机制引起了极大的兴趣，因为改变了库 可以潜在地用于对IVIG治疗有反应的疾病的治疗益处， 抗肿瘤抗体的活性，以预防自身抗体介导的组织疾病，或提高 疫苗接种过程中产生的抗体。

PROJECT SUMMARY/ABSTRACT IgG antibodies are central mediators of human immunity that can both protect against infections and have the potential to mediate autoimmune diseases. While antibody-mediated immunity has been studied for decades, the heterogeneity that exists among people in IgG-mediated effector capabilities is only now being fully appreciated. This heterogeneity arises from differences in the structural determinants of IgG Fc domains; this, in turn, impacts Fc-Fc receptor interactions which mediate antibody effector functions. Our ongoing experiments have defined distinctions in immune functioning and susceptibility to diseases that arise from Fc domain diversity. Specifically, we have found that specific Fc domain repertoires can enhance vaccine responses and increase susceptibility to disease during dengue infection. Given these findings, a critical question emerges: how is the Fc domain repertoire regulated? Studies in this proposal are designed to identify regulators of the IgG Fc domain repertoire. We will define how heritable influences, age and sex influence the repertoire. In addition, we will study how basal Fc domain repertoires impact durable B and T cell responses to vaccination. Mechanisms regulating the Fc domain repertoire are of great interest since shifting the repertoire could potentially be done for therapeutic benefit in diseases responsive to IVIG treatment, to enhance the activity of anti-tumor antibodies, to prevent autoantibody-mediated tissue diseases, or to enhance the quality of antibodies generated during vaccination.