Regulation of the IgG Fc domain repertoire

项目摘要/摘要 Ig G抗体是人类免疫的中心介质，既能预防感染，又能 调节自身免疫性疾病的可能性。虽然抗体介导的免疫研究已经有几十年的历史了， 人与人之间在免疫球蛋白介导的效应器能力上存在的异质性直到现在才得到充分发挥。 感激不尽。这种异质性源于免疫球蛋白Fc结构域的结构决定因素的差异；这， 进而影响介导抗体效应器功能的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FC引起的疾病的易感性的区别 领域多样性。具体地说，我们发现特定的Fc结构域可以增强疫苗 登革热感染期间的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域曲目是如何监管的？这项提案中的研究旨在确定 免疫球蛋白Fc结构域的调节器。我们将定义可遗传的影响，年龄和性别如何影响 曲目。此外，我们还将研究基本的Fc结构域谱如何影响持久B和T细胞对 接种疫苗。由于转移了Fc域指令库，因此管理Fc域指令库的机制非常有趣 可能在IVIG治疗后的疾病中获得治疗益处，以增强 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 在接种疫苗期间产生的抗体。

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.