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Regulation of the IgG Fc domain repertoire

IgG Fc 结构域库的调控

基本信息

批准号：
10082423
负责人：
Taia Wang
金额：
$ 55.89万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10082423
关键词：
Adult Age Antibodies Antibody Activation Antibody Repertoire Antibody Response Antibody-mediated protection Antigen-Antibody Complex Antigens Autoantibodies Autoimmune Diseases Automobile Driving B-Lymphocytes Binding CD4 Positive T Lymphocytes Cell physiology Clinical Communicable Diseases Complex Dengue Infection Disease Effector Cell Fab domain Fc Receptor Fc domain Follow-Up Studies Growth Hemagglutinin Heritability Heterogeneity Human IgG Receptors Immune response Immunity Immunoglobulin G Infection Inflammatory Influenza Hemagglutinin Influenza vaccination Intravenous Immunoglobulins Link Mediating Mediator of activation protein Memory Methods Monozygotic twins Mouse Strains Mus Pathway interactions Phagocytosis Polysaccharides Population Predisposition Production Regulation Sampling Specificity Structure T cell response T memory cell T-Lymphocyte T-Lymphocyte Subsets Therapeutic Tissues Tumor Antibodies Vaccination aged antibody-dependent cell cytotoxicity cell type cytokine design experimental study immune function influenza virus vaccine interest prevent receptor expression recruit response severe dengue sex sialylation vaccine response

项目摘要

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.

项目概要/摘要 IgG 抗体是人体免疫的核心介质，既可以预防感染，也可以介导自身免疫性疾病的潜力。虽然抗体介导的免疫已经研究了数十年，人们之间在 IgG 介导的效应能力方面存在的异质性现在才被充分认识到赞赏。这种异质性源于 IgG Fc 结构域结构决定因素的差异；这，反过来，影响介导抗体效应功能的 Fc-Fc 受体相互作用。我们正在进行的实验已经明确了免疫功能和对由 Fc 引起的疾病的易感性的区别域多样性。具体来说，我们发现特定的 Fc 结构域库可以增强疫苗登革热感染期间的反应并增加对疾病的易感性。鉴于这些发现，一个关键的问题出现了：Fc 结构域库是如何监管的？本提案中的研究旨在确定 IgG Fc 结构域库的调节因子。我们将定义遗传影响、年龄和性别如何影响剧目。此外，我们将研究基础 Fc 结构域库如何影响 B 和 T 细胞的持久反应疫苗接种。自从改变指令集以来，调节 Fc 域指令集的机制引起了人们极大的兴趣可能会为对 IVIG 治疗有反应的疾病带来治疗效果，以增强抗肿瘤抗体的活性，预防自身抗体介导的组织疾病，或提高质量疫苗接种过程中产生的抗体。