Integrating innate and adaptive pathways in vaccine responses

摘要--总体 在过去的三十年里，基础免疫学研究取得了重大进展，导致了许多医学上的 介绍并剖析了人类免疫系统对外源免疫应答的一般机制。 抗原。然而，对所涉及的协调分子机制有更实质性的理解 将需要免疫，因为每个病毒病原体对免疫系统和 被激发的免疫反应的特征是影响疾病易感性的显著异质性。 和发病机制。事实上，B细胞对不同病毒病原体的反应是独一无二的 在感染过程中进化以塑造免疫球蛋白抗体的功能活性。病毒感染性疾病的研究 已经表明，抗病毒抗体具有调节广泛的相反功能的能力：(I) 保护功能，包括中和、病毒调理和清除受感染的细胞和(Ii) 增强病毒传染性、疾病易感性和严重性的致病活动；一种被称为 作为抗体介导的疾病增强(ADE)。ADE机制此前曾被建议 说明对登革热的易感性，因为流行病学数据支持先前感染黄病毒的人是 登革热的主要危险因素，意味着存在交叉反应、非中和抗体 这一过程。了解感染或接种疫苗时产生的免疫球蛋白反应的异质性 因此，不同的病毒抗原对于描述驱动人类免疫机制至关重要 免疫，并测定免疫球蛋白抗体的保护和致病活性。我们的中心将有三个 由Nussenzweig和Nussenzweig博士指导的项目(项目1：登革热疾病中Fc结构域效应器的活性) 莱斯(项目2：了解B细胞记忆对不同病毒感染的反应)和王(项目3： 对登革热病毒的免疫)，由一个科学核心(核心A：转基因小鼠核心)和 管理核心(核心B)。通过三个项目之间的一系列合作研究，我们的中心 目的研究人类在感染和接种疫苗过程中的抗病毒免疫反应，并表征其免疫特性 调节人类免疫球蛋白抗体功能的机制。更具体地说，我们的目标是描述 接种疫苗或感染不同的病毒病原体引起的免疫球蛋白反应的异质性，包括 乙肝病毒和黄病毒，如寨卡病毒和登革热。此外，我们还将剖析免疫球蛋白G 抗体介导疾病增强活动并有助于登革热疾病的易感性和 发病机制。这些研究将为推动保护性免疫和 调节抗体功能，对制定疫苗接种策略产生更广泛的影响 传染性病原体。

ABSTRACT – Overall Significant progress in basic immunology research over the last three decades has resulted in numerous medical advances and dissected the general mechanisms by which the human immune system responds to foreign antigens. However, a much more substantial understanding of the coordinated molecular mechanisms involved in eliciting immunity will be required, as each viral pathogen poses unique challenges to the immune system and the elicited immune responses are characterized by substantial heterogeneity that impacts disease susceptibility and pathogenesis. Indeed, it is expected that B-cell responses against diverse viral pathogens are uniquely evolved during infection to shape the functional activity of IgG antibodies. Studies from viral infectious diseases have shown that antiviral IgG antibodies have the capacity to mediate a wide spectrum of opposing functions: (i) protective functions, including neutralization, viral opsonization, and clearance of infected cells and (ii) pathogenic activities, which enhance viral infectivity, disease susceptibility and severity; a phenomenon termed as antibody-mediated enhancement (ADE) of disease. ADE mechanisms have been previously suggested to account for susceptibility to dengue disease, as epidemiological data support that prior flavivirus infection is the major risk factor for dengue disease, implicating the presence of cross-reactive, non-neutralizing IgG antibodies to this process. Understanding the heterogeneity of IgG responses elicited upon infection or vaccination with diverse viral antigens is therefore critical for characterizing the immunological mechanisms that drive human immunity and determine the protective vs. pathogenic activity of IgG antibodies. Our Center will feature three Projects directed by Drs. Ravetch (Project 1: Fc domain effector activity in dengue disease), Nussenzweig and Rice (Project 2: Understanding B cell memory in response to diverse virus infections), and Wang (Project 3: Immunity to dengue viruses), supported by a scientific core (Core A: Transgenic mouse core) and the administrative core (Core B). Through a series of collaborative studies between the three Projects, our Center aims to study human antiviral immune responses during infection and vaccination and characterize the immune mechanisms that regulate the function of IgG antibodies in humans. More specifically, we aim to characterize the heterogeneity of IgG responses elicited upon vaccination or infection with diverse viral pathogens, including HBV and flaviviruses, like Zika and dengue. Additionally, we will dissect the ADE mechanisms by which IgG antibodies mediate disease-enhancing activities and contribute to dengue disease susceptibility and pathogenesis. These studies will provide novel insights into the mechanisms that drive protective immunity and modulate antibody function, having a broader impact on the development of vaccination strategies against infectious pathogens.