Tissue and organ specific human B cell immunity

总体而言：组织和器官特异性人类B细胞免疫 项目摘要 使用转基因小鼠和模型病原体或抗原进行的实验塑造了我们的 目前对获得性免疫的理解。从这些研究中可以清楚地看出，B细胞和T细胞免疫都是 根据病原体或抗原精致地定制的。此外，数据显示，适应性免疫反应在 淋巴组织和外周组织同时存在于粘膜和全身部位，可能有很大的不同。 因此，我们现在知道，研究单个淋巴组织中的免疫来模拟抗原，虽然信息丰富，但确实 并不能完全揭示适应性免疫反应的复杂性。这一课通过使用鼠标模型学习，可以 也适用于人类的免疫反应。到目前为止，绝大多数人类免疫反应只有 在鲜血中被质疑。这种方法不仅将我们的分析局限于 循环，但也限制了我们只检查一小部分细胞(通常是1-2%) 在给定时间内的发行量。这种“有限抽样方法”也削弱了我们检测抗原的能力-- 特殊的淋巴细胞，因为这些细胞是稀有的群体，即使在正在进行的免疫反应中，也是 在动态平衡条件下基本检测不到。因此，我们对这种表型知之甚少， 人类免疫细胞的分子编程、寿命和功能主要驻留在 动态平衡状态。此外，我们基本上对抗原之间的克隆联系一无所知 人体不同组织中的特定细胞。这些代表着我们在基本生活中的根本差距 了解人类免疫系统，降低我们设计新疫苗以防止新出现的能力 感染，创造可用于治疗癌症、自身免疫和慢性病的免疫疗法 开发诱导耐受的方案，以改善移植结果。因此，总的目标是 这个U19计划的目的是确定人类记忆B之间的分子和功能关系 肺、肠和脂肪中发现的淋巴细胞和抗体分泌细胞(ASC)群 在动态平衡条件下的组织。这个U19项目，由三个项目和三个项目组成 科学核心，将检验我们的中心假设，即抗原特异的、经历过抗原的人类组织驻留 B细胞在表型、转录组、反应广度和功能方面是不同的。我们 预计我们的研究将揭示具有独特组织特征的新的抗原性B细胞亚群的特性。 具体的“签名”。这一结果将为未来基础人类免疫生物学的研究提供信息，并将 可能会影响未来的翻译和临床研究，因为B细胞是病毒抗原和细菌的特异性细胞 细胞壁成分是疫苗接种的重要目标，是宿主防御多种疾病所必需的 不同的生物防御A类和C类病原体。

Overall: Tissue and organ-specific human B cell immunity Project Summary Experiments conducted using genetically modified mice and model pathogens or antigens have shaped our current understanding of adaptive immunity. From these studies, it is clear that both B and T cell immunity is exquisitely tailored to the pathogen or antigen. Furthermore, the data show that adaptive immune responses in lymphoid and peripheral tissues, which are found in both mucosal and systemic sites, can differ dramatically. Thus, we now know that studying immunity in a single lymphoid tissue to model antigens, while informative, does not reveal the full complexity of the adaptive immune response. This lesson, learned using mouse models, can also be applied to human immune responses. To date, the vast majority of human immune responses have only been queried in the blood. This approach has not only limited our analysis to the lymphocytes that are in circulation but has also restricted us to examining a small fraction of the cells (typically 1-2%) that are in circulation at a given time. This “limited sampling approach” has also impaired our capacity to examine antigen- specific lymphocytes as these cells are rare populations, even during an ongoing immune response, and are largely undetectable under homeostatic conditions. Thus, we know exceedingly little about the phenotype, molecular programming, lifespan and function of human immune cells that reside primarily in tissues under homeostatic conditions. Moreover, we know essentially nothing about the clonal connections between antigen- specific cells in the different tissues of the human body. These represent fundamental gaps in our basic knowledge of the human immune system and reduce our ability to design new vaccines to prevent emerging infections, to create immunotherapies that can be used to treat cancer, autoimmunity and chronic disease and to develop tolerance-inducing regimens that will improve transplantation outcomes. Therefore, the overall goal of this U19 Program is to determine the molecular and functional relationships between human memory B lymphocyte and antibody secreting cell (ASC) populations that are found in pulmonary, intestinal and adipose tissues under homeostatic conditions. This U19 Program, which is composed of three Projects and three scientific Cores, will test our central hypothesis that antigen-specific, antigen-experienced human tissue-residing B cells are heterogeneous with respect to phenotype, transcriptome, breadth of reactivity, and function. We expect our studies to reveal the identity of novel subsets of antigen-experienced B cells exhibiting unique tissue- specific “signatures”. This outcome will inform future studies of fundamental basic human immunobiology and is likely to influence future translational and clinical studies, as B cells specific for the viral antigens and bacterial cell wall components are important targets for vaccination and are required for host defense against a number of different Biodefense Category A and C pathogens.