Tissue and organ specific human B cell immunity

总体：组织和器官特异性人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 目前对适应性免疫的认识。从这些研究中可以清楚地看出，B和T细胞免疫都是 对病原体或抗原进行精确的调整此外，数据显示，在小鼠中的适应性免疫应答 存在于粘膜和全身部位的淋巴和外周组织可以显著不同。 因此，我们现在知道，研究单个淋巴组织中的免疫模型抗原，虽然信息丰富， 并不能揭示适应性免疫反应的全部复杂性。这一课，学习使用鼠标模型，可以 也可以应用于人类免疫反应。到目前为止，绝大多数人类免疫反应只有 在血液中被询问。这种方法不仅将我们的分析局限于淋巴细胞， 但也限制了我们检查一小部分细胞（通常为1-2%）， 在给定的时间内循环。这种“有限的取样方法”也削弱了我们检查抗原的能力- 特异性淋巴细胞，因为这些细胞是罕见的群体，即使在持续的免疫应答期间， 在体内平衡的条件下很难检测到。因此，我们对表型知之甚少， 分子编程、寿命和主要存在于组织中的人类免疫细胞的功能， 稳态条件此外，我们对抗原之间的克隆连接基本上一无所知- 人体不同组织中的特定细胞。这些代表了我们的基本 人类免疫系统的知识，并降低我们设计新疫苗的能力，以防止出现新的免疫系统。 感染，以创造可用于治疗癌症，自身免疫和慢性疾病的免疫疗法， 开发出能够改善移植结果的耐受诱导方案。因此，总体目标 这个U19项目的主要目的是确定人类记忆B 淋巴细胞和抗体分泌细胞（ASC）群体，发现在肺，肠和脂肪 在稳态条件下的组织。该U19计划由三个项目和三个 科学核心，将测试我们的中心假设，抗原特异性，抗原经历的人类组织驻留 B细胞在表型、转录组、反应性宽度和功能方面是异质的。我们 希望我们的研究能够揭示抗原感受B细胞的新亚群的身份，这些亚群表现出独特的组织- 具体的“签名”。这一结果将为未来的基础人类免疫生物学研究提供信息， 可能会影响未来的转化和临床研究，因为B细胞对病毒抗原和细菌抗原具有特异性， 细胞壁成分是疫苗接种的重要靶点， 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.