CD19 Tyrosine-mediated Signal Transduction in vivo

描述(申请人提供)：B淋巴细胞是宿主防御感染病原体所必需的，但B细胞的异常激活可导致自身免疫。因此，B细胞在广泛的生理和病理生理过程中起着重要作用。脾中的成熟B细胞进入两个隔室中的一个，即边缘地带或滤泡。B区边缘细胞负责对进入循环的病原体做出快速反应。滤泡B细胞被招募到生发中心，在那里亲和力成熟和记忆B细胞的产生导致随后遇到病原体时反应增强，这对疫苗免疫至关重要。缺乏CD19(一种B细胞表面受体)的小鼠无法形成边缘带B细胞或生发中心，并有产生自身抗体的倾向。我们的新数据表明，缺乏边缘带B细胞会导致边缘带其他成分的缺陷，包括边缘带巨噬细胞和树突状细胞。然而，在通过过继转移野生型B细胞重建边缘带B细胞后，巨噬细胞和树突状细胞重新出现。目的1将剖析B细胞上CD19调节MZ B细胞分化的机制，从而调节边缘带的其他成分。更多新的初步数据表明，CD19-/-小鼠未能形成生发中心与卵泡树突状细胞(FDC)激活失败有关。过继转移野生型B细胞也重建了CD19/-受体小鼠激活FDC的能力，恢复了形成生发中心的能力。在目标2中，我们将检验关于CD19依赖的机制如何调节FDC的三个假说：通过激活滤泡B细胞，通过对控制向FDC递送抗原的边缘区域的影响，以及通过形成免疫复合体。在目标3中，我们将通过实验来确定CD19是如何调节自身免疫的，以测试CD19在中枢选择、外围选择和自身免疫模型中的作用。这些目的不仅是为了了解CD19的功能，而且是为了利用CD19来探索在没有自身免疫的情况下进行免疫和保护病原体的基本机制。与公共卫生相关：脾的边缘区域是已到达血液的感染生存所必需的，而生发中心在疫苗接种和免疫记忆中至关重要。尽管它们在预防感染中起着至关重要的作用，但对边缘区域和生发中心的反应却知之甚少。这个项目将使用CD19，一种表达在B淋巴细胞上的蛋白质，这是两种类型的反应所必需的，作为一种工具来研究体内边缘区域和生发中心的B细胞的功能。

DESCRIPTION (provided by applicant): B lymphocytes are required for host defense against infectious pathogens but abnormal activation of B cells can lead to autoimmunity. Thus, B cells are important in a wide range of physiologic and pathophysiologic processes. Mature B cells in the spleen enter into one of two compartments, the marginal zone or the follicular. Marginal zone B cells are responsible for rapid responses to pathogens that have reached the circulation. Follicular B cells are recruited into germinal centers, where affinity maturation and the generation of memory B cells lead to heightened responses upon subsequent encounters with a pathogen, which is crucial to immunization by vaccines. Mice lacking CD19, a B cell surface receptor, fail to form marginal zone B cells or germinal centers and have a propensity to produce autoantibodies. Our new data demonstrate that lack of marginal zone B cells results in defects in other components of the marginal zone, including marginal zone macrophages and dendritic cells. However, the macrophages and dendritic cells reappear following reconstitution of the marginal zone B cells by adoptive transfer of wild type B cells. Aim 1 will dissect the mechanisms by which CD19 on B cells regulates the differentiation of MZ B cells, and thereby other constituents of the marginal zone. Additional new preliminary data suggest that that failure to form germinal centers is associated with a failure of activation of Follicular Dendritic Cells (FDC) in CD19-/- mice. Adoptive transfer of wild type B cells also reconstitutes the ability to activate FDC in CD19-/- recipient mice, which recover the ability to form germinal centers. In Aim 2, we will test three hypotheses as to how CD19- dependent mechanisms regulate FDC: through activation of follicular B cells, through effects on the marginal zone that control delivery of antigen to FDC, and through formation of immune complexes. In Aim 3, we will determine how CD19 regulates autoimmunity by experiments to test the role of CD19 in central selection, selection in the periphery, and in a model of autoimmunity. These aims are proposed not just to understand the function of CD19, but to use CD19 to probe basic mechanisms that are fundamental to immunization and protection from pathogens, without autoimmunity. Public Health Relevance: The marginal zone of the spleen is required for survival of infections that have reached the blood while germinal centers are of fundamental importance in vaccination and immunological memory. Despite their crucial roles in protection from infections, the marginal zone and the germinal center responses are poorly understood. This project will use CD19, a protein expressed on B lymphocytes that is required for both types of response, as a tool to investigate the functions of B cells in the marginal zone and in germinal centers in vivo.