CD19 Tyrosine-mediated Signal Transduction in vivo

描述（由申请人提供）：B淋巴细胞是宿主防御感染性病原体所必需的，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。脾脏成熟的B细胞进入两个区室之一，边缘区或滤泡。边缘区B细胞负责对进入血液循环的病原体作出快速反应。滤泡B细胞被招募到生发中心，在那里亲和成熟和记忆B细胞的产生导致随后遇到病原体时的反应增强，这对疫苗免疫至关重要。缺乏CD19（一种B细胞表面受体）的小鼠不能形成边缘区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，缺乏边缘区B细胞会导致边缘区其他成分的缺陷，包括边缘区巨噬细胞和树突状细胞。然而，巨噬细胞和树突状细胞通过过继转移野生型B细胞重建边缘区B细胞后重新出现。目的1将剖析B细胞上的CD19调控MZ B细胞分化的机制，从而剖析边缘区其他成分。另外，新的初步数据表明，在CD19-/-小鼠中，生发中心形成失败与滤泡树突状细胞（FDC）激活失败有关。野生型B细胞的过继转移也在CD19-/-受体小鼠中重建了激活FDC的能力，恢复了形成生发中心的能力。在目标2中，我们将测试关于CD19依赖机制如何调节FDC的三种假设：通过激活滤泡B细胞，通过对控制抗原递送到FDC的边缘区域的影响，以及通过形成免疫复合物。在Aim 3中，我们将通过实验来确定CD19如何调节自身免疫，以测试CD19在中心选择、外周选择和自身免疫模型中的作用。这些目标的提出不仅是为了了解CD19的功能，而且是为了利用CD19来探索免疫和保护病原体的基本机制，而不是自身免疫。公共卫生相关性：脾脏的边缘区域是感染进入血液后存活所必需的，而生发中心在疫苗接种和免疫记忆中具有根本的重要性。尽管边缘区和生发中心在预防感染方面起着至关重要的作用，但人们对它们的反应知之甚少。该项目将使用CD19作为工具，研究B细胞在边缘区和生发中心的功能。CD19是B淋巴细胞上表达的一种蛋白质，两种类型的反应都需要它。

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.