Chemokines and Lymphoid Tissue Organization and Function

趋化因子和淋巴组织的组织和功能

• 批准号: 8440325
• 负责人: Jason G Cyster
• 金额: $ 26.79万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2014-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8440325
• 关键词: Adoptive Transfer; Affinity; Allergens; Allergic Disease; Antibody Affinity; Antibody Formation; Antigens; Area; Autoimmune Diseases; B-Lymphocytes; BLR1 gene; Behavior; CXCR4 gene; Cell Communication; Cell physiology; Cells; Cues; Development; Event; Flow Cytometry; Fluorescence Microscopy; Follicular Dendritic Cells; Funding; G-Protein-Coupled Receptors; Gene Expression; Gene Targeting; Generations; Grant; Image; Imagery; Immune response; Immunoglobulins; Knowledge; Lead; Lymph Node Subcapsular Sinus; Lymphoid; Lymphoid Tissue; Measurement; Microscopy; Mus; Organ; Pathogenesis; Positioning Attribute; Role; Site; Source; Sphingosine-1-Phosphate Receptor; Structure of germinal center of lymph node; T-Lymphocyte; Testing; To autoantigen; Vaccines; Work; base; cell motility; chemokine; chemokine receptor; improved; lymph nodes; macrophage; novel strategies; pathogen; public health relevance; response; segregation; two-photon

DESCRIPTION (provided by applicant): Humoral immune responses are critical for protection against pathogens and are a cause of pathogenesis in autoimmune and allergic diseases. Despite their importance, fundamental questions remain regarding how antibody responses are mounted. A major focus of this grant has been to characterize the chemokines and related organizer cues in lymphoid organs that facilitate antibody responses. Key findings pertinent to the current proposal have been: identification of lymph node subcapsular sinus (SCS) macrophages as a site of B cell encounter with opsonized antigen; demonstration that B cells function as antigen transport cells; characterization of CXCR4 and CXCR5 as organizers of the germinal center (GC); visualization of cell migration dynamics in the GC; measurement of B cell -T cell contacts at the follicle-T zone boundary and in the GC leading to evidence that GC B cell selection may occur in part through competition for T cell help. Based on these findings we propose to focus the application on the following three specific aims. One, we seek to further assess how SCS macrophages capture antigen and interact with B cells using fluorescence microscopy, flow cytometry and two-photon imaging approaches. In addition, we will identify chemokine requirements for SCS macrophage positioning using gene expression studies and analysis of gene targeted mice. B cell interaction with follicular dendritic cells will also be visualized. Second we aim to characterize cellular events associated with selection of high affinity B cells in the Germinal Center (GC). We will use adoptive transfer approaches with immunoglobulin `knockin' B cells to study the impact on antibody affinity maturation of chemokine receptor deficiencies that disrupt GC B cell positioning. Third, we will examine the role in the GC response of a further G-protein coupled receptor found to be transcriptionally upregulated in GC B cells. These studies should lead to an improved understanding of how B cells encounter antigen and undergo selection, knowledge that has implications for development of improved vaccines and may suggest novel approaches for reducing unwanted responses to autoantigens or allergens.

描述（由申请人提供）：体液免疫反应对于保护病原体至关重要，并且是自身免疫性和过敏性疾病发病机理的原因。尽管它们的重要性，但关于如何安装抗体反应仍然存在基本问题。该赠款的主要重点是表征促进抗体反应的淋巴机器人中趋化因子和相关的组织者提示。与当前建议相关的主要发现是：鉴定淋巴结亚囊窦（SCS）巨噬细胞是与抗原抗原的B细胞相遇部位；证明了B细胞充当抗原转运细胞。 CXCR4和CXCR5作为生发中心（GC）的组织者的表征； GC中细胞迁移动力学的可视化；在卵泡区域边界和GC处的B细胞-T细胞接触的测量，导致证据表明，GC B细胞的选择可能部分是通过竞争T细胞帮助而发生的。根据这些发现，我们建议将应用程序集中在以下三个特定目标上。第一，我们寻求进一步评估SCS巨噬细胞如何使用荧光显微镜，流式细胞术和两光子成像方法捕获抗原并与B细胞相互作用。此外，我们将使用基因表达研究和基因靶向小鼠的分析来确定SCS巨噬细胞定位的趋化因子需求。 B细胞与卵泡树突状细胞的相互作用也将被可视化。其次，我们旨在表征与选择生发中心（GC）选择高亲和力B细胞有关的细胞事件。我们将使用免疫球蛋白“敲击蛋白” B细胞的产物转移方法来研究破坏GC B细胞定位的趋化因子受体缺乏症的抗体亲和力成熟的影响。第三，我们将研究在GC B细胞中发现转录上调的进一步G蛋白偶联受体的GC反应中的作用。这些研究应提高人们对B细胞如何遇到抗原和进行选择的了解，这对改善疫苗的开发具有意义，并可能提出减少对自身抗原或过敏原的不良反应的新方法。