BLC AND BLR1 AND IMMUNE FUNCTION AND DYSFUNCTION

BLC 和 BLR1 与免疫功能和功能障碍

• 批准号: 2840860
• 负责人: Jason G Cyster
• 金额: $ 16.89万
• 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 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2840860
• 关键词: B lymphocyte; T lymphocyte; cell differentiation; cell migration; chemokine; cytokine receptors; disease /disorder model; gene targeting; genetically modified animals; green fluorescent proteins; inflammation; laboratory mouse; leukocyte activation /transformation; macrophage; pancreatic islet disorder; receptor expression; tissue /cell culture

Chemokines are well characterized as small chemotactic cytokines that recruit cells from the blood to sites of infection. Recent studies have uncovered a role for chemokines in cell trafficking through lymphoid tissues. In mice deficient in Burkitt's Lymphoma Receptor 1 (BLR1/CXC- R5), B cell follicles fail to form in spleen and Peyer's patches and inguinal lymph nodes do not develop. B-Lymphocyte Chemoattractant (BLC/BCA1), the only known ligand for BLR1, is expressed by follicular stromal cells in these tissues. How BLR1 and BLC function to organize cells in follicles is not understood. The long-term objective of this propose is to define the contribution of BLR1/BLC to cell migration and organization in both lymphoid and non-lymphoid tissues. The first of three aims seeks to determine if changes in BLR1 expression or BLC responsiveness contribute to the changes in B cell tropism that occur upon activation and differentiation. Similar studies will also be performed on T cells since T cell migration into follicles is essential for germinal center reactions and may also permit access to antigen trapped on follicular dendritic cells such as HIV in patients with AIDS. Aim 1 will also test if a splice variant of BLR1 in human macrophages is expressed in the mouse and will determine the BLC responsiveness of macrophage subsets. In Aim 2 the mouse BLC gene will be inactivated by gene targeting. BLC-deficient mice are important for reestablishing the role of BLC in follicular compartmentalization of B cells, for determining whether BLC is the only ligand for BLR1 and for characterizing whether BLC has functions in addition to a role in cell homing to follicles. The targeting construct will also introduce the green fluorescent protein gene (GFP) into the BLC locus to permit characterization of BLC expressing cells. In patients suffering chronic inflammatory diseases such as rheumatoid arthritis and diabetes, there are often large accumulations of B cells in the affected tissue. The third aim will explore whether BLC is expressed at sites of chronic inflammation in mouse models and, using the gene targeted mice, test to what extent BLC contributes to the inflammation. This aim will also test the effect of BLC expression to an ectopic site (the pancreatic islets) using a transgenic approach both to determine whether BLC is sufficient to promote follicle formation and to establish a system where the relationship between B cell accumulation and pathology can be studied.

趋化因子被很好地表征为小的趋化性细胞因子， 从血液中募集细胞到感染部位。最近的研究 揭示了趋化因子在淋巴细胞运输中的作用， 组织中在伯基特淋巴瘤受体1（BLR 1/CXC-1）缺陷的小鼠中， R5），B细胞滤泡不能在脾和派尔集合淋巴结中形成， 腹股沟淋巴结不发育。B淋巴细胞趋化因子 (BLC/BCA 1），BLR 1的唯一已知配体，由滤泡上皮细胞表达。 这些组织中的基质细胞BLR 1和BLC如何组织 卵泡中的细胞还不清楚。长期目标是 我们的建议是确定BLR 1/BLC对细胞迁移的贡献， 在淋巴和非淋巴组织中的组织。中的第一 三个目标是确定BLR 1表达或BLC的变化是否 反应性导致B细胞趋向性的变化， 激活和分化。类似的研究也将在 由于T细胞迁移到卵泡中是必不可少的， 也可以允许接触抗原 被困在滤泡树突状细胞上，如艾滋病患者的艾滋病毒。 目的1还将测试BLR 1在人巨噬细胞中的剪接变体是否是 在小鼠中表达，并将决定BLC的反应性， 巨噬细胞亚群在目标2中，小鼠BLC基因将通过以下方法失活： 基因靶向。BLC缺陷小鼠对于重建 BLC在B细胞滤泡区室化中的作用， 确定BLC是否是BLR 1的唯一配体， 表征BLC除了在细胞中的作用之外是否具有功能 归巢到毛囊。靶向构建体还将引入 将绿色荧光蛋白基因（GFP）导入BLC基因座， BLC表达细胞的表征。在患有慢性 炎症性疾病如类风湿性关节炎和糖尿病， 通常是B细胞在受影响的组织中大量积聚。的 第三个目标是探索BLC是否在慢性炎症部位表达。 炎症小鼠模型，并使用基因靶向小鼠，测试， BLC在炎症中的作用程度。这一目标也将考验 BLC表达对异位部位（胰岛）的影响 使用转基因方法来确定BLC是否足以 以促进卵泡形成并建立一个系统， 可以研究B细胞积累和病理学之间的关系。