REGULATION OF HUMORAL IMMUNITY BY COMPLEMENT RECEPTORS

补体受体对体液免疫的调节

• 批准号: 6170077
• 负责人: HECTOR D MOLINA
• 金额: $ 24.65万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170077
• 关键词: B lymphocyte; T lymphocyte; complement receptor; genetically modified animals; humoral immunity; laboratory mouse; leukocyte activation /transformation; receptor expression

Many of the immunological effects attributed to the third component of complement (C3) are mediated by specific cell membrane complement receptors. Complement receptor 1 (CR1) is the immune adherence receptor and participates in C3b- dependent phagocytosis, lymphocyte function and the regulation of C3 activation. Complement receptor 2 (CR2) is involved in lymphocyte activation, in the primary immune response to antigens and in the generation of immunological memory. In some rheumatologic disorders, such as SLE , the levels of these receptors are abnormal, suggesting a role in the pathophysiology of the disease. CR1/CR2 deficient mice have been developed using gene targeting techniques. These mice are unable to mount a normal humoral immune response to specific antigen stimulation. Since mouse CR1 and 2 are the alternatively spliced product of the same gene, the CR1/CR2 deficient mice lack expression of both proteins. However, previous studies have indicated unique functions for each protein. The relative contributions of CR1 versus CR2 to the immune abnormalities observed in the receptor deficient mice, therefore, are not yet defined. We propose to selectively reconstitute each of these proteins in our CR1/CR2 deficient mice using tansgenic technology. Constructs will be designed containing cDNAs encoding each specific complement receptor under the kappa light chain promoter/enhancer transcriptional control, which will direct receptor expression to B lymphocytes. Other promoters will be considered based on their ability to direct tissue specific expression of these receptors. These constructs will be injected individually to generate transgenic mice that express only one of these receptors. Following backcrossing into CR1/CR2 deficient mice, the immune response to different antigens will then be evaluated. These experiments will clarify the different roles of these proteins in the immune response.

许多免疫效应归因于第三种 补体成分(C3)由特定细胞介导 膜补体受体。补体受体1(CR1) 是免疫黏附受体，参与C3b- 依赖吞噬功能、淋巴细胞功能及其调节 C3激活。补体受体2(CR2)参与 淋巴细胞活化，在初级免疫反应中 抗原和免疫记忆的产生。在……里面 一些风湿病，如系统性红斑狼疮，这些水平 受体异常，提示在病理生理学中起作用。 这种疾病的危害。已培育出CR1/CR2缺陷小鼠 使用基因打靶技术。这些老鼠不能上马 对特定抗原的正常体液免疫反应 刺激。由于鼠标CR1和2是交替拼接的 同一基因的产物，CR1/CR2缺陷小鼠缺乏 这两种蛋白都有表达。然而，之前的研究已经 显示了每种蛋白质的独特功能。相对的 CR1和CR2在免疫异常中的作用 因此，在受体缺陷小鼠中观察到的 已定义。我们建议有选择地重建其中每一个 利用转基因技术研究CR1/CR2基因缺陷小鼠的蛋白质 技术构建物将设计为包含cDNA 在kappa光下编码每个特定的补体受体 链启动子/增强子转录调控，这将指导 B淋巴细胞的受体表达。其他发起人将是 根据他们引导组织特异性的能力来考虑 这些受体的表达。这些构造将被注入 单独产生只表达以下其中一种的转基因小鼠 这些受体。在回交进入CR1/CR2缺陷之后 小鼠对不同抗原的免疫反应将会是 已评估。这些实验将阐明不同的角色 这些蛋白质在免疫反应中起作用。