REGULATION OF HUMORAL IMMUNITY BY COMPLEMENT RECEPTORS

补体受体对体液免疫的调节

• 批准号: 2887335
• 负责人: HECTOR D MOLINA
• 金额: $ 23.93万
• 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/2887335
• 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.

许多免疫学效应归因于第三种 补体成分（C3）由特定细胞介导 膜补体受体 补体受体1（CR 1） 是免疫粘附受体，参与C3 b- 依赖性吞噬作用，淋巴细胞功能和调节 C3激活 补体受体2（CR2）参与 淋巴细胞活化，在初级免疫反应， 抗原和免疫记忆的产生。 在 一些风湿性疾病，如SLE，这些水平 受体异常，提示在病理生理学中的作用 的疾病。 已经开发了CR 1/CR2缺陷小鼠， 使用基因靶向技术。 这些老鼠无法 对特定抗原的正常体液免疫反应 刺激. 由于小鼠CR 1和CR2是选择性剪接的， CR 1/CR2缺陷小鼠缺乏相同基因的产物， 两种蛋白质的表达。 然而，以前的研究 表明每种蛋白质都有独特的功能。 的相对 CR 1与CR2对免疫异常的贡献 因此，在受体缺陷小鼠中观察到的， 定义了 我们建议有选择地重组每一个 我们的CR 1/CR2缺陷小鼠中的蛋白质， 技术.构建体将被设计为含有cDNA 在κ光下编码每种特异性补体受体 链启动子/增强子转录控制，这将指导 受体表达至B淋巴细胞。 其他发起人将 根据其引导组织特异性 这些受体的表达。 这些构造将被注入 以产生仅表达以下之一的转基因小鼠 这些受体。 在回交到CR 1/CR2缺陷型中之后， 小鼠，对不同抗原的免疫反应将被 评估。 这些实验将阐明 免疫反应中的这些蛋白质。