Anti-Sm B-1 Cell Differentiation and Function

抗 Sm B-1 细胞分化和功能

• 批准号: 6632456
• 负责人: Stephen H Clarke
• 金额: $ 25.46万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632456
• 关键词: B lymphocyte; CD5 molecule; autoantigens; cell differentiation; cellular pathology; disease /disorder model; genetically modified animals; immune tolerance /unresponsiveness; laboratory mouse; ribonucleoproteins; systemic lupus erythematosus

DESCRIPTION: (provided by applicant): The long-range goal of this project is to understand B cell tolerance and how tolerance is broken in disease. The focus is on B cells specific for the Smith (Sm) antigen, a ribonucleoprotein involved in RNA splicing found in all cells, and a target of the immune system in systemic lupus erythematosus. To understand the regulation of anti-Sm B cells Ig H chain transgenic (2-12H Tg) mice using the rearrangement from an anti-Sm B cell have been generated. Anti-Sm B cells are present in the spleens of non-autoimmune 2-12H Tg mice and most are transitional B cells. In addition, about30 percent of peritoneal B-l cells are anti-Sm in these mice. Although these mice respond to Sm immunization, indicating that tolerance is maintained by ignorance, pre-immune serum anti-Sm levels are no different from those of non-Tg mice. This is paradoxical, since B-l cells are responsible for most circulating IgM. In autoimmune MRL/lpr mice, anti-Sm B cells are activated but they do not differentiate to B-l. The three aims of this application test the following hypothesis: anti-Sm transitional B cells are driven by antigen to differentiate to B-1, but they are inhibited from activation by the expression of CD5, a negative regulator of B cell activation. In autoimmune mice, where differentiation to B-1 is blocked, anti-Sm B cells differentiate to B-2 where they are more readily activated. In the first aim, the ability of anti-Sm transitional, B cells to differentiate to B-1 will be determined by transfer of 2-12H Tg transitional. B cells to non-Tg mice. In addition, the V repertoires of anti-Sm transitional and B-1 cells of 212H Tg mice will be analyzed to determine whether differentiation to B-l is selective. In the second aim, anti-Sm B-1 cell function will be assessed in vitro and in vivo, and the role of CD5 determined in 2-12H Tg/CD54-/-mice. In the final aim, the fate of B cells that normally differentiate to B-l will be determined in autoimmune MRL/lpr mice using a Tg model system of B-l differentiation.

描述：（由申请人提供）：该项目的长期目标是 了解 B 细胞耐受性以及疾病中耐受性如何被破坏。焦点 位于对史密斯 (Sm) 抗原具有特异性的 B 细胞上，该抗原涉及一种核糖核蛋白 存在于所有细胞中的 RNA 剪接中，并且是免疫系统的目标 系统性红斑狼疮。了解抗 Sm B 细胞的调节 使用抗 Sm B 重排的 Ig H 链转基因 (2-12H Tg) 小鼠 细胞已生成。抗 Sm B 细胞存在于脾脏中 非自身免疫 2-12H Tg 小鼠，大多数是过渡 B 细胞。此外， 这些小鼠中约 30% 的腹膜 B-1 细胞具有抗 Sm 活性。虽然 这些小鼠对 Sm 免疫有反应，表明耐受性得以维持 由于无知，免疫前血清抗 Sm 水平与免疫前血清抗 Sm 水平没有什么不同。 非 Tg 小鼠。这是自相矛盾的，因为 B-l 细胞负责大部分 循环 IgM。在自身免疫 MRL/lpr 小鼠中，抗 Sm B 细胞被激活，但 它们不区分 B-l。该应用程序的三个目标测试 以下假设：抗 Sm 移行 B 细胞由抗原驱动 分化为 B-1，但它们的激活受到表达的抑制 CD5 是 B 细胞激活的负调节因子。在自身免疫小鼠中， 向 B-1 的分化被阻断，抗 Sm B 细胞向 B-2 分化，其中 它们更容易被激活。第一个目标，抗Sm能力 过渡时期，B 细胞分化为 B-1 将通过转移来确定 2-12H Tg 过渡。非 Tg 小鼠的 B 细胞。此外，V曲目 将分析 212H Tg 小鼠的抗 Sm 移行细胞和 B-1 细胞 确定向 B-1 的分化是否具有选择性。在第二个目标中， 抗 Sm B-1 细胞功能将在体外和体内进行评估，并评估其作用 在 2-12H Tg/CD54-/- 小鼠中测定 CD5 的含量。最终目标是B的命运 正常分化为 B-1 的细胞将在自身免疫中测定 使用B-1分化的Tg模型系统的MRL/lpr小鼠。