B CELLS IN AUTOIMMUNE DIABETES

自身免疫性糖尿病中的 B 细胞

• 批准号: 6334878
• 负责人: Ali Naji
• 金额: $ 16.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6334878
• 关键词: B lymphocyte; MHC class I antigen; MHC class II antigen; NOD mouse; antibody formation; antigen presentation; autoantibody; cellular pathology; complement; disease /disorder model; immune tolerance /unresponsiveness; insulin dependent diabetes mellitus; leukocyte activation /transformation; pathologic process; tissue /cell culture

Insulin dependent diabetes mellitus (IDDM) in humans and NOD mice is an autoimmune disease caused by the selective destruction of pancreatic beta cells by autoreactive T lymphocytes. In addition to the well characterize loss of T cell tolerance to islet autoantigens, the presence of anti-islet antibodies highlights a concomitant dysregulation of B cell tolerance to these antigens. The requisite role of B cells in diabetogenesis has recently been established in studies of B cell deficient NOD mice where were found to be protected from insulitis and diabetes. Whether the role of B cells in NOD diabetogenesis is mediated by the activated autoreactive B cells and whether this role involves antigen presentation by B cells is unknown. In the present proposal we plan to study the mechanisms underlying the role of B cells in NOD diabetogenesis. Thus, specific Aim 1 will be focused on elucidating the contribution of MHC class I- and class II-mediated antigen presentation by B cells to NOD diabetogenesis. In specific Aim 2 we propose studies to assess the contribution of the autoreactive subset of B cells to NOD diabetogenesis by skewing the NOD B cell repertoire away from diabetes associated Ig specificities. Specific aim 3 will address the importance of C3-mediated B cell activation and antigen uptake in the development of anti-islet autoantibodies and diabetogenesis in NOD mice. Finally, in specific aim 4 we will pursue studies aimed at elucidating the regulation of self-reactive B cells in the NOD microenvironment. Insights into the mechanisms by which B cells contribute to the etiology of autoimmune diabetes will provide the basis for the design of novel strategies for the prevention of IDDM.

人类中的胰岛素依赖性糖尿病（IDDM），点头小鼠是一种 由胰腺β的选择性破坏引起的自身免疫性疾病 通过自身反应性T淋巴细胞的细胞。除了良好的特征 T细胞对胰岛自身抗原的耐受性丧失，抗ISLET的存在 抗体突出了B细胞耐受性的不体调节 这些抗原。 B细胞在糖尿病发生中的必要作用 最近在研究B细胞不足的NOD小鼠的研究中建立了 发现被保护免受胰岛炎和糖尿病的保护。是否角色 激活的自动反应介导了糖尿病生成中的B细胞的介导 B细胞以及该作用是否涉及B细胞的抗原表现为 未知。在本提案中，我们计划研究机制 B细胞在糖尿病发生中的作用。因此，具体目标 1将侧重于阐明MHC I类和 B细胞对II类介导的抗原介绍对糖尿病发生。 在特定目标2中，我们提出了研究以评估 B细胞的自动反应性子集通过偏向点头B细胞对糖尿病发生 细胞库远离糖尿病相关的Ig特异性。具体的 AIM 3将解决C3介导的B细胞激活的重要性和 抗抗原自身抗体的抗原吸收和 点头小鼠的糖尿病发生。最后，在特定目标4中，我们将追求 旨在阐明自反应B细胞调节的研究 点头微环境。深入了解B细胞的机制 有助于自身免疫性糖尿病的病因 用于设计预防IDDM的新型策略。