ALTERED N-LINKED OLIGOSACCHARIDES ON IGG IN RHEMATOID ARTHRITIS

类风湿性关节炎中 IGG 上 N 联寡糖的改变

• 批准号: 6100675
• 负责人: RUSSELL D. SALTER
• 金额: $ 13.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6100675
• 关键词: MHC class II antigen; T lymphocyte; clinical research; crosslink; dendritic cells; electron microscopy; human subject; immune tolerance /unresponsiveness; immunoglobulin G; immunoglobulin isotypes; inflammation; intracellular transport; lymphocyte proliferation; oligosaccharides; receptor binding; rheumatoid arthritis

Chronic inflammatory responses leading to destruction of synovial tissue is characteristic of rheumatoid arthritis (RA), an autoimmune disease of unknown etiology. Dendritic cells in the joint are likely to play a crucial role in initiating the disease by presenting peptide antigens derived from self proteins to autoreactive T cells. We have observed increased uptake by dendritic cells of IgGs bearing altered N-oligosaccharides, shown previously to be present in the serum and synovial fluid of RA patients. This suggests that modified IgG (G0 IgG) taken up by dendritic cells may be processed and presented via class II histocompatibility proteins quite efficiently, leading to a breakdown in tolerance of T cells reactive with IgG-derived peptides. To further characterize binding of G0 IgG to dendritic cells and test whether IgG-reactive T cells might contribute to the disease, we will perform the following experiments. In specific aim 1, novel assays will be developed which provide a highly sensitive means of detecting binding of G0 IgG to dendritic cells. IgG isotype will also be tested as a determinant of binding. Subcellular localization of internalized Go IgG will determined using electron microscopy, and intersection of G0 IgG with the class II h istocompatibiity processing pathway assessed using biochemical assays. In specific aim 2, receptors on the surface of dendritic cells responsible for binding G0 IgG will be identified using chemical crosslinking and gel electrophoretic analyses. In specific aim 3, T cells from patients and normal controls will be tested for proliferative responses to dendritic cells pulsed with G0 IgG. These experiments should determine if G0 IgG taken up by dendritic cells can be efficiently processed and presented via class II histocompatibility molecules to peripheral T cells which are potentially autoreactive.

导致滑膜破坏的慢性炎症反应 组织是类风湿性关节炎（RA）的特征， 病因不明的疾病。 关节中的树突细胞很可能 通过呈递肽在引发疾病中起关键作用 从自身蛋白衍生的抗原到自身反应性T细胞。 我们 已经观察到带有IgG的树突状细胞的摄取增加 改变的N-寡糖，先前显示存在于 RA患者血清和关节滑液中。 这表明 被树突细胞摄取的修饰的IgG（G0 IgG）可以是 通过II类组织相容性蛋白进行加工和呈递， 有效地，导致T细胞反应性耐受性的破坏， 与IgG衍生的肽。 进一步表征G0的结合 IgG对树突状细胞的作用，并测试IgG反应性T细胞是否可能 我们将采取以下措施 实验 在具体目标1中，将开发新的测定法 其提供了检测G0结合的高度灵敏的手段 免疫球蛋白G致树突状细胞。 IgG同种型也将作为 约束力的决定因素 内化Go的亚细胞定位 IgG将使用电子显微镜测定， G0 IgG与II类组织相容性处理途径 使用生物化学测定进行评估。 在具体目标2中， 负责结合G0 IgG的树突状细胞的表面将 用化学交联和凝胶电泳鉴定 分析。 在具体目标3中，来自患者和正常人的T细胞 对照将测试对树突细胞的增殖反应 用G0 IgG脉冲。 这些实验应该确定G0 由树突细胞摄取的IgG可以被有效地加工， 通过II类组织相容性分子呈递给外周T细胞 潜在的自体反应细胞。