Apoptotic Cells As Immunogens In SLE

凋亡细胞作为系统性红斑狼疮的免疫原

• 批准号: 6653251
• 负责人: Keith B. Elkon
• 金额: $ 21.31万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6653251
• 关键词: antibody formation; antinuclear autoantibody; apoptosis; clinical research; complement pathway; cytokine; human subject; laboratory mouse; macrophage; pathologic process; phagocytosis; protein biosynthesis; receptor; systemic lupus erythematosus

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the production of autoantibodies to nucleoprotein antigens. We have shown that complement and certain acute phase proteins are deposited on the surface of apoptotic cells and facilitate phagocytosis of the dying cell. Based on the clinical observations that patients with deficiencies of the early complement components develop SLE, that mice deficient in Clq or SAP develop lupus-like autoimmunity and that Clq deficient mice have increased numbers of apoptotic cells in their kidneys, we propose that autoantibodies in SLE arise through failure to process and clear dying cells, particularly at sites of inflammation. To test this idea, we will perform the following studies: In Aim 1, we will define how complement is activated on the surface of dying cells and how pentraxins modulate this process. In Aim 2, we will determine which receptors on macrophages are engaged by different opsonins on the dying cells and will determine the consequences of receptor engagement in terms of anti- or pro-inflammatory cytokine production. In Aim 3, uptake and processing of dying cells will be examined in vivo using two different experimental systems under baseline and inflammatory conditions. The responses will be compared between wild type and mice deficient in opsonins (Aim 1) or receptors (Aim 2) implicated in phagocytosis of dying cells. These studies should elucidate whether the hypothesis proposed is correct. If correct, it will provide the solid scientific background from which to define the molecular basis of human SLE.

描述（由申请人提供）：系统性红斑狼疮 (SLE) 是一种 复杂的自身免疫性疾病，其特征是产生自身抗体 核蛋白抗原。我们已经证明补体和某些急性期 蛋白质沉积在凋亡细胞表面并促进 死亡细胞的吞噬作用。根据临床观察 早期补体成分缺乏的患者会患上系统性红斑狼疮 (SLE)， 缺乏 Clq 或 SAP 的小鼠会产生狼疮样自身免疫，并且 Clq 有缺陷的小鼠肾脏中的凋亡细胞数量增加，我们 提出 SLE 中的自身抗体是由于未能处理和清除而产生的 垂死的细胞，特别是在炎症部位。为了测试这个想法，我们将 进行以下研究： 在目标 1 中，我们将定义补体如何在死亡表面激活 细胞以及五聚蛋白如何调节这一过程。 在目标 2 中，我们将确定巨噬细胞上的哪些受体与 垂死细胞上的不同调理素将决定其后果 受体参与抗炎或促炎细胞因子的产生。 在目标 3 中，将使用以下方法在体内检查垂死细胞的摄取和处理： 基线和炎症条件下的两个不同的实验系统。 将比较野生型和缺乏调理素的小鼠的反应 （目标 1）或参与死亡细胞吞噬作用的受体（目标 2）。这些 研究应该阐明所提出的假设是否正确。如果 正确的，它将提供坚实的科学背景来定义 人类 SLE 的分子基础。