Apoptotic Cells As Immunogens In SLE

描述(申请人提供)：系统性红斑狼疮(SLE)是一种 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的表面，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SLE， 缺乏Clq或SAP小鼠出现狼疮样自身免疫，而Clq 我们发现，基因缺陷的小鼠肾脏中的凋亡细胞数量增加 提出系统性红斑狼疮自身抗体的产生是由于未能处理和清除 死亡的细胞，特别是在发炎部位。为了测试这一想法，我们将 执行以下研究： 在目标1中，我们将定义补体是如何在染色表面被激活的 细胞，以及五氢呋喃如何调节这一过程。 在目标2中，我们将确定巨噬细胞上的哪些受体参与 不同的调色素对死亡细胞的影响，将决定 受体参与抗炎或促炎细胞因子的产生。 在目标3中，死亡细胞的摄取和处理将在体内使用 在基线和炎症条件下的两种不同的实验系统。 这些反应将在野生型和缺乏调理素的老鼠之间进行比较 (AIM 1)或受体(AIM 2)与垂死细胞的吞噬作用有关。这些 研究应该澄清所提出的假设是否正确。如果 正确，它将提供坚实的科学背景来定义 人类系统性红斑狼疮的分子基础。

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.