Apoptotic Cells As Immunogens In SLE

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种 一种复杂的自身免疫性疾病，其特征是产生抗 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， 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发生SLE， Clq或SAP缺陷小鼠产生狼疮样自身免疫，Clq 缺陷小鼠肾脏中的凋亡细胞数量增加， 我认为SLE中的自身抗体是由于不能处理和清除 垂死的细胞，特别是在炎症部位。为了验证这个想法，我们将 进行以下研究： 在目标1中，我们将定义补体是如何在死亡的表面被激活的。 以及五聚素如何调节这一过程。 在目标2中，我们将确定巨噬细胞上的哪些受体被 不同的调理素对垂死的细胞，并将决定的后果 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加工： 在基线和炎症条件下的两个不同的实验系统。 将在野生型和调理素缺陷小鼠之间比较反应 (Aim 1）或受体（Aim 2）参与吞噬垂死细胞。这些 研究应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， 人类SLE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.