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: 7103193
• 负责人: Keith B. Elkon
• 金额: $ 30.8万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7103193
• 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): Under normal steady state conditions, dying cells are removed by the immune system and an active immune response against cellular constituents is prevented. On the other hand, if dying cells are not efficiently removed, they may provoke autoimmunity. A large number of factors determine the outcome of the dying cell / phagocyte interaction. Amongst these factors are the efficiency of opsonization of apoptotic cells by serum components, especially early components of the classical complement (CCC) pathway; active immunosuppression of the phagocyte, the state of maturation of dendritic cells (DCs) and the cytokines in the milieu. In the first Aim, using purified components and component deficient serum, we will test the hypothesis that CCC are the dominant ligands responsible for immunosuppression of antigen presenting cells (ARC) that have ingested opsonized apoptotic cells. We will also determine how C-reactive protein (CRP) exerts its immunosuppressive effect on ARC and whether the suppressive effects exerted by these pathways can attenuate inflammatory properties of SLE blood cells. Using a defined T cell transgenic system and pseudo self antigen, the second Aim will determine how ingestion of apoptotic cells tolerize CD4+ T cells under steady state conditions. Having discovered novel alterations in DC populations that have ingested apoptotic cells, we will investigate whether suppressive changes fail to be initiated in lupus models that are accelerated by DCs that have ingested apoptotic cells. We have previously shown that maturation of DCs breaks tolerance to intracellular antigens but does not induce clinical disease in normal mice. In the third Aim we will determine what additional factors are required to produce pathogenic autoantibodies. Specifically the roles of type 1 interferons and regulatory T cells will be examined. Successful completion of these specific aims will lead to improved understanding of the mechanisms responsible for low complement and low CRP leading to SLE, for understanding how apoptotic cells attenuate T cell responses to self and will elucidate what specific immunological abnormalities need to be dysregulated in order to change what is normally a tolerizing signal in the immune system into a potent source of self antigen for autoimmunization.

描述（由申请人提供）：在正常稳态条件下，死亡细胞被免疫系统清除，并且防止针对细胞成分的主动免疫反应。 另一方面，如果死亡细胞没有被有效清除，它们可能会引发自身免疫。 许多因素决定了垂死细胞/吞噬细胞相互作用的结果。 这些因素包括血清成分，特别是经典补体（CCC）途径的早期成分对凋亡细胞调理作用的效率；吞噬细胞的主动免疫抑制、树突状细胞 (DC) 的成熟状态和环境中的细胞因子。 在第一个目标中，使用纯化的成分和成分缺乏的血清，我们将检验以下假设：CCC 是负责对摄入调理过的凋亡细胞的抗原呈递细胞 (ARC) 进行免疫抑制的主要配体。 我们还将确定 C 反应蛋白 (CRP) 如何对 ARC 发挥其免疫抑制作用，以及这些途径产生的抑制作用是否可以减弱 SLE 血细胞的炎症特性。 使用确定的 T 细胞转基因系统和假自身抗原，第二个目标将确定凋亡细胞的摄入如何在稳态条件下耐受 CD4+ T 细胞。 在发现了摄入凋亡细胞的 DC 群体中的新变化后，我们将研究狼疮模型中是否无法启动抑制性变化，而摄入凋亡细胞的 DC 会加速这种变化。 我们之前已经表明，DC 的成熟会破坏对细胞内抗原的耐受性，但不会在正常小鼠中诱发临床疾病。 在第三个目标中，我们将确定产生致病性自身抗体需要哪些额外因素。 具体而言，将检查 1 型干扰素和调节性 T 细胞的作用。 成功完成这些具体目标将有助于更好地理解导致 SLE 的低补体和低 CRP 的机制，了解凋亡细胞如何减弱 T 细胞对自身的反应，并阐明需要调节哪些特定的免疫异常才能将免疫系统中通常的耐受信号改变为自身免疫的有效自身抗原来源。