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）：在正常的稳态条件下，通过免疫系统去除垂死的细胞，并防止了针对细胞成分的主动免疫反应。 另一方面，如果没有有效去除垂死的细胞，它们可能会引起自身免疫性。 大量因素决定了垂死的细胞 /吞噬细胞相互作用的结果。 这些因素包括血清成分对凋亡细胞的调子化效率，尤其是经典补体（CCC）途径的早期成分；吞噬细胞的主动免疫抑制，树突状细胞的成熟状态（DC）和环境中的细胞因子。 在第一个目标中，使用纯化的成分和缺乏血清的成分，我们将测试CCC是负责抗原呈现抗原细胞（ARC）免疫抑制的主要配体的假设，这些配体摄入了已摄入的凋亡细胞。 我们还将确定C反应蛋白（CRP）如何对ARC施加免疫抑制作用，以及这些途径所施加的抑制作用是否可以减弱SLE血细胞的炎症特性。 使用定义的T细胞转基因系统和伪自抗原，第二个目标将决定凋亡细胞在稳态条件下摄入CD4+ T细胞的摄入。 在发现了摄入凋亡细胞的DC种群中的新变化后，我们将研究是否在由摄入凋亡细胞的DC加速的狼疮模型中启动抑制性变化。 我们先前已经表明，DC的成熟会破坏对细胞内抗原的耐受性，但不会诱导正常小鼠的临床疾病。 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其他因素。 特别是1型干扰素和调节性T细胞的作用。 这些特定目标的成功完成将导致人们对负责较低补体和低CRP的机制的了解，以了解凋亡细胞如何减轻T细胞对自我的反应，并将阐明需要将哪些特定的免疫异常失调，以便为了改变自动化的自动化的自动化源，以将其正常耐受性信号转移到自动范围内。