Apoptotic Cells as Immunogens in SLE

描述（由申请人提供）：在正常的稳态条件下，死亡细胞被免疫系统清除，对细胞成分的主动免疫反应被阻止。另一方面，如果死亡细胞不能被有效清除，它们可能会引发自身免疫。许多因素决定死亡细胞/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理效率，特别是经典补体（CCC）途径的早期成分；白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，我们将使用纯化的成分和成分缺乏血清来验证CCC是主要配体的假设，该配体负责抗原提呈细胞（ARC）的免疫抑制，这些抗原提呈细胞摄入了活化的凋亡细胞。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，以及这些途径所发挥的抑制作用是否可以减轻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身抗原，第二个目标将确定在稳态条件下摄入的凋亡细胞如何耐受CD4+ T细胞。在摄入凋亡细胞的DC群体中发现了新的变化，我们将研究是否抑制变化未能在狼疮模型中启动，这些变化被摄入凋亡细胞的DC加速。我们之前的研究表明，成熟的dc会破坏对细胞内抗原的耐受性，但不会在正常小鼠中诱导临床疾病。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附加因素。具体来说，1型干扰素和调节性T细胞的作用将被检查。成功完成这些特定目标将有助于提高对导致SLE的低补体和低CRP机制的理解，有助于理解凋亡细胞如何减弱T细胞对自身的反应，并将阐明哪些特定的免疫异常需要失调，以便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。

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.