Apoptotic Cells as Immunogens in SLE

描述（由申请方提供）：在正常稳态条件下，免疫系统会清除垂死细胞，并防止针对细胞成分的主动免疫应答。 另一方面，如果死亡细胞没有被有效地去除，它们可能会引起自身免疫。 大量的因素决定死亡细胞/吞噬细胞相互作用的结果。 在这些因素中，有血清组分，特别是经典补体（CCC）途径的早期组分对凋亡细胞的调理作用的效率;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，使用纯化的组分和组分缺乏的血清，我们将测试的假设，CCC是占主导地位的配体负责免疫抑制的抗原呈递细胞（ARC），已摄取调理凋亡细胞。 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，以及这些途径产生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细胞转基因系统和假自身抗原，第二个目标将确定在稳态条件下摄取凋亡细胞如何耐受CD 4 + T细胞。 已经发现了新的改变，在DC群体已经摄取凋亡细胞，我们将调查是否抑制性变化未能启动狼疮模型，已摄取凋亡细胞的DC加速。 我们以前已经证明，成熟的树突状细胞打破细胞内抗原的耐受性，但不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所需的其他因素。 特别是1型干扰素和调节性T细胞的作用将被检查。 这些特定目标的成功完成将导致对导致SLE的低补体和低CRP的机制的更好理解，用于理解凋亡细胞如何减弱T细胞对自身的应答，并将阐明需要失调哪些特定的免疫异常，以将免疫系统中通常的耐受信号改变为自身免疫的自身抗原的有效来源。

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.