The Role of Recycling Immune Complexes in the Breakdown of Tolerance

描述（由申请人提供）：凋亡细胞的清除缺陷和循环免疫复合物（IC）的增加一再与系统性红斑狼疮（SLE）中细胞因子分泌增加有关。尽管有清除缺陷的证据，并且推测TLR配体进入内体的途径减少，但已经发现细胞因子分泌是由活化的内体TLR引起的。这一悖论提出了一种可能性，即一个更复杂的模型，涉及TLR依赖性和TLR非依赖性机制调节细胞因子分泌。我们的初步数据表明，IgG-IC（IgG-apop IC）结合部分通过Fc？Rs在来自自身免疫易感MRL/lpr小鼠的DC和MF表面上升高30倍。我们表明，这种积累的结果从降解缺陷，促进回收的内化Fc？Rs结合IgG-1C。在体内和体外，IC的积累提高BAFF分泌。在本申请中，我们将检验中心假设，即由于内吞/吞噬途径中靶向或降解IC的缺陷，IgG-apop IC在DC和MF上积累。这导致致病性细胞因子的生产作为遗传易感性和慢性TLR和/或Fc？RS信号。我们在目标1中提出确定降解途径中IC进展减弱的位置。在目标2，我们假设，慢性Fc？当IC与Fc结合时，Rs信号传导结果如何？Rs保持聚集在回收过程中，慢性TLR信号传导的结果时，IC加载的Fc？Rs在这些通路中花费很长时间。最后，我们提出，虽然遗传易感性可能是导致IC再循环的缺陷的基础，但也可能需要遗传事件来提高细胞因子分泌。我们将通过在非自身免疫小鼠中诱导IC再循环来分离这些推定的遗传事件，并评估这是否导致细胞因子产生增加。总的来说，该提议是重要的，因为它确定了IC在DC和MF上积累，并定义了TLR依赖性和TLR非依赖性机制如何有助于狼疮相关细胞因子水平升高的更复杂机制。

DESCRIPTION (provided by applicant): The defective clearance of apoptotic cells and the increase in circulating immune complexes (ICs) have repeatedly been implicated in heightened cytokine secretion in systemic lupus erythematosus (SLE). Despite evidence of clearance defects, and presumably diminished access of TLR ligands to the endosome, cytokine secretion has been found to result from activated endosomal TLRs. This paradox raised the possibility that a more complicated model involving TLR-dependent and TLR-independent mechanisms regulates cytokine secretion. Our preliminary data show that IgG-ICs (IgG-apop ICs) bound in part via Fc?Rs are elevated 30-fold on the surface of DCs and MFs from autoimmune prone MRL/lpr mice. We show that this accumulation results from a degradation defect that promotes the recycling of internalized Fc?Rs bound IgG-ICs. In vivo and in vitro, the accumulation of ICs heightens BAFF secretion. In this application we will test the central hypothesis that IgG-apop ICs accumulate on DCs and MFs due to defects in targeting or degrading ICs within the endocytic/phagocytic pathway. This leads to pathogenic cytokine production as a consequence of genetic predisposition and chronic TLR and/or Fc?Rs signaling. We propose in aim 1 to identify where in the degradative pathway the progression of ICs is attenuated. In aim 2, we postulate that chronic Fc?Rs signaling results when ICs bound to Fc?Rs remain aggregated during the recycling process, and that chronic TLR signaling results when the IC-loaded Fc?Rs spend prolonged time within these pathways. Lastly, we propose that although genetic predisposition might underlie the defects leading to the recycling of ICs, genetic events might also be required for heightened cytokine secretion. We will separate these putative genetic events by pharmacologically inducing IC recycling in non-autoimmune mice and assessing whether this leads to heightened cytokine production. Overall, this proposal is significant because it identifies that ICs accumulate on DCs and MFs and defines a more intricate mechanism for how TLR-dependent and TLR- independent mechanisms might contribute to elevated levels of lupus-related cytokines.