REGULATION OF IMMUNITY BY DEAD CELLS

摘要 死亡细胞对免疫系统的影响取决于细胞死亡的方式，以及电流 人们认为，坏死性细胞充当“危险”信号，而凋亡性细胞则“沉默”。用于适应性免疫 反应，许多研究已经证明了坏死细胞的免疫原性，但现在很清楚 那就是，凋亡细胞可以引发耐受性反应。而很明显，正常组织和淋巴细胞 死亡可以诱导免疫耐受其他研究表明，在某些情况下，凋亡的细胞可以 免疫原性。了解这种动态依赖于发现由死亡细胞引发的因素 调解这些影响。我们在过去三年的研究已经建立了分子之间的联系 细胞凋亡途径和免疫耐受过程。我们在一个系统中探索了这一点，在这个系统中 与细胞凋亡残留物相关的抗原抑制免疫反应。我们现在 了解caspase激活、MOMP(线粒体外膜通透性)和ROS(反应性 氧物种)在细胞凋亡过程中的产生是重要的。此外，细胞凋亡过程中产生的ROS 修饰危险信号HMGB1(代表高迁移率族蛋白1)，阻止其免疫刺激作用 效果。在这一应用中，我们将进一步探讨HMGB1在诱导免疫耐受中的作用。 凋亡性细胞。我们提出了三个目标：1)定义HMGB1阻断耐受的机制(S) 2)我们将确定ROS修饰的HMGB1是否保留其促炎功能；3)我们将 确定其他细胞死亡途径是否通过改变危险信号来调节免疫反应 ROS生产。我们发现细胞凋亡过程中ROS的产生改变了危险信号HMGB1 代表了危险信号生物学的重大范式转变。因此，HMGB1的数量并不是 有货，就是质量问题。我们进一步认为，并非所有的ROS都是有害的，但可能会提供保护 对抗不必要的免疫反应。我们相信，这些新原则具有广泛的适用性，而且 这里提出的研究将进一步定义这些机制，并确定是否存在模仿这些机制的可能性 调节免疫反应的治疗方法的机制。

Abstract The impact of dying cells on the immune system depends on the manner in which cells die, and the current perception is that necrotic cells act as "danger" signals while apoptotic cells are "silent". For adaptive immune responses, many studies have documented the immunogenic activity of necrotic cells, however it is now clear that apoptotic cells can illicit a tolerogenic response. While it is apparent that normal tissue and lymphocyte death can induce immune tolerance other studies have shown that in some cases apoptotic cells can be immunogenic. Understanding this dynamic depends on discovering the factors elicited by dying cells that mediate these effects. Our studies over the past 3 years have established a link between the molecular pathways of apoptosis and the process of immune tolerance. We have explored this in a system in which antigens associated with the remnants of cells undergoing apoptosis suppress the immune response. We now know that caspase activation, MOMP (mitochondrial outer membrane permeablization), and ROS (reactive oxygen species) production during apoptosis are important. Additionally ROS produced during apoptosis modifies the danger signal HMGB1 (for high mobility group box 1 protein) preventing its immunostimulatory effects. In this application we will further explore the effect of HMGB1 on the induction of immune tolerance by apoptotic cells. We propose 3 aims: 1) We will define the mechanism(s) by which HMGB1 blocks tolerance by apoptotic cells; 2) We will determine if ROS-modified HMGB1 retains its proinflammatory functions; 3) We will determine if other cell death pathways modulate the immune response by modifying danger signals through ROS production. Our finding that ROS production during apoptosis modifies the danger signal HMGB1 represents a major paradigm shift in the biology of danger signals. Thus, it is not the quantity of HMGB1 that is available, it is the quality. We would further suggest that not all ROS are harmful but may provide protection against unwanted immune responses. We believe that these new principles are wildly applicable and the studies proposed here will further define these mechanisms and determine if the potential exists to mimic those mechanisms in a therapeutic approach to modulating the immune response.