REGULATION OF IMMUNITY BY DEAD CELLS

描述（由申请人提供）：死亡细胞对免疫系统的影响取决于细胞死亡的方式，目前的看法是坏死细胞充当“危险”信号，而凋亡细胞则是“沉默”的。对于适应性免疫反应，许多研究已经记录了坏死细胞的免疫原活性，但是现在很清楚凋亡细胞可以引起耐受性免疫反应。虽然正常组织和淋巴细胞死亡可以诱导免疫耐受是显而易见的，但其他研究表明，在某些情况下，凋亡细胞可能具有免疫原性。理解这种动态取决于发现由死亡细胞引发的介导这些影响的因素。我们在过去3年的研究已经建立了细胞凋亡的分子途径与免疫耐受过程之间的联系。我们已经在一个系统中探索了这一点，在这个系统中，与细胞凋亡残余相关的抗原抑制了免疫反应。我们现在知道，凋亡过程中caspase的激活、线粒体外膜透性（MOMP）和活性氧（ROS）的产生是重要的。此外，细胞凋亡过程中产生的ROS改变了危险信号HMGB1（高迁移率组框1蛋白），阻止了其免疫刺激作用。在本应用中，我们将进一步探讨HMGB1对凋亡细胞诱导免疫耐受的作用。我们提出了三个目标：1)我们将确定HMGB1阻止凋亡细胞耐受的机制；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ROS产生改变危险信号来调节免疫反应。我们发现细胞凋亡过程中ROS的产生改变了危险信号HMGB1，这代表了危险信号生物学的重大范式转变。因此，可用的不是HMGB1的数量，而是质量。我们进一步认为，并非所有的活性氧都是有害的，但可能提供保护，以防止不必要的免疫反应。我们相信这些新原理是广泛适用的，这里提出的研究将进一步定义这些机制，并确定是否有可能在治疗方法中模仿这些机制来调节免疫反应。公共卫生相关性：我们的免疫系统保护我们免受感染和其他伤害。在器官移植和自身免疫过程中，它们也会转而攻击我们自己的细胞。这里提出的研究将提高我们对免疫系统的理解，并导致治疗的发展，可以用来控制免疫反应，为我们的利益。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Our immune systems protect us from infection and other injuries. They can also turn against us and attack our own cells during organ transplantation and autoimmunity. The studies proposed here will improve our understanding of the immune system and lead to the development of therapies that can be use to control the immune response for our benefit.