Mechanisms of Dendritic Cell Responses to Endogenous DNA

描述（由申请人提供）： 由于完整细胞的快速吞噬以及细胞外和细胞内DNA酶的丰富，免疫系统通常在细胞凋亡期间受到保护免于暴露于自身DNA。然而，在组织坏死、炎症或感染后，抗原呈递细胞（APC），包括树突状细胞（DC），可能暴露于增加的细胞DNA负荷，并且细胞碎片的不适当处理可能导致耐受性丧失。虽然哺乳动物DNA以前被认为是中性的，甚至抑制APC，我们最近观察到，细胞摄取裸哺乳动物DNA或含有免疫复合物的某些DNA可以诱导DC活化。本提案的目的是研究内源性DNA激活DC的基本机制，包括与垂死细胞和抗DNA自身抗体相关的DNA。我们假设SLE中的病理性IFN应答是哺乳动物DNA通过摄取死亡或垂死细胞进入细胞质的结果，并且这种应答被抗原/抗DNA免疫复合物的一小部分放大，所述抗原/抗DNA免疫复合物具有独特的结合特异性并接合多个细胞受体，导致部分或完全DC活化。具体目标是：i）研究允许内源性DNA或含DNA的颗粒刺激DC产生IFN的机制，ii）确定内源性抗原（包括DNA/核小体）在DC对抗DNA免疫复合物的应答中的作用，以及iii）确定哪些信号传导途径是抗DNA免疫复合物激活DC所需的。这些研究将使我们更好地了解内源性遗传物质是如何处理的，以获得对自身免疫发病机制的基本见解。大卫·马丁医生是个医学博士。他已经完成了内科住院医师培训和风湿病学奖学金，并希望发展一个独立的研究生涯，专注于自身免疫的分子机制。

DESCRIPTION (provided by applicant): The immune system is normally protected from exposure to self-DNA during apoptosis due to the rapid engulfment of intact cells as well as by the abundance of extra- and intracellular DNases. However, following tissue necrosis, inflammation or infection, antigen presenting cells (APCs), including dendritic cells (DCs), may be exposed to an increased load of cellular DNA, and inappropriate handling of cellular debris can lead to loss of tolerance. While mammalian DNA was previously thought to be neutral or even inhibitory to APCs, we have recently observed that cellular uptake of naked mammalian DNA or certain DNA containing immune complexes can induce DC activation. The goal of this proposal is to study the basic mechanisms of DC activation by endogenous DNA, including DNA associated with dying cells and with anti- DNA autoantibodies. We hypothesize that the pathological IFN response in SLE is a consequence of mammalian DNA which gains access to the cytoplasm through the uptake of dead or dying cells, and that this response is amplified by a small subset of antigen/anti-DNA immune complexes that have unique binding specificity and engage multiple cellular receptors leading to partial or full DC activation. The specific aims are: i) to study mechanism(s) allowing endogenous DNA or DNA-containing particles to stimulate DC production of IFN, ii) to determine the role of endogenous antigens, including DNA/nucleosomes, in DC responses to anti-DNA immune complexes, and iii), to determine which signaling pathways are required for DC activation by anti-DNA immune complexes. These studies will allow us to better understand how endogenous genetic material is handled in order to gain fundamental insight into the pathogenesis of autoimmunity. Dr. David Martin, the PI, is an M.D. who has completed residency training in Internal Medicine and a Fellowship in Rheumatology, and wishes to develop an independent research career focusing on the molecular mechanisms of autoimmunity.