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丰富的细胞外和细胞内DNA酶，免疫系统通常在凋亡过程中免受自身DNA的影响。然而，在组织坏死、炎症或感染后，包括树突状细胞(DC)在内的抗原提呈细胞(APC)可能会暴露在细胞DNA负荷增加的环境中，如果对细胞碎片处理不当，可能会导致耐受性丧失。虽然哺乳动物DNA以前被认为对APC是中性的，甚至是抑制的，但我们最近观察到，细胞摄取裸露的哺乳动物DNA或某些含有DNA的免疫复合物可以诱导DC激活。这项建议的目的是研究内源性DNA激活DC的基本机制，包括与濒死细胞相关的DNA和抗DNA自身抗体。我们假设SLE的病理性干扰素反应是哺乳动物DNA通过摄取死亡或濒死细胞进入细胞质的结果，这种反应被具有独特结合特异性的一小部分抗原/抗DNA免疫复合体放大，这些免疫复合体具有独特的结合特异性，并结合多个细胞受体导致部分或全部DC激活。其具体目的是：1)研究内源性脱氧核糖核酸或含脱氧核糖核酸颗粒刺激DC产生干扰素的机制；2)确定包括脱氧核糖核酸/核小体在内的内源性抗原在抗脱氧核糖核酸免疫复合体应答DC中的作用；3)确定抗脱氧核糖核酸免疫复合体激活DC所需的信号通路。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，以便从根本上洞察自身免疫的发病机制。大卫·马丁博士是一名医学博士，已完成内科住院医师培训，并获得风湿病学奖学金，希望发展一项专注于自身免疫分子机制的独立研究事业。

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.