NKT cells in lipoprotein Metabolism and atherosclerosis

描述（由申请人提供）：动脉粥样硬化是一种慢性炎症性疾病，涉及先天和适应性免疫系统，由高脂血症和动脉壁内脂质的保留和修饰引起。适应性免疫系统已被证明可以调节动脉粥样硬化在特定动脉部位的程度，并影响脂质/脂蛋白代谢。自然杀伤T细胞（NKT）对CD1分子在抗原呈递细胞上呈递的脂质抗原产生应答。我们的研究结果表明，依赖于其他免疫细胞的存在，NKT细胞是促或抗动脉粥样硬化的，可以影响血浆脂质，特别是VLDL， NKT细胞或CD1d抑制B1细胞氧化脂质的特异性IgM的产生。此外，我们已经证明，LDLR-/-小鼠的血浆中含有抗原，以CD1d依赖的方式激活NKT细胞。在本提案中，我们将研究肝脏中NKT细胞和/或CD1d对脂质/脂蛋白代谢的影响（目的1），血管壁中对动脉粥样硬化的影响（目的2），以及B1细胞对氧化脂质的IgM抗体产生的特异性抑制（目的3）。NKT细胞/CD1d在所有这些过程中的作用有望有助于NKT细胞的促动脉粥样硬化机制。研究人员提出了一系列体内研究，其中NKT细胞水平或CD1d的表达被操纵，并在体外研究中进一步研究其作用机制。此外，我们将尝试识别激活NKT细胞的LDL或动脉粥样硬化斑块中的抗原。这些研究将有助于我们理解适应性免疫系统，特别是T细胞亚类在脂蛋白稳态和动脉粥样硬化中的作用，并将为内源性脂质抗原刺激iNKT细胞提供证据。公共卫生相关性：这些研究的目的是了解iNKT细胞对脂质抗原的反应如何影响脂蛋白代谢和动脉粥样硬化。这些研究将进一步加深我们对免疫系统在动脉粥样硬化相关慢性炎症中的作用的理解，并提供高脂血症与动脉粥样硬化发展之间的重要联系。

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory disease involving both the innate and adaptive immune system that is initiated in response to hyperlipidemia and the retention and modification of lipids within the artery wall. The adaptive immune system has been shown to modulate the extent of atherosclerosis at selected arterial sites and to influence lipid/lipoprotein metabolism. Natural killer T (NKT) cells respond to lipid antigens presented by CD1 molecules on antigen presenting cells. Our results demonstrate that depending upon the presence of other immune cells, NKT cells are pro- or anti-atherogenic and can influence plasma lipids, especially VLDL, and either NKT cells or CD1d repress the specific production of IgM to oxidized lipids by B1 cells. In addition we have shown that the plasma of LDLR-/- mice contain antigen(s) that activate NKT cells in a CD1d dependent manner. In this proposal we will examine the effect of NKT cells and/or CD1d in the liver on lipid/lipoprotein metabolism (aim 1), in the vessel wall on atherosclerosis (aim 2), and on the specific repression of the production of IgM antibodies to oxidized lipids by B1 cells (aim 3). The effect of NKT cells/CD1d on all these processes is expected to contribute to the pro-atherogenic mechanism of NKT cells. A series of in vivo studies in which the level of NKT cells or expression of CD1d is manipulated are proposed along with in vitro studies to further investigate mechanism of action. In addition, we will attempt to identify the antigen in LDL or atherosclerotic plaques that activate NKT cells. These studies will contribute to our understanding of the role of the adaptive immune system and specifically T cells subclasses on lipoprotein homeostasis and atherosclerosis and will provide evidence for endogenous lipid antigens that stimulate iNKT cells. PUBLIC HEALTH RELEVANCE: The goal of these studies is to understand how iNKT cells, which respond to lipid antigens, influence lipoprotein metabolism and atherosclerosis. These studies will further our understanding of the role of the immune system in the chronic inflammation associated with atherosclerosis and provide an important link between hyperlipidemia and the development of atherosclerosis.