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，涉及先天性和适应性免疫系统，其在高脂血症和动脉壁内脂质的保留和修饰反应中启动。适应性免疫系统已被证明可以调节选定动脉部位的动脉粥样硬化程度，并影响脂质/脂蛋白代谢。自然杀伤T（NKT）细胞对抗原呈递细胞上的CD 1分子呈递的脂质抗原作出应答。我们的研究结果表明，根据其他免疫细胞的存在，NKT细胞是促动脉粥样硬化或抗动脉粥样硬化的，可以影响血脂，特别是VLDL，无论是NKT细胞或CD 1d抑制IgM的特异性生产氧化脂质的B1细胞。此外，我们还发现LDLR-/-小鼠的血浆中含有以CD 1d依赖性方式激活NKT细胞的抗原。在本提案中，我们将研究NKT细胞和/或CD 1d在肝脏中对脂质/脂蛋白代谢的影响（目的1），在血管壁中对动脉粥样硬化的影响（目的2），以及对B1细胞产生氧化脂质IgM抗体的特异性抑制（目的3）。NKT细胞/CD 1d对所有这些过程的影响预计有助于NKT细胞的促动脉粥样硬化机制。提出了一系列体内研究，其中操纵NKT细胞水平或CD 1d表达，沿着体外研究以进一步研究作用机制。此外，我们将尝试识别LDL或动脉粥样硬化斑块中激活NKT细胞的抗原。这些研究将有助于我们理解适应性免疫系统的作用，特别是T细胞亚类对脂蛋白稳态和动脉粥样硬化，并将提供证据的内源性脂质抗原刺激iNKT细胞。公共卫生相关性：这些研究的目的是了解对脂质抗原有反应的iNKT细胞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与动脉粥样硬化相关的慢性炎症中的作用的理解，并提供高脂血症和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.