NKT cells in lipoprotein Metabolism and atherosclerosis

描述(申请人提供)：动脉粥样硬化是一种慢性炎症性疾病，涉及先天免疫系统和获得性免疫系统，它是对高脂血症和脂质在动脉壁内的滞留和修改而启动的。适应性免疫系统已被证明可以调节特定动脉部位的动脉粥样硬化程度，并影响脂/脂蛋白代谢。自然杀伤T(NKT)细胞对由抗原提呈细胞表面的CD1分子提呈的脂类抗原作出反应。我们的结果表明，依赖于其他免疫细胞的存在，NKT细胞是促进或抗动脉粥样硬化的细胞，并能影响血脂，尤其是VLDL，NKT细胞或CD1d细胞都能抑制B1细胞将IgM特异性地产生为氧化脂质。此外，我们还发现LDLR-/-小鼠的血浆中含有以CD1d依赖的方式激活NKT细胞的抗原(S)。在这项建议中，我们将研究NKT细胞和/或CD1d在肝脏中对脂/脂蛋白代谢的影响(目标1)，在血管壁中对动脉粥样硬化的影响(目标2)，以及对B1细胞产生氧化脂质的IgM抗体的特异性抑制(目标3)。NKT细胞/CD1d在所有这些过程中的作用可能有助于NKT细胞的促动脉粥样硬化机制。通过对NKT细胞水平或CD1d表达进行体内调控的一系列体内研究，以及进一步研究作用机制的体外研究被提出。此外，我们将尝试识别低密度脂蛋白或激活NKT细胞的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，并将为内源性脂类抗原刺激iNKT细胞提供证据。公共卫生相关性：这些研究的目标是了解iNKT细胞如何对脂类抗原做出反应，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，并为高脂血症与动脉粥样硬化的发展提供重要的联系。

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.