Role of iNKT Cells in Autoimmunity 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，与先天免疫反应和获得性免疫反应的激活有关。少数族裔人群和患有系统性红斑狼疮的年轻女性特别容易发生动脉粥样硬化。最近，一组独特的T淋巴细胞，被称为不变自然杀伤T细胞(iNKT细胞)，被认为与动脉粥样硬化和狼疮有关。该项目将测试iNKT细胞在高脂血症期间被慢性激活的假设，以及这种转换独特地参与调节和/或调节加剧动脉粥样硬化和免疫失调的炎症反应。这一假说基于关键的初步研究，证实：(A)在自发性高脂血症apoE-/-小鼠中，iNKT细胞的数量和功能发生了变化；(B)apoE-/-小鼠的iNKT细胞表达与野生型iNKT细胞不同的表型标志物，提示其被激活；(C)apoE-/-小鼠中缺乏iNKT细胞可减少动脉粥样硬化，但会加重狼疮；(D)在体内特异性激活iNKT细胞可导致动脉粥样硬化，但可以预防狼疮。基于这些发现，本项目的总体目标是描述免疫调节机制(S)，通过该机制，iNKT细胞促进动脉壁病变的形成。我们的具体目标是：(1)研究高脂血症和动脉粥样硬化对apoE-/-小鼠iNKT细胞数量和功能的影响；(2)探讨iNKT细胞产生细胞因子和随后的免疫激活在动脉粥样硬化中的作用；(3)确定iNKT细胞在狼疮加速的动脉粥样硬化中的作用。 与公共健康相关：在美国，与动脉粥样硬化相关的冠心病是导致死亡的主要原因。患有狼疮的年轻女性罹患致命心脏事件的风险极高。狼疮加速的动脉粥样硬化与胆固醇水平无关，被认为在很大程度上与自身免疫失调有关。INKT细胞代表了一些最强大的免疫调节器。因此，了解它们在狼疮和动脉粥样硬化中的意义将为下一代同时治疗狼疮和心脏病的免疫疗法提供有价值的见解。

DESCRIPTION (provided by applicant): Atherosclerosis is a chronic inflammatory disease associated with the activation of both innate and adaptive immune responses. Minority populations and young women with systemic lupus erythematosus are particularly prone to the development of atherosclerosis. Recently, a unique group of T lymphocytes, called invariant natural killer T (iNKT) cells, have been implicated in atherogenesis and lupus. This Project will test the hypothesis that iNKT cells are chronically activated during hyperlipidemia and that this conversion is uniquely involved in regulating and/or modulating an inflammatory response that exacerbates atherosclerosis and dysregulates immunity. This hypothesis is based on key preliminary studies demonstrating that (a) iNKT cell numbers and functions are altered in spontaneously hyperlipidemic apoE-deficient (apoE-/-) mice; (b) iNKT cells of apoE-/- mice express phenotypic markers distinct from wild type iNKT cells, suggesting activation; (c) absence of iNKT cells in apoE-/- mice reduces atherosclerosis but aggravates lupus; and (d) specific activation of iNKT cells in vivo is proatherogenic but protects against lupus. Based on these findings, the overall objective of this Project is to characterize the immunoregulatory mechanism(s) by which iNKT cells promote lesion formation in the artery wall. Our specific aims are to: (1) investigate the effects of hyperlipidemia and atherosclerosis on iNKT cell numbers and functions in apoE-/- mice; (2) investigate the role of cytokine production by iNKT cells and subsequent immune activation in atherosclerosis and (3) determine the role of iNKT cells in lupus-accelerated atherosclerosis. Relevance to Public Health: Coronary heart disease associated with atherosclerosis is the primary cause of mortality in the United States. At extremely high risk for suffering a fatal cardiac event are young women with lupus. Lupus-accelerated atherosclerosis is independent of cholesterol levels and is thought to be largely associated with autoimmune dysregulation. iNKT cells represent some of the most potent immune regulators. Therefore, understanding their significance in lupus and atherosclerosis will provide valuable insights for the future generation of immunotherapy to treat both lupus and heart disease.