Lipid Regulation of Autoimmunity

慢性炎症性自身免疫性疾病如系统性狼疮患者的易感性增加 红斑狼疮（SLE）和类风湿性关节炎（RA）发展为动脉粥样硬化是临床上的一个主要 问题.这种关联的基础是自身免疫和动脉粥样硬化之间的协同相互关系 在高胆固醇血症的实验动物模型中也观察到的疾病。然而，因素 常见于慢性炎症和高胆固醇血症，有助于这种协同作用仍然很差 表征了高胆固醇血症与肝细胞中促炎性磷脂的产生有关。 与慢性炎症性自身免疫性疾病的病因学联系。其中一种磷脂， 溶血磷脂酰胆碱（LPC）是脂蛋白氧化和磷脂酰胆碱的主要促动脉粥样硬化产物， 促炎性磷脂酶的水解，其过度产生被认为在病理生理学上起作用， 在SLE中的作用LPC通过G2 A刺激T细胞迁移，G2 A是一种G蛋白偶联受体，主要表达于 淋巴细胞和单核细胞衍生的细胞。我们最近确定G2 A的缺失在高胆固醇血症患者中， 低密度脂蛋白受体敲除（LDLR-/-）小鼠抑制动脉粥样硬化。高胆固醇血症 G2 A缺陷（G2 A-/-）LDLR-/-小鼠导致外周淋巴结淋巴细胞显著耗竭 伴随着活化和效应CD 4+细胞数量的减少。这表明， 正常的G2 A介导的循环淋巴细胞对血液LPC水平升高的迁移反应， 负责淋巴细胞减少性淋巴结的发展。我们假设G2 A调节适应性 通过促进淋巴细胞通过淋巴结的运输， 以确保有效的抗原监测。我们建议 由于与高胆固醇血症相关的LPC持续升高， 慢性炎症有助于动脉粥样硬化和自身免疫性疾病之间的协同作用， 促进T细胞介导的对自身抗原的免疫应答。我们将通过测量 G2 A缺乏对正常胆固醇血症和高脂血症下T细胞进出淋巴结影响 高胆固醇血症我们还将评估高胆固醇血症患者的动脉粥样硬化和自身免疫性。 在存在或不存在G2 A功能的狼疮倾向gld小鼠中，我们将确定G2 A功能的丧失是否 在高胆固醇血症的gld小鼠中，抑制对经典狼疮抗原的自身免疫应答，减弱 发展自身免疫的明显症状，并导致CD 4 + T细胞介导的免疫功能降低。 对动脉粥样硬化相关自身抗原的反应。这些研究将为新型脂质介导的 自身免疫和动脉粥样硬化之间协同相互关系的潜在机制

The increased susceptibility of patients with chronic inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) to the development of atherosclerosis is a major clinical problem. This association is underlied by a synergistic inter-relationship between autoimmune and atherosclerotic diseases which is also observed in experimental animal models of hypercholesterolemia. However, factors common to chronic inflammation and hypercholesterolemia that contribute to this synergism remain poorly characterized. Hypercholesterolemia is associated with the generation of pro-inflammatory phospholipids in the circulation with etiological connections to chronic inflammatory autoimmune disease. One such phospholipid, ysophosphatidylcholine (LPC), is a major pro-atherogenic product of lipoprotein oxidation and phospholipid hydrolysis by pro-inflammatory phospholipases whose over-production is believed to play a pathophysiological role in SLE. LPC stimulates T cell migration via G2A, a G protein-coupled receptor expressed predominantly in ymphocytes and monocyte-derived cells. We recently determined that deletion of G2A in hypercholesterolemic low-density lipoprotein receptor knockout (LDLR-/-) mice suppresses atherosclerosis. Hypercholesterolemia in G2A-deficient (G2A-/-) LDLR-/- mice resulted in significant depletion of lymphocytes from peripheral lymph nodes with concomitant reductions in the numbers of activated and effector CD4+ cells. This suggests that loss of normal G2A-mediated migratory responses of circulating lymphocytes to elevations in blood LPC levels are responsible for the development of lymphopenic lymph nodes. We hypothesize that G2A regulates adaptive immune responses during an inflammatory response by promoting lymphocyte trafficking through lymph nodes in response to transient elevations in circulating LPC levels to ensure efficient antigen surveillance. We propose that the deregulation of this mechanism due to sustained elevations in LPC associated with hypercholesterolemia and chronic inflammation contributes to the synergism between atherosclerotic and autoimmune diseases by promoting T cell-mediated immune responses to auto-antigens. We will test this hypothesis by measuring the impact of G2A deficiency on T cell entry into, and egress from, lymph nodes under normocholesterolemic and hypercholesterolemic conditions. We will also evaluate atherosclerosis and autoimmunity in hypercholesterolemic lupus-prone gld mice in the presence or absence of G2A function; we will determine whether loss of G2A function in hypercholesterolemic gld mice suppresses autoimmune responses to classical lupus antigens, attenuates the development of overt symptoms of autoimmunity, and results in reduced CD4+ T cell-mediated immune responses to atherosclerosis-related auto-antigens. These studies will provide important insight into novel lipidmediated mechanisms underlying the synergistic inter-relationship between autoimmunity and atherosclerosis