The Impact of Obesity and Leptin on the Development of Immune System Dysfunction and Hypertension in Females with Systemic Lupus Erythematous

项目摘要/摘要 系统性红斑狼疮(SLE)是一种慢性自身免疫性疾病，主要影响女性和 其特征是丧失自我耐受性和自身反应性B和T淋巴细胞的扩张，导致 产生自身抗体。自身抗体的产生会导致慢性炎症，导致高发病率。 高血压和心血管疾病。临床数据表明，患者的肥胖率增加。 患有系统性红斑狼疮，即使没有超重或肥胖的BMI，SLE患者的脂肪沉积也发生了变化。 与体重指数匹配的对照组相比，内脏脂肪增加。系统性红斑狼疮患者的循环也有升高。 脂肪因子瘦素水平，包括那些体重指数在正常范围的患者。这样做的中心目标是 该项目旨在研究肥胖和瘦素在糖尿病的发生和发展中的致病作用。 系统性红斑狼疮与高血压的发展。为了实现这一目标，两个临床相关的模型 对于SLE，将利用雌性NZBWF1小鼠和Pristane诱导的模型。这两种模式都在发展 随着疾病的进展，NZBWF1小鼠表现出肥胖和高瘦素血症。 正常的食物饮食。在目标1中，我们将使用NZBWF1小鼠来验证这样的假设：增加内脏 系统性红斑狼疮患者肥胖通过病原性免疫加重疾病进展和高血压的发展 脂肪组织中的细胞。我们将使用手术和药物技术来消耗脂肪组织或特定的 脂肪中的免疫细胞群，然后评估这些治疗方法对SLE疾病的效果 高血压的进展和发展。已发表的和初步的数据表明，瘦素具有 通过对免疫细胞的直接作用和通过大脑中的信号间接作用于免疫系统。评估 瘦素通过直接影响免疫细胞在SLE疾病进展中的作用，Aim 2将利用Pristane- 建立系统性红斑狼疮的诱导性模型，并验证SLE期间瘦素升高促进疾病进展的假说 通过直接作用于外周组织中的B和T淋巴细胞。我们将培育出缺乏瘦素受体的小鼠 在B或T淋巴细胞上，并使用Pristane诱导SLE。在目标3中，我们将检验瘦素促进 系统性红斑狼疮通过其在中枢神经系统的作用。首先，我们将在缺乏瘦素受体的小鼠中使用普里斯坦诱发狼疮 在中枢神经系统(Nestin-Cre x LepRflx/Flox)。我们还将测试瘦素对自身免疫性疾病的影响 进展是由交感神经系统通过肾上腺素能受体阻滞剂来调节的。 总之，拟议的研究将为肥胖和脂肪因子之间的不同机制提供洞察力。 系统性红斑狼疮患者的免疫系统功能紊乱，导致高血压的发生。

PROJECT SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that primarily affects women and is characterized by a loss of self-tolerance and expansion of autoreactive B and T lymphocytes, leading to the production of autoantibodies. The autoantibody production leads to chronic inflammation, resulting in high rates of hypertension and cardiovascular disease. Clinical data indicate that rates of obesity are increased in patients with SLE, and even in the absence of an overweight or obese BMI, patients with SLE have altered fat deposition and increased visceral adiposity compared to BMI-matched controls. SLE patients also have elevated circulating levels of the adipokine leptin, including those patients with a BMI in the normal range. The central goal of this project is to examine the pathogenic role of obesity and leptin in the development and progression of SLE disease and the development of hypertension. To accomplish this goal, two clinically relevant models of SLE, the female NZBWF1 mouse and the pristane-inducible model, will be utilized. Both models develop hypertension as the disease progresses, and the NZBWF1 mouse exhibits obesity and hyperleptinemia on a normal chow diet. In aim 1 we will use the NZBWF1 mouse to test the hypothesis that increased visceral adiposity in SLE exacerbates disease progression and the development of hypertension via pathogenic immune cells in adipose tissue. We will use surgical and pharmacological techniques to deplete adipose tissue or specific immune cell populations within the adipose, and then assess the effect of these treatments on SLE disease progression and the development of hypertension. Published and preliminary data indicate that leptin has effects on the immune system via both direct effects on immune cells, and indirectly via signaling in the brain. To assess the role of leptin in SLE disease progression by directly affecting immune cells, aim 2 will utilize the pristane- inducible model of SLE and test the hypothesis that elevated leptin during SLE promotes disease progression via direct effects on B and T lymphocytes in peripheral tissues. We will generate mice that lack leptin receptors on B or T lymphocytes and induce SLE using pristane. In aim 3, we will test the hypothesis that leptin promotes SLE disease via its actions in the CNS. First, we will induce lupus using pristane in mice that lack leptin receptors in the CNS (Nestin-Cre x LepRflox/flox). We will also test whether the effects of leptin on autoimmune disease progression are mediated by the sympathetic nervous system by utilizing adrenergic receptor blockade. Together, the proposed studies will provide insight into distinct mechanisms whereby obesity and adipokine dysregulation lead to immune system dysfunction and the development of hypertension in SLE.