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

项目总结/文摘

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.