Sexual Dimorphism and Dysregulated Immune Responses in SLE: The Role of Leptin

描述（由申请人提供）：本提案旨在推进当前对与女性系统性红斑狼疮（SLE）易感性增加相关的细胞和分子免疫事件的理解。性别差异与几种生物学差异有关，其中最明显的是两性在性激素及其受体水平上的明显差异。然而，尽管非常重要，但性激素表达和反应性的差异可能不足以完全解释女性SLE发病率增加的原因。在过去的十年里，我们的团队一直在研究脂肪因子瘦素对免疫反应的影响。我们和其他人已经证明，这种两性二态激素——在女性体内的浓度是体重指数相似的男性的5-10倍——具有促炎活性，极大地促进了包括SLE在内的几种自身免疫性疾病的发展和进展。我们还表明，瘦素限制了调节性T细胞在体外和体内抑制自身反应性免疫反应的能力，并与其他研究人员一起表明，调节性T细胞可以调节SLE疾病的活动性。在这里，我们提议剖析瘦素对SLE调节性T细胞的影响，通过验证女性瘦素水平升高可以调节SLE调节性T细胞的关键特征的假设。三个综合目标将在细胞、分子和生化水平上研究瘦素对SLE调节性T细胞表型和功能的影响。通过确定瘦素在SLE中可以调节的特定事件，我们的目标是最终确定治疗干预的替代标记物，从而更好地管理疾病。

DESCRIPTION (provided by applicant): This proposal aims to advance the current understanding of the cellular and molecular immune events that associate with the increased susceptibility to develop systemic lupus erythematosus (SLE) in females. Gender disparities associate with several biological differences that most apparently involve an evident dissimilarity between sexes in the levels of sex hormones and their receptors. However, although very important, the differences in the expression and responsiveness to sex hormones may not be sufficient to fully explain the increased incidence of SLE in females. During the past decade, our group has been interested in investigating the effects of the hormone adipokine leptin on immune responses. We and others have shown that this sexually dimorphic hormone - found at concentrations 5-10 times higher in females than in males with similar body mass index - has proinflammatory activities that greatly favor the development and the progression of several autoimmune diseases including SLE. We have also shown that leptin constraints the ability of regulatory T cells to suppress autoreactive immune responses in vitro and in vivo, and together with others we have shown that regulatory T cells can modulate SLE disease activity. Here we propose to dissect the effects of leptin on regulatory T cells in SLE by testing the hypothesis that elevated levels of leptin in females can modulate key characteristics of the regulatory T cells in SLE. Three integrated aims will study the influence of leptin on the phenotype and function of regulatory T cells in SLE at the cellular, molecular and biochemical levels. By identifying specific events that can be modulated by leptin in SLE, we aim to ultimately identify surrogate markers of therapeutic intervention that could lead to a better management of the disease. PUBLIC HEALTH RELEVANCE: In this application we will explore new mechanisms that may contribute to the increased susceptibility to develop systemic lupus erythematosus ( SLE) in females. We will investigate the role of a hormone that is expressed in much higher concentration in females as a possible major contributor to the pathogenesis of SLE. The role of this hormone, leptin, will be investigated in great detail for its capacity to inhibit the activity of cells that suppress autoimmunity in SLE, as preliminary work seems to suggest.