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

SLE 中的性别二态性和免疫反应失调：瘦素的作用

• 批准号: 8178630
• 负责人: ANTONIO LA CAVA
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-18 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8178630
• 关键词: Address; Affect; Age; Apoptosis; Autoantibodies; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Basal metabolic rate; Biochemical; Biological; Body fat; Body mass index; Cells; Characteristics; Chronic; Clinical Trials; Data; Development; Disease; Disease Management; Ethnic Origin; Event; Female; Functional disorder; Gender; Genes; Gonadal Steroid Hormones; High Prevalence; Homeostasis; Hormonal; Hormones; Immune; Immune response; In Vitro; Incidence; Inflammation; Inflammatory; Intervention; Investigation; Lead; Leptin; Longevity; Modality; Molecular; Mus; Organ; Pathogenesis; Pathway interactions; Patients; Phenotype; Predisposition; Regulation; Regulatory T-Lymphocyte; Role; Secondary to; Series; Serum; Suppressor-Effector T-Lymphocytes; Surrogate Markers; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Woman; Work; base; cytokine; design; human FRAP1 protein; in vivo; inhibitor/antagonist; interest; male; novel therapeutics; peripheral tolerance; receptor; research study; restoration; sex; sexual dimorphism

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.

描述（由申请人提供）：本提案旨在促进目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，其中最明显的是性别之间在性激素及其受体水平上的明显差异。然而，尽管非常重要，但对性激素的表达和反应性的差异可能不足以完全解释女性SLE发病率的增加。在过去的十年中，我们的小组一直有兴趣研究激素脂肪因子瘦素对免疫反应的影响。我们和其他人已经表明，这种性二型激素-在女性中的浓度比具有相似体重指数的男性高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，瘦素限制调节性T细胞的能力，抑制自身反应性免疫反应在体外和体内，和其他人一起，我们已经表明，调节性T细胞可以调节SLE疾病的活动。在这里，我们建议解剖瘦素对SLE调节性T细胞的影响，通过测试女性瘦素水平升高可以调节SLE调节性T细胞的关键特征这一假设。本论文从细胞、分子和生化水平研究瘦素对SLE调节性T细胞表型和功能的影响。通过确定特定的事件，可以调节瘦素在系统性红斑狼疮，我们的目标是最终确定替代标记物的治疗干预，可能会导致更好的管理疾病。 公共卫生关系：在这个应用程序中，我们将探索新的机制，可能有助于增加易感性发展系统性红斑狼疮（SLE）的女性。我们将研究一种在女性中表达浓度高得多的激素作为SLE发病机制的可能主要贡献者的作用。这种激素的作用，瘦素，将被研究在非常详细的能力，抑制细胞的活动，抑制自身免疫系统性红斑狼疮，初步工作似乎表明。