Cross-Talk Between Estrogen and T Cells Mediated Pathways in Lupus Pathogenesis

雌激素和 T 细胞之间的交互作用介导狼疮发病机制

• 批准号: 7351990
• 负责人: ALESSANDRA B PERNIS
• 金额: $ 40.08万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7351990
• 关键词: Affect; Autoantibodies; Autoimmune Diseases; B-Lymphocytes; Binding Proteins; Breast; Cell physiology; Cells; Defect; Development; Disease; Down-Regulation; Employee Strikes; Epithelial Cells; Epithelium; Estrogens; Event; Exhibits; Family; Feedback; Female; Functional disorder; GTP Phosphohydrolase Activators; Gender; Gene Expression; Genes; Glomerulonephritis; Goals; Gonadal Steroid Hormones; Homeostasis; Hormonal; Human; Hypergammaglobulinemia; Immune; Immunoglobulin G; Knowledge; Laboratories; Lupus; Lymphoid Cell; Mammary gland; Mediating; Modeling; Molecular; Molecular Target; Mus; Pathogenesis; Pathway interactions; Production; Proteinuria; Recruitment Activity; Regulation; Role; Sex Bias; Signal Transduction; Syndrome; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte; Testing; Transactivation; Woman; base; immunological synapse; innovation; insight; lead-binding proteins; lupus-like; member; novel; response; rho; rho GTP-Binding Proteins

Defects in the appropriate regulation of T cell function and homeostasis are fundamental to the pathogenesis of Systemic Lupus Erythematosus (SLE). Classically, SLE exhibits a striking gender bias and preferentially affects women. Although sex hormones, in particular estrogen, have been shown to affect the development and function of T cells, the molecular pathways by which the hormonal milieu modulates T cell responses are largely unknown. Our laboratory has cloned a novel molecule, termed IBP, which is highly expressed in T cells and is a novel member of a unique family of Rho GTPase activators, which is activated upon TCR engagement. Our studies in mice deficient for IBP have revealed that lack of IBP leads to the development of a lupus-like syndrome characterized by the accumulation of effector T cells and IgG+ B cells, profound hypergammaglobulinemia, autoantibody production, proteinuria and glomerulonephritis. Like human SLE, development of these manifestations primarily affects the female gender. Although IBP is highly expressed in lymphoid cells, IBP can also be found in epithelial cells from the mammary gland and our studies indicate that its expression in both breast epithelium and immune cells can be regulated by estrogen. Furthermore, we have recently found that expression of ERa is downregulated upon T cell stimulation in wt T cells but not in IBP deficient T cells. Taken all together these findings have led us to hypothesize that IBP is an estrogen regulated gene that controls a regulatory feedback loop aimed at restricting estrogen signaling during the activation of T cells. The major goal of this proposal is to dissect the cross-talk between IBP and sex hormones and determine whether IBP can be utilized as a novel molecular target to understand, at a mechanistic level, how sex hormones affect T cell physiology and pathophysiology. Specifically, we will: 1. Assess the mechanisms by which IBP controls the expression of ERa in T cells. 2. Investigate the role of estrogen on the lupus-like syndrome that develops in the absence of IBP.

T细胞功能和稳态调节的缺陷是系统性红斑狼疮(SLE)发病的基础。传统上，系统性红斑狼疮表现出明显的性别偏见，并优先影响女性。虽然性激素，特别是雌激素，已经被证明影响T细胞的发育和功能，但分子通路通过 荷尔蒙环境对T细胞反应的调节在很大程度上是未知的。我们实验室已经克隆了一个新的分子，称为IBP，它在T细胞中高表达，是一个独特的Rho GTP酶激活剂家族的新成员，它可以在TCR参与时被激活。我们对IBP缺乏的小鼠的研究表明，缺乏IBP会导致狼疮样综合征的发展，特征是效应性T细胞和 免疫球蛋白阳性B细胞、重度高丙种球蛋白血症、自身抗体产生、蛋白尿和肾炎。与人类系统性红斑狼疮一样，这些表现的发展主要影响女性。虽然IBP在淋巴样细胞中高表达，但在乳腺上皮细胞中也可以发现，我们的研究表明，它在乳腺上皮和免疫细胞中的表达都可以受到雌激素的调节。此外，我们最近发现，ERA的表达随着T细胞的刺激而下调，但在IBP缺乏的T细胞中不表达。综上所述，这些发现使我们假设IBP是一种雌激素调节基因，它控制着旨在限制T细胞激活期间雌激素信号的调节反馈回路。这项建议的主要目的是剖析IBP和性激素之间的相互作用，并确定IBP是否可以作为一个新的分子靶点，从机制水平上了解性激素如何影响T细胞生理学和病理生理学。具体地说，我们将：1.评估IBP控制T细胞Era表达的机制。2.探讨雌激素在无IBP的狼疮样综合征中的作用。