Do estrogen receptors in B cells and DC mediate sex bias in murine lupus?

B 细胞和 DC 中的雌激素受体是否介导小鼠狼疮的性别偏见？

• 批准号: 7512934
• 负责人: A Darise Farris
• 金额: $ 19.88万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7512934
• 关键词: Affect; Alleles; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Bone Marrow; Breast Cancer Treatment; CD19 gene; Cell Count; Cells; Commit; Dendritic Cells; Development; Disease; Drug usage; Elevation; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exploratory/Developmental Grant; Exposure to; Female; Future; Gender; Gene Transfer Techniques; Genetic; Gonadal Steroid Hormones; Health; Hematopoiesis; Hematopoietic; Hormonal; Human; ITGAX gene; Immune; Immune system; Immunity; Infection; Inflammatory; Interferons; Interleukin-12; Knowledge; Lead; Ligands; Link; Longevity; Lupus; Lupus Erythematosus; Lupus Nephritis; Mediating; Modeling; Mus; Numbers; Osteoporosis; Pathogenesis; Penetrance; Phenotype; Physiological; Phytoestrogens; Play; Predisposition; Production; Public Health; Publishing; Reporting; Research; Role; Science; Serological; Sex Bias; Signal Transduction; Staging; Study models; Systemic Lupus Erythematosus; Technology; Testing; Toll-like receptors; Trauma; Woman; Women' s Health; cell type; cytokine; differentiated B cell; immune function; mortality; mouse model; novel; progenitor; promoter; recombinase; reproductive; response; sex

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disease that preferentially affects women (9:1) in their reproductive years, indicating that sex specific factors including the sex hormone estradiol play an important role in lupus pathogenesis. Murine models of lupus show natural earlier expression of disease and ensuing mortality in female mice. The Sle1 and Sle3 lupus susceptibility loci present in NZM2410 mice direct increased penetrance of disease in females, which is consistent with studies showing that elevation of systemic estradiol or exposure to estrogenic environmental compounds accelerate lupus development. An understanding of the mechanisms underlying the female preponderance of SLE requires that we precisely determine how endogenous estrogens and estrogen receptors (ER) regulate the function of immune cells such as B lymphocytes and dendritic cells (DC), which express ER and have been implicated in lupus pathogenesis. However, current models for the study of estrogen effects on immune cells often have involved systemic exposure to supra-physiological levels of estradiol or global loss of ER, which creates hormonal imbalances. Elevated systemic levels of estradiol result in a profound depletion of hematopoietic progenitors, leading to alterations in numbers and phenotype of B cells and DC. To circumvent these effects of ER ligands on immune cell development, we propose to develop and use a novel model of murine lupus in which ERalpha expression may be specifically ablated in differentiated B cells or DC. We will use lentiviral transgenesis to deliver Cre recombinase driven by the CD19 or CD11c promoters to lupus prone B6.Sle13 bicongenic mice bearing a conditional ERalpha allele. This approach will allow us to determine whether aberrant DC or post-bone marrow B cell phenotypes associated with the sex sensitive Sle1 and Sle3 loci are mediated by direct effects of endogenous estrogens on B cells or DC. In Aim 1, we will determine if the elevated DC numbers or hyper-activated DC phenotypes leading to pro-inflammatory cytokine production in female B6.Sle13 bicongenic mice are a result of the direct action of endogenous estrogen on DC. In Aim 2, we will determine whether perturbations in transitional B cell subsets and subsequent enhanced loss of serologic tolerance in female B6.Sle13 bicongenic mice are a result of the direct action of endogenous estrogen on committed B cells and/or DC. The successful implementation of this lentiviral transgenesis strategy to delete ERalpha in specific cell types will establish a versatile model that could be used to study the role of ERalpha signaling in any cell type during the development of lupus nephritis. PUBLIC HEALTH RELEVANCE Cells of the human and murine immune systems are capable of responding to estrogens, phytoestrogens and drugs used for treatment of breast cancer and osteoporosis. We seek to understand how estrogens control the development and function of key regulatory cells of the immune system, termed dendritic cells and B cells, during the autoimmune disease Systemic Lupus Erythematosus. This knowledge will help to understand why autoimmune diseases preferentially afflict women.

描述（由申请人提供）：全身性红斑狼疮（SLE）是一种自身免疫性疾病，在其生殖年中优先影响女性（9：1），表明包括性激素雌二醇在内的性特定因素在狼疮的病理中起着重要作用。狼疮的鼠模型显示出疾病的早期表达和雌性小鼠死亡率的自然表达。 NZM2410小鼠中存在的SLE1和SLE3狼疮易感性基因座直接增加了女性疾病的渗透率，这与表明全身性雌二醇的升高或暴露于雌激素环境化合物的研究一致。对SLE女性优势的机制的理解要求我们精确地确定内源性雌激素和雌激素受体（ER）如何调节免疫细胞的功能，例如B淋巴细胞和树突状细胞（DC），这些功能表达ER并已在卢普斯病原体中表现出来。然而，目前研究雌激素对免疫细胞的影响的模型通常涉及全身暴露于雌二醇上的生理学水平或ER的全球丧失，这会导致激素失衡。雌二醇的全身水平升高导致造血祖细胞的严重耗竭，从而导致B细胞和DC的数量和表型改变。为了避免ER配体对免疫细胞发育的这些影响，我们建议开发和使用新型的鼠狼疮模型，其中可以在分化的B细胞或DC中特异性地消融Eralpha表达。我们将使用慢病毒转基因来传递由CD19或CD11C启动子驱动的CRE重组酶到俯卧的B6.SLE13双足小鼠，带有条件性Eralpha等位基因。这种方法将使我们能够确定与性敏感SLE1和SLE3基因座相关的异常DC或骨髓B细胞表型是否是由内源性雌激素对B细胞或DC的直接作用介导的。在AIM 1中，我们将确定升高的直流数量或过度激活的直流表型是否导致雌性B6的促炎细胞因子产生。SLE13双基因小鼠是内源性雌激素对DC的直接作用的结果。在AIM 2中，我们将确定在雌性B6中的过渡B细胞亚群中的扰动以及随后增强血清学耐受性的损失是否是内源性雌激素对承诺的B细胞和/或DC的直接作用的结果。在特定细胞类型中删除Eralpha的这种慢病毒转基因策略的成功实施将建立一种多功能模型，该模型可用于研究Eralpha信号在狼疮性肾炎发展过程中任何细胞类型中的作用。人和鼠免疫系统的公共卫生相关细胞能够对雌激素，植物雌激素和用于治疗乳腺癌和骨质疏松症的药物做出反应。我们试图了解雌激素如何控制免疫系统的关键调节细胞的发育和功能，称为树突状细胞和B细胞，在自身免疫性疾病全身性红斑狼疮期间。这些知识将有助于理解为什么自身免疫性疾病优先折磨女性。