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）：系统性红斑狼疮（SLE）是一种自身免疫性疾病，优先影响育龄女性（9:1），表明包括性激素雌二醇在内的性别特异性因素在狼疮发病机制中发挥重要作用。狼疮小鼠模型显示出雌性小鼠疾病的自然早期表达和随后的死亡。 NZM2410 小鼠中存在的 Sle1 和 Sle3 狼疮易感位点直接增加了女性疾病的外显率，这与表明全身雌二醇升高或暴露于雌激素环境化合物会加速狼疮发展的研究一致。要了解女性多患 SLE 的机制，我们需要精确确定内源性雌激素和雌激素受体 (ER) 如何调节 B 淋巴细胞和树突状细胞 (DC) 等免疫细胞的功能，这些细胞表达 ER，并与 SLE 相关。狼疮发病机制。然而，目前研究雌激素对免疫细胞影响的模型通常涉及全身暴露于超生理水平的雌二醇或雌激素受体的整体丧失，从而造成激素失衡。雌二醇全身水平升高会导致造血祖细胞严重耗竭，从而导致 B 细胞和 DC 的数量和表型发生变化。为了规避 ER 配体对免疫细胞发育的影响，我们建议开发和使用一种新的小鼠狼疮模型，其中 ERα 表达可以在分化的 B 细胞或 DC 中被特异性消除。我们将使用慢病毒转基因将由 CD19 或 CD11c 启动子驱动的 Cre 重组酶传递给携带条件 ERalpha 等位基因的狼疮倾向 B6.Sle13 双基因小鼠。这种方法将使我们能够确定与性别敏感的 Sle1 和 Sle3 位点相关的异常 DC 或骨髓后 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。在目标 1 中，我们将确定导致雌性 B6.Sle13 双基因小鼠中促炎细胞因子产生的 DC 数量升高或过度激活的 DC 表型是否是内源性雌激素对 DC 直接作用的结果。在目标 2 中，我们将确定雌性 B6.Sle13 双基因小鼠中过渡 B 细胞亚群的扰动以及随后血清学耐受性丧失的增强是否是内源性雌激素对定型 B 细胞和/或 DC 的直接作用的结果。这种删除特定细胞类型中 ERα 的慢病毒转基因策略的成功实施将建立一个多功能模型，可用于研究 ERα 信号传导在狼疮性肾炎发展过程中任何细胞类型中的作用。公共卫生相关性人类和鼠类免疫系统的细胞能够对雌激素、植物雌激素以及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在自身免疫性疾病系统性红斑狼疮期间如何控制免疫系统关键调节细胞（称为树突状细胞和 B 细胞）的发育和功能。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。