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，优先影响育龄妇女（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起重要作用。狼疮的小鼠模型在雌性小鼠中显示出疾病的自然早期表达和随后的死亡率。NZM 2410小鼠中存在的Sle 1和Sle 3狼疮易感性基因座直接增加了雌性的疾病发病率，这与显示全身雌二醇升高或暴露于雌激素环境化合物加速狼疮发展的研究一致。要了解SLE女性优势的潜在机制，需要我们精确地确定内源性雌激素和雌激素受体（ER）如何调节免疫细胞如B淋巴细胞和树突状细胞（DC）的功能，这些细胞表达ER并参与狼疮发病机制。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ER的整体损失，这会造成激素失衡。雌二醇的全身水平升高导致造血祖细胞的严重耗竭，导致B细胞和DC的数量和表型的改变。为了规避ER配体对免疫细胞发育的这些影响，我们建议开发和使用一种新的小鼠狼疮模型，其中ER α表达可以特异性地在分化的B细胞或DC中消除。我们将使用慢病毒转基因技术将由CD 19或CD 11 c启动子驱动的Cre重组酶传递给携带条件性ER α等位基因的狼疮易感B6.Sle13双基因小鼠。这种方法将使我们能够确定与性敏感Sle 1和Sle 3基因座相关的异常DC或骨髓后B细胞表型是否由内源性雌激素对B细胞或DC的直接作用介导。在目的1中，我们将确定是否升高的DC数量或过度活化的DC表型导致促炎细胞因子的产生在雌性B6.Sle13双基因小鼠中是内源性雌激素对DC的直接作用的结果。在目的2中，我们将确定是否在过渡B细胞亚群的扰动和随后增强的血清学耐受性的损失，在雌性B6.Sle 13双基因小鼠的内源性雌激素对定向B细胞和/或DC的直接作用的结果。成功实施这种慢病毒转基因策略以删除特定细胞类型中的ER α，将建立一种通用模型，可用于研究狼疮肾炎发展过程中任何细胞类型中ER α信号传导的作用。人类和小鼠免疫系统的细胞能够对雌激素、植物雌激素和用于治疗乳腺癌和骨质疏松症的药物产生反应。我们试图了解雌激素如何控制免疫系统的关键调节细胞，称为树突状细胞和B细胞，在自身免疫性疾病系统性红斑狼疮的发展和功能。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。