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Progesterone & Estrogen Differentially Regulate DC Function in Lupus Autoimmunity

黄体酮

基本信息

批准号：
8309418
负责人：
Grant Hughes
金额：
$ 12.2万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-16 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309418
关键词：
Adoptive Transfer Androgens Animal Disease Models Antigen-Antibody Complex Antigens Antiviral Response Apoptotic Autoantibodies Autoimmune Responses Autoimmunity B-Lymphocytes Back CD4 Positive T Lymphocytes Cell Differentiation process Cell Survival Cell physiology Cells DNA Data Defect Dendritic Cells Dendritic cell activation Development Disease Disease model Estrogens Exhibits Feeds Female Fostering Genetic Genetic Recombination Glomerulonephritis Gonadal Steroid Hormones Health Helper-Inducer T-Lymphocyte Homeostasis Hormonal Hormones Human Immunity Immunoglobulin Class Switching Immunosuppressive Agents Incidence Interferon-alpha Lupus Lymphocyte Lymphoid Tissue Mediating Mediator of activation protein Menarche Menopause Modeling Mus Myasthenia Gravis Myelogenous Natural Immunity Nephritis Nuclear Nuclear Antigens Nucleic Acids Pathogenesis Pathway interactions Patients Phenotype Population Pregnancy Process Production Progesterone RNA Receptor Activation Receptor Signaling Regulation Regulatory T-Lymphocyte Research Design Role SLEB1 gene SLEB2 gene SLEB3 gene Serum Signal Transduction System Systemic Lupus Erythematosus T-Lymphocyte Testing Therapeutic Tissues Toll-like receptors Woman adaptive immunity autoreactive B cell base congenic cytokine disorder prevention hormone regulation human TLR7 protein inhibitor/antagonist insight interferon regulatory factor-7 interleukin-12 subunit p40 lupus-like migration mortality novel therapeutic intervention pathogen reconstitution research study response sex

项目摘要

Dendritic cells (DCs) maintain tolerance by disabling autoreactive T helper cells and generating regulatory T cells. In systemic lupus erythematosus (SLE), tolerance is broken through aberrant activation and homeostasis of DCs. In health, DCs discern self from non-self and infected tissues via toll-like receptors (TLRs). In SLE, however, immune complexes (ICs) comprised of autoantibodies (autoAbs) and nuclear antigens (Ags), through TLRs 7 and 9, activate myeloid DCs (mDCs) and stimulate plasmacytoid DCs (pDCs) to make large amounts of interferon-alpha (IFN-a), which feeds back to enhance activation of mDCs and autoreactive lymphocytes. Female sex steroids are implicated in SLE pathogenesis because 1) nine out of ten patients are female; 2) SLE patients show increased estrogen (E) activity and decreased progesterone (Pg) and androgen activity; 3) in SLE animal models, disease is exacerbated by E; and 4) E has direct stimulatory effects on B cells and DCs. In contrast, Pg is an immunosuppressive female sex steroid. How female sex steroids, particularly Pg, regulate DC functions and lupus autoimmunity is poorly understood. We have shown that Pg suppresses TLR-induced IFN-a production by pDCs in mice, which suggested Pg could regulate lupus disease. Indeed, our new preliminary data show that continuous Pg treatment significantly decreased mortality and nephritis in lupus-prone NZB x NZW F1 (NZB/W) mice. We now hypothesize that Pg and E have opposing effects on lupus disease development through differential regulation of DC functions. To test this, we will compare the effects of E and Pg on DC cytokine production, migration, and T cell stimulation in normal C57BL/6 (B6) mice. To ask whether hormonal regulation of DC functions is operational and normal in lupus mice, we will compare DC functions in B6 mice with those in a model of spontaneous lupus on a B6 background. The B6.Sle1.Sle2.Sle3 triple congenic (B6.TC) model closely reconstitutes the NZB/W phenotype of female-predominant anti-dsDNA Abs, glomerulonephritis and mortality. We will take advantage of this model with genetic studies designed to answer two important questions: 1) are Pg effects on DCs alone sufficient to regulate lupus-like autoimmunity; and 2) does endogenous Pg regulate DCs and disease development? These proposed studies will provide critical insight into hormonal regulation of SLE disease development. Moreover, they will identify novel therapeutic approaches for treatment and prevention of disease development in SLE patients.

树突状细胞（DC）通过使自身反应性T辅助细胞失活并产生调节性T细胞来维持耐受性。细胞在系统性红斑狼疮（SLE）中，耐受性通过异常激活而被打破， DC的稳态。在健康状态下，DCs通过Toll样受体区分自身与非自身和感染组织（TLR）。然而，在SLE中，由自身抗体（autoAb）和核抗体组成的免疫复合物（IC）可被称为免疫复合物（IC）。抗原（Ag）通过TLR 7和9激活髓样DC（mDC）并刺激浆细胞样DC （pDC）产生大量干扰素-α（IFN-α），其反馈以增强mDC的活化和自身反应性淋巴细胞。女性性类固醇与SLE发病机制有关，因为：1） SLE患者雌激素（E）活性升高，孕酮（P）活性降低 (Pg)和雄激素活性; 3）在SLE动物模型中，E加重疾病;和4）E具有直接的对B细胞和DC的刺激作用。相反，Pg是一种免疫抑制性雌性类固醇。如何女性性类固醇，特别是Pg，调节DC功能和狼疮自身免疫性知之甚少。我们已经表明Pg抑制小鼠中TLR诱导的pDC产生IFN-α，这表明Pg可以调节狼疮疾病。事实上，我们新的初步数据表明，连续Pg治疗显着在狼疮倾向的NZB x NZW F1（NZB/W）小鼠中降低死亡率和肾炎。我们现在假设 Pg和E通过对DC的差异调节对狼疮疾病的发展具有相反的作用功能协调发展的为了验证这一点，我们将比较E和Pg对DC细胞因子产生、迁移和T细胞增殖的影响。正常C57 BL/6（B6）小鼠中的细胞刺激。要问是否激素调节DC功能，在狼疮小鼠中，我们将比较B6小鼠中的DC功能与狼疮小鼠模型中的DC功能。 B6背景的自发性狼疮B6.Sle1.Sle2.Sle3三重同源（B6.TC）模型重建女性占主导地位的抗dsDNA抗体的NZB/W表型，肾小球肾炎和 mortality.我们将利用这一模型与遗传研究，旨在回答两个重要的问题：1）Pg单独对DCs的作用是否足以调节狼疮样自身免疫; 2）Pg对DCs的作用是否足以调节狼疮样自身免疫？内源性前列腺素调节树突状细胞和疾病发展？这些拟议的研究将提供关键的见解 SLE疾病发展的激素调节。此外，他们将确定新的治疗方法，治疗和预防SLE患者疾病发展的方法。