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

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

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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）通过禁用自动T辅助细胞并产生调节t来保持耐受性细胞。在全身性红斑狼疮（SLE）中，通过异常激活和 DCS的稳态。在健康方面，DC通过Toll样受体从非自我和感染的组织中辨别自我（TLR）。然而，在SLE中，由自身抗体（自动抗体）和核复合物（IC）（ICS）抗原（AGS）通过TLR 7和9，激活髓样DC（MDC）并刺激浆细胞样DC （PDC）制作大量干扰素-Alpha（IFN-A），该阿尔法会返回以增强MDC的激活和自动反应性淋巴细胞。女性性类固醇与SLE发病机理有关，因为1）九十名患者是女性； 2）SLE患者显示雌激素（E）活性增加和孕酮降低（PG）和雄激素活性； 3）在SLE动物模型中，疾病会因E加剧； 4）E有直接对B细胞和DC的刺激作用。相比之下，PG是一种免疫抑制性女性类固醇。如何女性性类固醇，尤其是PG，调节直流功能和狼疮自身免疫性知之甚少。我们已经表明，PG抑制了小鼠PDC抑制TLR诱导的IFN-A产生，这表明PG可以调节狼疮疾病。确实，我们的新初步数据表明，连续PG处理显着狼疮易发的NZB X NZW F1（NZB/W）小鼠的死亡率和肾炎降低。我们现在假设 PG和E通过DC的差异调节对狼疮疾病的发展有相反的影响功能。为了测试这一点，我们将比较E和PG对DC细胞因子生产，迁移和T的影响正常C57BL/6（B6）小鼠中的细胞刺激。询问DC功能的激素调节是否是在狼疮小鼠中的操作和正常 B6背景上的自发狼疮。 B6.SLE1.SLE2.SLE2.SLE3三重高基因（B6.TC）模型紧密重构女性促抗DSDNA ABS的NZB/W表型，肾小球肾炎和死亡。我们将利用该模型，旨在回答两个重要的遗传研究问题：1）单独对DC的PG影响足以调节类似狼疮的自身免疫性； 2）做内源性PG调节DC和疾病发展？这些拟议的研究将提供关键的见识进入SLE疾病发展的激素调节。而且，他们将确定新颖的治疗性 SLE患者的治疗和预防疾病发展的方法。