Progesterone and Estrogen Differentially Regulate DC Functions in Lupus Autoimmun

黄体酮和雌激素差异调节狼疮自身免疫中的 DC 功能

基本信息

批准号：
7919720
负责人：
Grant Hughes
金额：
$ 5万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-12 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7919720
关键词：
Africa Agonist Androgens Animal Disease Models Animal Model Animals Antigen-Antibody Complex Antigens Autoantibodies Autoimmune Diseases Autoimmunity B-Lymphocytes Back CD4 Positive T Lymphocytes Cell physiology Cells Data Defect Dendritic Cells Dendritic cell activation Development Disease Employee Strikes Epidemic Estrogens Exhibits Experimental Arthritis Feeds Female Fetus Genetic Glomerulonephritis Gonadal Steroid Hormones Grant HIV Health Helper-Inducer T-Lymphocyte Homeostasis Hormonal Hormones Human Human Herpesvirus 2 Immune Immunity Immunosuppressive Agents Interferon-alpha Interferons Lupus Lymphocyte Mediating Mediator of activation protein Mifepristone Modeling Mus Myelogenous Natural Immunity Nephritis Nuclear Antigens Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Population Predisposition Pregnancy Prevalence Prevention Production Progesterone Proteinuria Regulation Research Design Research Personnel Role SLEB1 gene SLEB2 gene SLEB3 gene Sex Characteristics Skin Synthetic Progestogens Systemic Lupus Erythematosus T-Lymphocyte Testing Tissues Toll-like receptors Viral Virus Woman Women&apos s Role base birth control cell motility clinically significant congenic cytokine dimorphism disorder prevention hormone regulation human TLR7 protein immune function in vivo inhibitor/antagonist insight lupus prone mice lupus-like microbial migration mortality novel therapeutic intervention programs receptor reconstitution sex

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：树突状细胞（DC）通过禁用自动反应性T辅助细胞并产生调节性T细胞来保持耐受性。在全身性红斑狼疮（SLE）中，通过异常激活和DC的稳态破坏了公差。在健康方面，DC通过Toll样受体（TLR）从非自身和感染组织中辨别自我。 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）十分之九的患者是女性； 2）SLE患者显示雌激素（E）活性增加，孕酮（PG）和雄激素活性降低； 3）在SLE动物模型中，疾病会因E加剧； 4）E对B细胞和DC具有直接的刺激作用。相比之下，PG是一种免疫抑制性女性类固醇。雌性性类固醇（尤其是PG）如何调节直流功能和狼疮自身免疫性。我们已经表明，PG抑制了PDC在小鼠中抑制TLR诱导的IFN-i-IFN-IFN的产生，这表明PG可能调节狼疮性疾病。实际上，我们的新初步数据表明，连续PG治疗可显着降低狼疮易发的NZB X NZW F1（NZB/W）小鼠的死亡率和肾炎。现在，我们假设PG和E通过DC功能的差异调节对狼疮疾病的发展有相反的影响。为了测试这一点，我们将比较正常C57BL/6（B6）小鼠中E和PG对DC细胞因子产生，迁移和T细胞刺激的影响。询问DC功能的激素调节是否在狼疮小鼠中是操作且正常的，我们将在B6背景下比较B6小鼠的DC功能与自发狼疮模型中的DC功能。 B6。 SLE1.SLE22.SLE3三重先生（B6.TC）模型紧密地重构女性 - 促剂抗DSDNA ABS的NZB/W表型，肾小球肾炎和死亡率。我们将利用该模型的遗传研究来回答两个重要问题：1）仅对DC对DC的影响就足以调节狼疮样的自身免疫性； 2）内源性PG是否调节DC和疾病发展？这些提出的研究将为SLE疾病发展的激素调节提供批判性的见解。此外，他们将确定SLE患者的治疗和预防疾病发展的新型治疗方法。