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

• 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
• 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' 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

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）通过禁用自身反应性 T 辅助细胞并生成调节性 T 细胞来维持耐受性。在系统性红斑狼疮 (SLE) 中，DC 的异常激活和稳态会破坏耐受性。在健康状态下，树突状细胞通过 Toll 样受体 (TLR) 区分自身与非自身组织和感染组织。然而，在 SLE 中，由自身抗体 (autoAbs) 和核抗原 (Ags) 组成的免疫复合物 (IC) 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-a)，后者进行反馈以增强 mDC 的激活和 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) 十分之九的患者是女性； 2）SLE患者表现出雌激素（E）活性升高，孕激素（Pg）和雄激素活性降低； 3) 在SLE动物模型中，E会加剧疾病； 4) E 对 B 细胞和 DC 具有直接刺激作用。相比之下，Pg 是一种免疫抑制女性性类固醇。人们对女性性类固醇（尤其是 Pg）如何调节 DC 功能和狼疮自身免疫的了解甚少。我们已经证明，Pg 可以抑制小鼠 pDC 中 TLR 诱导的 IFN-α 产生，这表明 Pg 可以调节狼疮疾病。事实上，我们的新初步数据表明，连续 Pg 治疗显着降低了狼疮易发性 NZB x NZW F1 (NZB/W) 小鼠的死亡率和肾炎。我们现在假设 Pg 和 E 通过 DC 功能的差异调节对狼疮疾病的发展产生相反的影响。为了测试这一点，我们将比较 E 和 Pg 对正常 C57BL/6 (B6) 小鼠 DC 细胞因子产生、迁移和 T 细胞刺激的影响。为了询问狼疮小鼠中 DC 功能的激素调节是否有效且正常，我们将比较 B6 小鼠中的 DC 功能与 B6 背景下自发性狼疮模型中的 DC 功能。 B6。 Sle1.Sle2.Sle3 三重同源 (B6.TC) 模型紧密重建了女性主导的抗 dsDNA Abs、肾小球肾炎和死亡率的 NZB/W 表型。我们将利用该模型进行遗传学研究，旨在回答两个重要问题：1）仅 Pg 对 DC 的作用是否足以调节狼疮样自身免疫？ 2) 内源性 Pg 是否调节 DC 和疾病发展？这些拟议的研究将为系统性红斑狼疮疾病发展的激素调节提供重要的见解。此外，他们还将确定治疗和预防 SLE 患者疾病发展的新治疗方法。