Progesterone & Estrogen Differentially Regulate DC Function in Lupus Autoimmunity

树突状细胞(DC)通过禁用自身反应性T辅助细胞和产生调节性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和 DC的动态平衡。在健康中，树突状细胞通过Toll样受体将自身与非自我和感染组织区分开来 (TLRS)。然而，在SLE中，由自身抗体(AutoAbs)和核组成的免疫复合体(IC) 抗原(AGs)通过TLR 7和9激活髓系树突状细胞(MDCs)和刺激浆细胞样树突状细胞 (PDC)产生大量干扰素-α(干扰素-a)，从而反馈增强MDCS的激活 和自身反应性淋巴细胞。女性性激素与系统性红斑狼疮的发病有关，因为1) 2)系统性红斑狼疮患者表现出雌激素(E)活性升高和孕酮降低 (PG)和雄激素活性；3)在SLE动物模型中，E加剧了疾病；4)E直接 对B细胞和DC的刺激作用。相比之下，PG是一种免疫抑制的女性性激素。多么 女性类固醇，特别是前列腺素，调节DC功能，而狼疮自身免疫知之甚少。我们 已发现PG抑制TLR诱导的小鼠pDC产生干扰素-α，这提示PG可以 规范狼疮病。事实上，我们新的初步数据显示，持续的PG治疗显著 降低易患狼疮的NZB x NZW F1(NZB/W)小鼠的死亡率和肾炎。我们现在假设 PG和E通过对DC的不同调控对狼疮疾病的发展起相反的作用 功能。为了测试这一点，我们将比较E和PG对DC细胞因子产生、迁移和T细胞的影响 正常C57BL/6(B6)小鼠的细胞刺激。询问激素对DC功能的调节是否 在狼疮小鼠中，我们将比较B6小鼠和B6小鼠的DC功能。 有B6背景的自发性狼疮。B6.Sle1.Sle2.Sle3三同基因(B6.TC)模型 重组NZB/W表型，女性为主的抗dsDNA抗体，肾小球肾炎和 死亡率。我们将利用这一模型进行基因研究，以回答两个重要的问题 问题：1)PG单独对DC的作用是否足以调节狼疮样自身免疫；以及2)是否 内源性PG调控DC和疾病发展？这些拟议的研究将提供批判性的见解 关于系统性红斑狼疮疾病发展的激素调节。此外，他们将发现新的治疗方法 治疗和预防系统性红斑狼疮患者疾病发展的方法。

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.