Progesterone and Estrogen Differentially Regulate DC Functions in Lupus Autoimmun

描述（由申请人提供）：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。在系统性红斑狼疮（SLE）中，耐受性通过DC的异常激活和稳态被打破。在健康状态下，DC通过Toll样受体（TLR）将自身与非自身和感染组织区分开。然而，在SLE中，由自身抗体（autoAb）和核抗原（Ag）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）以产生大量干扰素-α（IFN-α），其反馈以增强mDC和自身反应性淋巴细胞的激活。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，E使疾病恶化;和4）E对B细胞和DC具有直接刺激作用。相反，Pg是一种免疫抑制性雌性类固醇。女性性类固醇，特别是前列腺素，如何调节DC功能和狼疮自身免疫性知之甚少。我们已经证明Pg抑制小鼠中TLR诱导的pDCs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治疗显着降低死亡率和肾炎狼疮倾向NZB x NZW F1（NZB/W）小鼠。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具有相反的作用。为了验证这一点，我们将比较E和Pg对正常C57 BL/6（B6）小鼠中DC细胞因子产生、迁移和T细胞刺激的影响。要问是否激素调节的DC功能是可操作的和正常的狼疮小鼠，我们将比较DC功能在B6小鼠与自发性狼疮模型的B6背景。B6。Sle1.Sle2.Sle3三重同源（B6.TC）模型紧密地重建了女性占优势的抗dsDNA抗体、肾小球肾炎和死亡率的NZB/W表型。我们将利用这一模型的遗传学研究，旨在回答两个重要的问题：1）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和疾病的发展？这些拟议的研究将提供关键的洞察激素调节SLE疾病的发展。此外，他们将确定新的治疗方法，用于治疗和预防SLE患者的疾病发展。

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.