Progesterone and Estrogen Differentially Regulate DC Functions in Lupus Autoimmun

描述(申请人提供)：树突状细胞(DC)通过禁用自身反应性T辅助细胞和产生调节性T细胞来维持耐受性。在系统性红斑狼疮(SLE)中，通过树突状细胞的异常激活和动态平衡来打破耐受性。在健康环境中，树突状细胞通过Toll样受体(Toll-like Receptor，TLRs)将自身与非自身及感染组织区分开来。然而，在SLE中，由自身抗体(AutoAbbs)和核抗原(Ags)组成的免疫复合物(IC)通过TLR7和9激活髓系树突状细胞(MDCs)并刺激浆细胞样DC(PDCs)产生大量干扰素-α(IFN-a)，从而促进MDCs和自身反应性淋巴细胞的激活。女性性激素参与了SLE的发病机制，因为1)10个患者中有9个是女性；2)SLE患者雌激素(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加重了疾病；4)E对B细胞和DC有直接刺激作用。相比之下，PG是一种免疫抑制的女性性激素。女性性激素，尤其是前列腺素，是如何调节DC功能和狼疮自身免疫的，人们知之甚少。我们发现PG抑制TLR诱导的小鼠pDCs产生的干扰素-α，提示PG对狼疮疾病有调节作用。事实上，我们的新的初步数据显示，持续的PG治疗显著降低了易患狼疮的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功能的不同调节而在狼疮疾病的发展中具有相反的作用。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DC功能的激素调节是否有效和正常，我们将B6小鼠的DC功能与B6背景下的自发性狼疮模型中的DC功能进行比较。B6。Sle1.Sle2.Sle3三基因同源(B6.TC)模型与女性为主的抗dsDNA抗体、肾小球肾炎和死亡率的NZB/W表型密切相关。我们将利用这一模型进行遗传学研究，旨在回答两个重要问题：1)PG单独对DC的影响是否足以调节狼疮样自身免疫；以及2)内源性PG是否调节DC和疾病的发展？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关键的洞察力。此外，他们还将确定治疗和预防SLE患者疾病发展的新的治疗方法。

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.