FDRC1 AND FOLLICULAR DENDRITIC CELL SIGNALING PATHWAYS

描述(申请人提供)：树突状细胞(DC)有助于协调和桥接先天性和获得性免疫反应。树突状细胞大多是短暂的；它们的寿命有多长，在哪里可能会影响它们是否会诱导免疫、耐受或自身免疫性疾病。DC的命运和细胞因子的产生部分受RANK(核因子-kappaB配体受体激活剂)、TRAIL(肿瘤坏死因子-α相关乳头病诱导配体)受体和与RANK配体(RANKL)和TRAIL结合的可溶性骨保护素(OPG)的调节。我们的数据表明，在没有OPG的情况下，DC细胞因子的产生和存活受到失调的调节。我们计划界定RANKL/RANK/OPG制度在规管区议会方面所扮演的角色。我们将验证OPG通过调节RANKL/RANK和TRAIL/TRAIL受体通路来调节树突状细胞存活的假设。我们将测试OPG-/-或RANK-/-DC在体外或体内的存活情况是否与野生型DC不同。在OPG-/-和RANK-/-小鼠中，将评估过表达存活蛋白Bcl-2对DC限制性CD11c启动子的影响。我们预测，通过改变体内DC的寿命，疾病、骨稳态和外周淋巴发育方面的潜在缺陷将会改变。我们还将检验这一假设，即人类未成熟DC(IDCs)和成熟DC(MDCs)在ANK/OPG/TRAIL受体通路和caspase调控方式上存在差异。接下来，我们将检验OPG调节DC亚群产生的细胞因子的分布和水平的假设。我们将确定OPG或RANK的缺失如何影响体外细胞因子的产生，并测试OPG-/-和RANK-/-小鼠的细胞因子失调是否会影响体内对内毒素(LPS)和多肽诱导的实验性自身免疫性脑脊髓炎(EAE)的反应。OPG、RANKL和TRAIL受体的表达受17-β-雌二醇(E_2)的调节。因此，我们将验证E2通过OPG依赖的途径调节多肽诱导的EAE、DC存活和细胞因子产生的假设。如果E2需要OPG才能下调EAE，我们会探讨这是否部分是由于E2对区议会的直接影响。进一步了解DC的寿命和细胞因子分泌是如何调节的，可能会为类风湿性关节炎和多发性硬化症等慢性免疫性疾病的病因和治疗带来新的见解。拟议的研究也可能有助于理解E2和OPG如何促进炎性免疫反应的发展。

DESCRIPTION (provided by applicant): Dendritic cells (DCs) help to coordinate and bridge innate and adaptive immune responses. DCs for the most part are short lived; how long they live and where may influence whether they induce immunity, tolerance or autoimmune disease. DC fate and cytokine production are regulated in part by RANK (receptor activator of NF-kappaB ligand), receptors for TRAIL (tumor necrosis factor-alpha-related papooses-inducing ligand) and the soluble 'decoy' receptor osteoprotegerin (OPG), which binds RANK ligand (RANKL) and TRAIL. Our data suggest that DC cytokine production and survival are dysregulated in the absence of OPG. We plan to define the role the RANKL/RANK/OPG system plays in regulating DCs. We will test the hypothesis that OPG regulates dendritic cell survival by modulating the RANKL/RANK and TRAIL/TRAIL receptor pathways. We will test whether OPG -/- or RANK -/- DCs differ from wild type DCs in their survival in vitro or in vivo. The effect of overexpressing the survival protein Bcl-2 on the Dc restricted CD11c promoter will be evaluated in OPG -/- and RANK -/- mice. We predict that by altering the lifespan of DCs in vivo, that underlying defects in disease, bone homeostasis and peripheral lymphoid development will be altered. We will also test the hypothesis that human immature DCs (iDCs) and mature DCs (mDCs) differ in how they are regulated by the ANK/OPG/TRAIL receptor pathways and by caspases. Next we will test the hypothesis that OPG regulates the profile and levels of cytokines produced by DC subsets. We will define how the absence of OPG or RANK affects cytokine production in vitro and test whether the cytokine dysregulation in OPG -/- and RANK -/- mice influences in vivo responses to lipopolysaccharide (LPS) and peptide-induced experimental autoimmune encephalomyelitis (EAE). The expression of OPG, RANKL and TRAIL receptors is regulated by 17-beta-estradiol (E2). Therefore, we will test the hypotheses that E2 modulates peptide-induced EAE, DC survival and cytokine production via an OPG-dependent pathway. If OPG is required for E2 to downregulate EAE, we will explore if this is due in part to direct effects of E2 on DCs. Further understanding of how DC longevity and cytokine secretion are regulated may lead to new insights into the causes of and treatments for chronic immunologic diseases like rheumatoid arthritis and multiple sclerosis. The proposed studies may also contribute to understanding of how E2 and OPG contribute to the development of inflammatory immune responses.