Type I interferon dependent and independent roles of IL-27 in Sjogren's

项目摘要 干燥综合症是一种自身免疫性疾病，主要针对泪腺和唾液腺，估计影响400万人 美国人缺乏足够的早期诊断有助于缺乏有效的治疗来停止或 限制自身免疫过程因此，患者在腺体广泛损伤后被诊断， 经验：严重的眼部和口腔干燥，可能出现威胁视力的并发症，口腔不良 健康;几乎可以影响任何器官的腺体外表现;严重的疼痛和疲劳;以及 淋巴瘤的风险增加。有一个关键需要了解的早期机制，有助于 泪腺和唾液腺自身免疫。我们研究的长期目标是确定 导致泪腺和唾液腺的初始炎症，以促进可靠的早期诊断， 有效的治疗靶点。IL-27是一种多效性细胞因子，具有促炎和抗炎作用。 角色取决于上下文。最近，IL-27被证明在儿童舍格伦的唾液中高度升高， 患者IL-27是由p28和EB病毒诱导的3（EBI 3）组成的异二聚体细胞因子， 通过包含IL-27 R α和gp 130的异二聚体受体发出信号。它是由树突状细胞产生的 (DCs)、单核细胞、巨噬细胞和B细胞。I型干扰素（IFN）信号传导可以驱动IL-27的产生，但 最近的数据还表明，即使在缺乏IL-27的情况下，IL-27也可以驱动I型IFN刺激基因的上调。 I型IFN信号传导。非肥胖糖尿病（NOD）小鼠自发发生外分泌腺自身免疫 类似于人类的干燥综合征通过细胞因子IL-27 p28敲除（KO）或 受体IL-27 R α KO，可防止泪腺炎症的发生。干燥综合征被定义为I型 IFN介导的自身免疫性疾病。保护IFNAR 1 KO雄性NOD小鼠免于泪腺发育 疾病鉴于IL-27和I型干扰素之间复杂的相互作用，尚不清楚IL-27是否有助于 或增强I型IFN应答，或者如果IL-27可以独立地介导I型IFN-型应答， 模型本研究的目的是阐明IL-27在NOD小鼠中驱动IFN样应答的能力 以IFN依赖或独立的方式以及其如何促进泪腺自身免疫。我们 中心假设是IL-27可以驱动NOD小鼠中的IFN应答，而不依赖于IFN， 与泪腺炎症有关在我的第一个目标中，我将确定DC衍生的IL-27上调IFN-γ的能力。 利用体外方法在DC和T细胞中检测与干燥样疾病相关的信号。在我 第二个目的，我将在一个小鼠模型中以I型IFN-依赖的方式确定IL-27的作用。 舍格伦在使用体内系统完成这项研究后，我将有一个更大的了解， IL-27在促进与干燥综合征相关的IFN依赖性和非依赖性应答中的作用。定义这些 早期疾病机制将促进早期诊断生物标志物的发展， 早期干预的机会和潜在的治疗目标。

PROJECT SUMMARY Sjögren’s, an autoimmune disease that targets the lacrimal and salivary glands, is estimated to affect 4 million Americans. The absence of adequate early diagnostics contributes to the lack of effective therapies to halt or limit the autoimmune process. Thus, patients are diagnosed after extensive damage to the glands and experience: profound ocular and oral dryness with potential for vision-threatening complications, poor oral health; extra-glandular manifestations that may affect nearly any organ; profound pain and fatigue; and an increased risk of lymphoma. There is a critical need to understand the early mechanisms that contribute to lacrimal and salivary gland autoimmunity. The long-term goal of our research is to define the mechanisms that lead to the initial inflammation of the lacrimal and salivary glands to promote reliable early diagnostics and effective therapeutic targets. IL-27 is a pleiotropic cytokine with both proinflammatory and anti-inflammatory roles depending on context. Recently, IL-27 was shown to be highly elevated in the saliva of pediatric Sjögren patients. IL-27 is a heterodimeric cytokine composed of p28 and Epstein-Barr virus Induced 3 (EBI3) and signals through a heterodimeric receptor which comprises IL-27Rα and gp130. It is produced by dendritic cells (DCs), monocytes, macrophages, and B cells. Type I interferon (IFN) signaling can drive IL-27 production, but recent data also suggest IL-27 can drive upregulation of type I IFN-stimulated genes even in the absence of type I IFN signaling. Nonobese diabetic (NOD) mice spontaneously develop exocrine gland autoimmunity similar to human Sjögren’s. NOD mice lacking IL-27 signals, by either the cytokine IL-27p28 knock-out (KO) or receptor IL-27Rα KO, are protected from developing lacrimal gland inflammation. Sjӧgren’s is defined as type I IFN mediated autoimmune disease. IFNAR1 KO male NOD mice are protected from developing lacrimal gland disease. Given the complex interplay between IL-27 and type I interferons, it is unknown if IL-27 contributes to or augments the type I IFN response or if IL-27 can independently mediate the type I IFN-type response in this model. The objective of this proposal is to elucidate the ability of IL-27 to drive IFN-like responses in NOD mice in an IFN-dependent or independent manner and how that contributes to lacrimal gland autoimmunity. Our central hypothesis is that IL-27 can drive an IFN response in NOD mice independent of IFN which contributes to lacrimal gland inflammation. In my first aim, I will define the ability of DC derived-IL-27 to upregulate the IFN signature associated with Sjögren’s-like disease in both DCs and T cells utilizing in vitro methods. In my second aim, I will define the effects of IL-27 in a type I IFN-independent manner in a mouse model of Sjögren’s utilizing an in vivo system. Upon completion of this study, I will have a greater understanding of the role of IL-27 in promoting both IFN-dependent and -independent responses related to Sjӧgren’s. Defining these early disease mechanisms will promote development of early diagnostic biomarkers, which will provide opportunities for early interventions and potential therapeutic targets.