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

项目总结 Sjögren‘s是一种针对泪腺和唾液腺的自身免疫性疾病，估计有400万人受到影响 美国人。缺乏足够的早期诊断导致缺乏有效的治疗方法来阻止或 限制自身免疫过程。因此，患者在腺体广泛受损和 经历：严重的眼部和口腔干燥，有可能出现危及视力的并发症，口腔功能差 健康；可能影响几乎任何器官的腺外表现；深度疼痛和疲劳；以及 罹患淋巴瘤的风险增加。迫切需要了解有助于 泪腺和唾液腺自身免疫。我们研究的长期目标是定义 导致泪腺和唾液腺的初始炎症，以促进可靠的早期诊断和 有效的治疗靶点。IL-27是一种兼具促炎和抗炎作用的多效性细胞因子 角色取决于上下文。最近，儿童Sjögren的唾液中IL-27被证明高度升高 病人。IL-27是由p28和EB病毒诱导的3(EBI3)组成的异源二聚体细胞因子。 通过由IL-27R、α和gp130组成的异二聚体受体传递信号。它由树突状细胞产生 (DC)、单核细胞、巨噬细胞和B细胞。I型干扰素(IFN)信号可以推动IL-27的产生，但 最近的数据还表明，即使在缺乏I型干扰素刺激的情况下，IL-27也可以推动I型干扰素刺激基因的上调 I型干扰素信号。非肥胖糖尿病(NOD)小鼠自发形成外分泌腺自身免疫 与人类Sjögren相似。NOD小鼠缺乏IL-27信号，通过细胞因子IL-27p28基因敲除(KO)或 受体IL-27RαKO，可防止泪腺发炎。SjӧGREN被定义为类型I 干扰素介导的自身免疫性疾病。IFNAR1 KO雄性NOD小鼠防止泪腺发育 疾病。鉴于IL-27和I型干扰素之间复杂的相互作用，目前尚不清楚IL-27是否参与了 或增强I型干扰素反应，或者如果IL-27能够独立地介导I型干扰素反应 模特。这项建议的目的是阐明IL-27在NOD小鼠体内驱动干扰素样反应的能力 以干扰素依赖或独立的方式，以及这如何有助于泪腺自身免疫。我们的 中心假说是，IL-27可以在NOD小鼠体内驱动干扰素反应，而不依赖于干扰素的作用 泪腺发炎。在我的第一个目标中，我将定义DC衍生的IL-27上调干扰素的能力 利用体外方法在DC和T细胞中发现与Sjögren类疾病相关的特征。在我的 第二个目的是，我将在小鼠模型中以I型干扰素非依赖性的方式确定IL-27的作用。 Sjögren正在利用体内系统。完成这项研究后，我会更了解 IL-27在促进与SjӧGREN相关的干扰素依赖和非依赖反应中的作用 早期疾病机制将促进早期诊断生物标记物的发展，这将提供 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.