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

IL-27 在干燥病中的 I 型干扰素依赖性和独立作用

基本信息

批准号：
10678363
负责人：
Ivy Lynne Debreceni
金额：
$ 3.53万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2024-05-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10678363
关键词：
Address Affect American Anti-Inflammatory Agents Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Childhood Coculture Techniques Complex Data Dendritic Cells Development Diagnosis Diagnostic Diagnostic tests Disease Disease Progression Dry Eye Syndromes Dryness Early Intervention Exocrine Glands Family Fatigue Genes Gland Goals Human Human Herpesvirus 4 IFNAR1 gene IL6ST gene Immune system In Vitro Inbred NOD Mice Inflammation Inflammatory Inflammatory Response Interferon Type I Interferon alpha Interferons Interleukin-10 Interleukin-12 Interleukin-6 Knock-out Lacrimal gland structure Lymphoma Macrophage Measures Mediating Methods Modeling Mus Oral Oral health Organ Outcome Pain Patients Production Regulatory T-Lymphocyte Reporter Research Risk Role STAT1 gene STAT3 gene Saliva Salivary Glands Signal Transduction Sjogren&apos s Syndrome System T-Lymphocyte Testing Up-Regulation Vision Wild Type Mouse Xerostomia autoimmune rheumatologic disease chronic autoimmune disease cytokine diagnostic biomarker effective therapy experience in vivo male member monocyte mouse model prevent receptor response therapeutic target therapeutically effective

项目摘要

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.

项目概要干燥病是一种针对泪腺和唾液腺的自身免疫性疾病，估计影响 400 万人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停止。限制自身免疫过程因此，患者在腺体和细胞受到广泛损伤后被诊断出来。经验：严重的眼部和口腔干燥，可能会出现威胁视力的并发症，口腔状况不佳健康；可能影响几乎任何器官的腺外表现；以及迫切需要了解导致淋巴瘤的早期机制。我们研究的长期目标是确定泪腺和唾液腺自身免疫的机制。导致泪腺和唾液腺的最初炎症，以促进可靠的早期诊断和 IL-27 是一种具有促炎和抗炎作用的多效性细胞因子。最近，IL-27 在儿童干燥症患者唾液中的水平显着升高。 IL-27 是一种由 p28 和 Epstein-Barr 病毒诱导 3 (EBI3) 组成的异二聚体细胞因子。通过包含 IL-27Rα 和 gp130 的异二聚体受体发出信号，它由树突状细胞产生。 (DC)、单核细胞、巨噬细胞和 B 细胞可以驱动 IL-27 的产生。最近的数据还表明，即使在缺乏 I 型 IFN 刺激基因的情况下，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) 小鼠自发产生外分泌腺自身免疫。与缺乏 IL-27 信号的人类 Sjögren 小鼠相似，通过细胞因子 IL-27p28 敲除 (KO) 或受体 IL-27Rα KO 可以防止发生泪腺炎症，被定义为 I 型。 IFN 介导的自身免疫性疾病 IFNAR1 KO 雄性 NOD 小鼠可免受泪腺发育。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 是否会导致疾病。或增强 I 型 IFN 反应，或者 IL-27 是否可以独立介导 I 型 IFN 型反应该模型的目的是阐明 IL-27 在 NOD 小鼠中驱动 IFN 样反应的能力。以干扰素依赖或独立的方式，以及它如何促进泪腺自身免疫。中心假设是 IL-27 可以在 NOD 小鼠中独立于 IFN 驱动 IFN 反应，这有助于在我的第一个目标中，我将定义 DC 衍生的 IL-27 上调 IFN 的能力。在我的体外方法中，在 DC 和 T 细胞中发现了与干燥病相关的特征。第二个目标，我将在小鼠模型中以 I 型 IFN 独立的方式定义 IL-27 的作用完成这项研究后，我将对 Sjögren 使用体内系统有更深入的了解。 IL-27 在促进与干燥相关的 IFN 依赖性和非依赖性反应中的作用。早期疾病机制将促进早期诊断生物标志物的开发，这将提供早期干预和潜在治疗目标的机会。