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

• 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
• 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' 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

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.

项目摘要 Sjögren's是一种靶向富富（Acroimal）和唾液洗衣店的自身免疫性疾病，估计会影响400万 美国人。缺乏足够的早期诊断会导致缺乏停止或 限制自身免疫过程。这是在对腺体的广泛损害后被诊断出来的 经验：深度眼和口腔干燥，有潜力威胁视力并发症，口腔差 健康;可能影响任何器官的晶状外表现；深刻的痛苦和疲劳；和一个 淋巴瘤的风险增加。迫切需要了解有助的早期机制 泪腺和唾液腺自身免疫性。我们研究的长期目标是定义机制 导致泪和唾液手套的初始炎症，以促进可靠的早期诊断和 有效的治疗靶标。 IL-27是一种多效细胞因子，具有促炎和抗炎 角色取决于上下文。最近，在小儿Sjögren的唾液中显示IL-27高度升高 患者。 IL-27是由P28和Epstein-Barr病毒组成的异二聚体细胞因子诱导的3（EBI3），并且 通过包含IL-27Rα和GP130的异二聚体受体的信号。它是由树突状细胞产生的 （DC），单核细胞，巨噬细胞和B细胞。 I型I Interferon（IFN）信号传导可以推动IL-27的生产，但是 最近的数据还表明，即使没有，IL-27也可以驱动I型IFN刺激的基因的上调 I型IFN信号。非肥胖糖尿病（点头）小鼠赞助发展外分泌腺自身免疫性 类似于人类Sjögren的。通过细胞因子IL-27P28敲除（KO）或 受体IL-27RαKO受到保护，免受泪腺注射的影响。 sjnamegren的定义为I类 IFN介导的自身免疫性疾病。 IFNAR1 KO雄性点头小鼠受到保护免受泪腺的发展 疾病。鉴于IL-27和I型干扰素之间的复杂相互作用，IL-27是否有助于 或增强I型IFN响应或IL-27是否可以独立介导I类IFN类型响应 模型。该提案的目的是阐明IL-27在NOD小鼠中驱动IFN样反应的能力 以IFN依赖性或独立的方式以及如何促进泪腺自身免疫性。我们的 中心假设是IL-27可以在与IFN无关的NOD小鼠中驱动IFN反应 致泪腺炎症。在我的第一个目标中，我将定义DC派生的IL-27更新IFN的能力 在DC和T细胞中使用体外方法的Sjögren样疾病相关的签名。在我的 第二个目的，我将以I型IFN非依赖性方式定义IL-27的效果 Sjögren利用体内系统。这项研究完成后，我将对 IL-27在促进与Sjnamegren相关的IFN依赖性和非依赖性响应中的作用。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，这将提供 早期干预和潜在治疗靶标的机会。