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

项目总结

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.