Understanding uveitis in a multi-system disease model of spondyloarthropathy

描述（由申请人提供）：脊椎关节病（spa）是一种慢性、免疫介导的炎症性疾病，其中强直性脊柱炎（AS）最为常见。平均而言，约有1%的人患有SpA。葡萄膜炎是此类疾病中常见的关节外器官。事实上，as相关性葡萄膜炎是患者中最常见的葡萄膜炎类型。然而，葡萄膜炎的发病机制尚不清楚，部分原因是目前缺乏实验模型。我们最近发现葡萄膜炎发生在已建立的蛋白多糖诱导的关节炎（PGIA）小鼠模型中，其中对软骨蛋白多糖的实验性免疫导致进行性多关节炎和脊柱炎。据我们所知，这是第一个疾病的小鼠模型，它将使我们能够研究临床上出现的关节炎和脊柱炎患者眼睛对疾病的易感性。此外，我们的数据支持眼睛与关节和脊柱疾病的不同持续机制，因为th1相关细胞因子IFNg的缺乏显著加剧了眼膜炎，但降低了关节炎和脊柱炎的严重程度。在缺乏IFNg的情况下，Th17反应似乎在葡萄膜炎中起主导作用。这些观察结果可能对我们如何治疗多系统疾病的葡萄膜炎产生巨大影响。这里提出的研究将告诉我们与葡萄膜炎有关的疾病机制，对我们理解SpA的发展也很重要。我们建议确定T细胞效应反应在葡萄膜炎发病机制中的功能，并确定它们与关节和脊柱疾病的关系。我们将确定眼睛的机制是否可以与关节和脊柱区分开来，并将探索IFNg在控制眼睛对疾病的敏感性和Th17反应中的调节作用。我们将探讨治疗干预如何影响特定器官。该模型将是一个有价值的工具，用于发现控制眼病的机制，因为它与疾病的系统性形式有关，并且对理解SpA的发病机制也有相当大的意义。

DESCRIPTION (provided by applicant): Spondyloarthropathies (SpAs) are chronic, immune-mediated, inflammatory disorders, of which ankylosing spondylitis (AS) is the most common. On average SpA affects ~1% of the general human population. Uveitis is a frequent extra-articular organ afflicted in such diseases. Indeed AS-associated uveitis is the most frequently observed type of uveitis in patients. Yet, the pathogenesis of uveitis is poorly understood in part due to a current lack of experimental models. We have recently discovered that uveitis occurs in an established mouse model of proteoglycan-induced arthritis (PGIA), wherein experimental immunity to the cartilage proteoglycan results in progressive polyarthrits and spondylitis. To our knowledge this is the first murine model of disease that will allow us to study the eye's susceptibility to disease in presence of arthritis and spondylitis as occurs clinically in patients. Moreover, our data support different ongoing mechanisms of disease in the eye versus joint and spine as deficiency in the Th1-related cytokine, IFNg, markedly exacerbates uveitis but diminishes the severity of arthritis and spondylitis. Th17 response appears to play a dominant role in uveitis in the absence of IFNg. These observations could have a huge impact on how we treat uveitis in a multi-system disease. The studies proposed here will inform us about mechanisms involved in the uveitis aspect of disease and will be important to our understanding of SpA development as well. We propose to identify the function of T cell effector responses in the pathogenesis of uveitis and define how they relate to joint and spine disease. We will determine whether mechanisms of the eye can be distinguished from the joint and spine and will explore the regulatory role for IFNg in controlling the eye's sensitivity to disease and Th17 response. We will explore how therapeutic intervention affects specific organs. This model will be a valuable tool for discovery of mechanisms controlling eye disease as it relates to systemic form of disease and will have considerable implications for understanding SpA pathogenesis as well.