从NOD样受体家族（NLRs）探讨三种不同性质葡萄膜炎发病机制的异质性

Uveitis is one of leading causes of blindness.Behcet's disease,Vogt-Koyanagi-Harada disease and acute anterior uveitis are the three most common uveitis entities in China.Our studies reveal that unbalance of Th1,Th17 and Treg cells is responsible for the development of uveitis.Our recent study shows an increased NLRP3,an NOD-like receptors,in association with excessive activation of Th1 and Th17 cells in active Behcet's disease patients,suggesting an involvelment of this molecule in this disease.Our study will focus on the role of NOD-like receptors in different uveitis entities.We firstly study the expression of NOD-like receptors by PBMC and DC in the patients with different uveitis entities at various diseases activity. Secondly we will investigate the effects of NOD-like receptors on the differentiation and function of DC,Th1,Th17 and Treg cells in these patients at different disease activity.Thirdly we will examine the role of NOD-like receptors in experimental autoimmune uveitis induced in mice and their effects on Th1,Th17 and Treg cells.Finally we will investigate the association of the polymorphisms of relevant NOD-like receptors with these three uveitis entities and their clinical parameters.Collectively this project will provide a new insight into the pathogenesis of uveitis and be hopefully expected to offer a new strategy in the study of the prevention and treatment of different uveitis entities.

葡萄膜炎是一类全球性常见致盲眼病。Behcet病、VKH综合征和急性前葡萄膜炎是我国最常见和最重要的类型。我们研究发现Th1/Th17/Treg细胞失衡是它们发病的重要机制。我们最近预实验发现,NLRP3（一种NOD样受体）在活动期Behcet病患者中表达增高,并伴有Th1、Th17细胞活化，提示NOD样受体可能参与葡萄膜炎发生。本项目以NOD样受体为切入点，以这三种不同类型的葡萄膜炎为研究对象，评价它们在PBMC及DC的表达及其差异；探讨NOD样受体对DC分化及功能的影响及机制；探讨相关NOD样受体对实验性自身免疫性葡萄膜炎发生、严重程度和转归及Th1、Th17、Treg细胞的影响；探讨NOD样受体基因多态与三种葡萄膜炎的相关性及可能机制。通过上述研究将可能在NOD样受体层面阐明三种不同性质葡萄膜炎发病机制的同质性和异质性，有望为它们预防和治疗研究寻找到重要靶分子和突破口。

Behcet 病、VKH 综合征是我国致盲率最高的葡萄膜炎类型，Th17 细胞过度激活、调节性 T（Treg）细胞功能和数量异常是其发病基础，Th17/Treg 细胞失衡可上溯至树突状细胞（DC）活化及功能异常。本项目以这两种疾病为研究对象，探讨NOD样受体对 DC 活化、功能状态及Th1/ Th17/Treg细胞分化的影响及机制，从而评价其在葡萄膜炎发病中的作用。主要研究成果包括以下四个方面：1. 发现活动期VKH综合征患者PBMC中NOD1、NOD2表达水平显著高于正常人。2. 激活NOD1、NOD2可使PBMC及DC分泌促炎因子增多，并促进DC分化、成熟，从而进一步激活Th1细胞和Th17细胞。3. 发现NOD1和CIITA基因与Behcet病的遗传易感性相关。4. 另外结合国内外最新研究进展，还发现一些IL-23/IL-17通路相关分子的基因多态与BD和VKH的相关性。这些研究为这两种疾病的防治提供了新的靶点。