从肠道微生物特异性代谢产物对DC诱导CD4+T细胞的作用探讨Vogt-小柳原田综合征的发病机制

Vogt-Koyanagi-Harada (VKH) disease is one of major causes for blindness. DC induced CD4+T cell immune response have been considered as the important mechanism of this disease. Previous studies have shown that gut microbiota could influence the host immune response through the microbiota-generated metabolites. Our previous study showed the dysbiosis of the gut microbiota in active VKH patients and also found a significant segregation of gut metabolite profiles between VKH patients and healthy controls. All these results suggested that gut microbiota-generated metabolites might contribute to the pathogenesis of this disease. Present study is therefore designed to investigate the effects of metabolites in VKH disease. Firstly, we will study the composition and abundance of metabolites in VKH patients and its correlation with abnormal CD4+T cell immune response. Secondly, the effect of metabolites on the function and differentiation of DC and CD4+T cells will be investigated as well as the possible mechanism. Intragastric administration of metabolites will be performed to evaluate the protective and treatment effects on experimental autoimmune uvetis (EAU) in mice. Collectively, these studies will provide a new insight into the pathogenesis of VKH disease and search for new strategies for the prevention and treatment of this disease through modulating metabolites.

Vogt-小柳原田综合征（VKH综合征）是一类常见的高致盲性眼病，DC细胞诱导的CD4+T细胞免疫反应是该病发生的重要机制。最近研究发现肠道微生物特异性代谢产物可调控宿主免疫反应。预实验已发现，VKH综合征患者体内肠道微生物特异性代谢产物的组成和结构显著改变，提示代谢产物可能参与到该病的发生。本研究以此为切入点，探讨VKH综合征患者肠道中代谢产物的组成、与患者体内异常的CD4+T细胞免疫反应的相关性，明确失调代谢产物种类及其是否与失调的免疫反应相关；探讨失调代谢产物对DC诱导CD4+T细胞分化及功能的作用及分子机制，确定其参与疾病发生的具体机制；利用动物模型探讨代谢产物对动物葡萄膜炎发生、严重程度及转归的影响及对局部和全身免疫反应的作用。通过上述研究，将有望获得肠道微生物特异性代谢产物参与VKH综合征发生的直接证据，进一步阐明VKH综合征的发病机理，为该病的预防和治疗研究提供新方向。

Vogt-小柳原田综合征(VKH综合征)是一类常见的高致盲性眼病，DC细胞诱导的CD4+T细 胞免疫反应是该病发生的重要机制。最近研究发现肠道微生物特异性代谢产物可调控宿主免疫反应。我们团队也发现，VKH综合征患者体内肠道微生物的组成和结构显著改变 。本研究VKH综合征患者肠道微生物及其代谢产物为切入点，探讨肠道微生物及其代谢产物在VKH综合征中的作用及其机制，结果发现：1.发现VKH综合征患者血清中代谢产物的组成与健康对照具有显著差异，并明确差异代谢产物为油酸及天冬氨酸；2. 发现油酸对LPS诱导的DCs的增值和成熟有抑制作用，同时能抑制DC诱导CD4+T细胞分化及功能；3. 虽未能在葡萄膜炎动物模型中验证代谢产物油酸及天冬氨酸对葡萄膜炎的防治作用呢，但我们成功在模拟无菌小鼠中建立葡萄膜炎动物模型，并利用此模型发现VKH患者肠道微生物可显著加重动物葡萄膜炎临床表现。这些研究为VKH综合征的防治提供了新靶点。