表皮微生态调节皮肤免疫系统在银屑病中的机制与临床干预的研究

The interaction between epidermal microecology and skin immune system is believed to be the most important factor in the development of psoriasis. IL-17 is the major pathogenic cytokine of the disease . During our long term study on the relationship between infection and psoriasis, cutaneous streptococcal DNA was shown to induce an abnormal activation of T cells and that dermal γδT cells are the major source of pathogenic IL-17. Moreover, we revealed that bacterial pathogen promote the production of IL-17 from dermal γδT cells and give B17 cell ( CD19intCD38+B cell ) the ability to secrete IL-17 in vivo. It has been reported that dermal innate lymphoid cells 3(ILC3) and neutrophils also produce IL-17. The question is what caused the disturbance in the skin immune system to induce the production of pathogenic IL-17 in psoriasis. Is it due to an abnormal skin microbiome? The aims of this project are to analyze the distribution pattern of psoriatic skin microorganisms with high-throughput sequencing, to search for corresponding biomarkers with metabonomics, and to establish a hypothesis: "the disturbance of skin barrier and cutaneous microbiome is initial factor resulting in psoriasis".

表皮微生态与皮肤免疫系统的相互作用在银屑病的发生与发展中是最为重要的。IL-17是银屑病关键性致病性细胞因子。课题组已发现链球菌DNA诱导T细胞活化；皮损IL-17来源于γδ T细胞，在细菌等刺激下产生IL-17显著提高；B17细胞（CD19intCD38+B细胞）在细菌、真菌的环境中也分泌IL-17。近报道皮肤中的ILC3和中性粒细胞也产生IL-17。导致银屑病皮肤免疫系统紊乱、产生IL-17的“源头”在哪里？是表皮菌群的异常？该项目拟明确银屑病表皮菌群特点，通过代谢组学寻找生物标志物，建立“皮肤屏障破坏、皮肤微生物菌群改变是银屑病发生、发展的始动因素”的假说。

表皮微生态与皮肤免疫系统的相互作用在银屑病的发生与发展中是最重要因素。本项目拟明确银屑病表皮菌群特点，建立中国人群银屑病表皮微生态数据库，并通过代谢组学寻找新的生物标志物。本研究通过对皮肤菌群定量PCR检测及高通量测序，发现银屑病皮损区微生物负荷增高，而菌群的多样性降低；棒状杆菌属是疾病相关的优势菌，丙酸杆菌属为缺失菌。小鼠细菌定植实验证明棒状杆菌具有活化皮肤局部免疫系统，促进皮肤及引流淋巴结中γδT 细胞产生IL-17的作用。通过液质联用方法发现8条异常的代谢通路（精氨酸与脯氨酸代谢通路，缬氨酸、亮氨酸和异亮氨酸的生物和降解，谷胱甘肽代谢通路）；4个异常代谢物（鸟氨酸、次黄嘌呤、巴豆酸和壬二酸）与银屑病相关。本研究初步建立“皮肤屏障破坏、皮肤微生物菌群改变—IL17产生—银屑病发生、发展”的假说。为通过保护皮肤屏障、调整表皮共生菌的种类或比例，开发银屑病有益菌的外用制剂奠定理论基础。