CD4+CD25+Treg细胞在牙龈卟啉单胞菌诱导动脉粥样硬化中的作用研究

CD4+CD25+Treg (Treg) cells may play a crucial role in autoimmune reaction during atherosclerosis (AS) development. Porphyromonas gingivalis (Pg) can induce cross-reaction against endothelial cells via Heat Shock Protein 60 (HSP60) and results in cellular autoimmune damage. This mechanism is the key point in the relationship between periodontitis and AS. However, the role of Treg cell in this process is still largely unknown. Our previous study demonstrated that oral inoculation of Pg caused AS plaque with larger size and more severity, and the number of Treg cells reduced in AS patients complicated with periodontitis, indicating Treg cells may participate in AS induced by Pg-related periodontitis. In our project, we will examine the level of Treg cells in periopheral blood of Pg-infected AS patients to analyze the potential role of Treg in the relationship between periodontitis and AS; Furthermore, we will explore the effect of Treg upregulation or downregulation on the formation of AS plaque in Pg-infected animal models. Finally, we will induce immune tolerance in Pg HSP60 specific T cells using corresponding epitope oligopeptide to elucidate the potential application of upregulating specific Treg cells as an intervention of Pg-induced AS .This project will demostrate the role of Treg cells in AS development induced by Pg infection, thus contribute to the design of novel intervention of AS by providing new insight into the mechanism of Pg-related AS.

CD4+CD25+Treg细胞（以下简称Treg）是动脉粥样硬化(AS)自身免疫反应中的关键性因素之一。牙龈卟啉单胞菌（Pg）通过热休克蛋白60（HSP60）与血管内皮细胞产生交叉反应，激发自身细胞免疫损害，是牙周炎与AS关系中的关键性问题，但Treg细胞在其中的意义尚不清楚。我们前期研究证实，口腔感染Pg后AS斑块面积加大、病变更为严重，预实验提示牙周炎合并AS患者Treg细胞水平下降，提示Treg细胞可能在Pg参与的牙周炎诱导AS中有重要作用。本项目通过检测Pg感染的AS患者外周血Treg水平，分析其在牙周炎与AS发病中的相关性；利用动物模型分析上调和下调Treg细胞对Pg诱发AS形成的影响；并以诱导PgHSP60特异性T细胞表位短肽免疫耐受为手段，探讨提高特异性Treg细胞在干预Pg诱导AS中的意义。本项目通过对Treg细胞在Pg参与AS作用的研究，将为AS干预新途径建立理论基础。

慢性牙周炎是一种常见的口腔慢性感染性疾病，慢性牙周炎的主要致病菌牙龈卟啉单胞菌（Pg）在慢性牙周炎与AS的相互关系中起到至关重要的作用。CD4+CD25+Treg细胞是动脉粥样硬化自身免疫反应中的关键性因素之一。Th17细胞和Treg细胞的分化决定了Th17/Treg的平衡，也调控着机体的免疫平衡。通过本研究，我们发现牙周炎合并动脉粥样硬化患者外周血Treg数目和功能均降低，Th17细胞上调，提示Pg与AS病变中Th17/Treg失衡的相关性。我们还发现，II型遗传型可能是Pg与AS Treg下调关系中的主要遗传型。进一步，我们通过动物实验证实，Pg可能通过影响Th17/Treg平衡改变斑块的稳定性，体外研究显示，Pg对Th17和Treg的影响过程可能是Pg通过激活APC，促进初始T细胞分化为Th17细胞，抑制分化为Treg细胞。此外，中药黄连素具有良好的抗炎和抑菌效果，5ug/ml 黄连素即可抑制Pg刺激的巨噬细胞分泌细胞因子，随着黄连素浓度的升高，31.3ug/ml时即可明显抑制Pg生长。除了抑菌和抑炎作用外，黄连素还促进骨髓间充质干细胞的成骨分化，可能通过b-caternin/wnt通路干预牙周炎的分化。本项目通过对Treg细胞在Pg参与AS中的作用，可能为AS干预新途径提供理论基础。