Oral Pathogens and Dendritic Cell Subsets

描述(申请人提供)：树突状细胞(DC)是皮肤和粘膜的“哨兵”，在这些组织中巡逻，寻找入侵的细菌和病毒。在其未成熟阶段，树突状细胞具有独特的抗原捕获能力，表达多种清道夫受体和其他模式识别受体。随着树突状细胞成熟并迁移到淋巴结，树突状细胞下调抗原捕获受体，上调抗原呈递受体。成熟的DC是最有效的抗原提呈细胞，也是唯一能够刺激幼稚T细胞的APC。树突状细胞亚群在慢性牙周炎(CP)中的作用；然而，在这些资助的研究之前，人们基本上不知道。到目前为止，我们实验室已经发表了11篇论文，其中3篇正在准备中，这可以归功于2005年11月发布的R01。我们的研究表明，牙龈未成熟DC在识别和摄取牙龈卟啉单胞菌(Pg)以及成熟DC与牙龈固有层中的CD4T细胞结合方面发挥着重要作用。CP患者牙周固有层中的主要DC是表达DC特异性ICAM-3非整合素结合阳性(DC-SIGN)的DC。DC-SIGN是C型凝集素家族的一员；它是一种II型跨膜受体，被包括HIV-1、幽门螺杆菌、肺炎克雷伯菌、结核杆菌、皮下利什曼原虫和白念珠菌在内的主要人类病原体用作逃逸机制。针对DC-SIGN的病原体的一个中心特征是它们引起的感染可以持续终生(如CP)，其次，这些病原体对Th1/Th2平衡的操纵是其持久性的核心。我们有证据表明PG及其PAMPs可能靶向DC上的C型凝集素受体，并调节Th1-Th2平衡；我们推测这与PG在口腔粘膜中的持久性有关。因此，这些后续研究将集中在C型凝集素和其他模式识别受体(PRR)在PG及其PAMPs的摄取/识别中的作用以及MDDC在细胞内路由中的作用，以及这如何调节获得性免疫反应，特别是T调节细胞的诱导。

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are the "sentinels" of the skin and mucosa, patrolling these tissues for invading bacteria and viruses. In their immature stage, DCs are uniquely equipped for antigen (Ag) capture, expressing a large variety of scavenger receptors and other pattern recognition receptors. As they mature and migrate to the lymph nodes, DCs downregulate Ag-capture receptors and upregulate Ag-presenting receptors. Mature DCs are the most efficient Ag-presenting cells (APCs), and the only APCs capable of stimulating naive T cells. The role of dendritic cell subpopulations in chronic periodontitis (CP); however, was largely unknown prior to these funded studies. Our lab has thus far published 11 papers, with 3 in preparation that can be credited to this R01, which terms in November of 2005. Our studies have identified an important role for gingival immature DC in the recognition and uptake of Porphyromonas gingivalis (Pg) in situ and in vitro, and for maturing DCs in engagement with CD4+ T cells in the gingival lamina propria. The principle DCs in the gingival lamina propria in CP are those that express DC-specific ICAM-3 grabbing non-integrin-positive (DC- SIGN) in CP. DC-SIGN is a member of a family of C-type lectins; it is a type II transmembrane receptor that is used as an "escape mechanism" by major human pathogens including HIV-1, Helicobacter pylori, Klebsiella pneumonia, M tuberculosis, Leishmania pifanoi and C albicans. A central feature of pathogens that target DC-SIGN is that they cause infections that can last a lifetime (i.e. such as CP) and second, that manipulation of the Th1- versus Th2-balance by these pathogens is central to their persistence. We have evidence that Pg and its PAMPs may target C-type lectin receptors on DCs and manipulate the Th1-Th2 balance; we posit that this is involved in persistence of Pg in the oral mucosa. These proposed continued studies will therefore focus on the role of C-type lectins and other pattern recognition receptors (PRR) in uptake/recognition of Pg, its PAMPs and in intracellular routing by MDDCs and how this modulates the adaptive immune response, in particular, the induction of T regulatory cells.