Oral Pathogens and Dendritic Cell Subsets

描述（由申请人提供）：树突状细胞（DC）是皮肤和粘膜的“哨兵”，巡逻这些组织以寻找入侵的细菌和病毒。在它们的未成熟阶段，DC被独特地装备用于抗原（Ag）捕获，表达多种清道夫受体和其他模式识别受体。当它们成熟并迁移到淋巴结时，DC下调Ag捕获受体并上调Ag呈递受体。成熟DC是最有效的Ag呈递细胞（APC），并且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，在很大程度上是未知的。到目前为止，我们的实验室已经发表了11篇论文，其中3篇正在准备中，可以归功于2005年11月的R 01。我们的研究已经确定了一个重要的作用，牙龈未成熟的DC在识别和摄取牙龈卟啉单胞菌（Pg）在原位和体外，并为成熟的DC与CD 4 + T细胞在牙龈固有层的参与。CP中牙龈固有层中的主要DC是在CP中表达DC特异性ICAM-3抓取非整合素阳性（DC-SIGN）的那些。DC-SIGN是C型凝集素家族的成员;它是一种II型跨膜受体，被主要的人类病原体用作“逃逸机制”，包括HIV-1、幽门螺杆菌、肺炎克雷伯菌、结核分枝杆菌、皮凡利什曼原虫和白色念珠菌。靶向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一生（即，如CP），其次，这些病原体对Th 1与Th 2平衡的操纵是它们持续存在的核心。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，并操纵Th 1-Th 2平衡;我们认为这与Pg在口腔粘膜中的持久性有关。因此，这些拟议的继续研究将集中在C型凝集素和其他模式识别受体（PRR）在摄取/识别Pg，其PAMP和MDDC的细胞内路由中的作用，以及这如何调节适应性免疫应答，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.