Monocyte Modulation in LAgP

描述(申请人提供)：局限性侵袭性牙周炎(LAgP)是一种主要影响磨牙和门牙的牙周组织炎症性疾病。LAgP是一种传染性疾病，与多种口腔病原体有关，最著名的是伴放线放线杆菌(AA)和牙龈卟啉单胞菌(PG)。然而，宿主的反应有助于疾病的进展，并可能决定疾病的模式和严重程度。多条证据表明LAgP单核细胞表现出独特的表型。例如，这些细胞对革兰氏阴性内毒素表现出夸大的反应，生物活性脂质血小板激活因子(PAF)的分解代谢减少，并产生可增强lgG2抗体反应的可溶性介质，而非牙周炎(NP)患者的单核细胞则没有这些作用。虽然LAgP和NP单核细胞均可分化为单核细胞来源的树突状细胞(DC)，但LAgP单核细胞经历这一过程的比例较高，提示LAgP的单核细胞分化向DC表型倾斜。基于这些观察，我们假设LAgP和NP单核细胞的基因表达谱可能不同，并使用微阵列分析来解决这个问题。我们的初步研究表明，&gt；600基因在两组单核细胞中的表达存在差异。其中许多与先天免疫和获得性免疫有关，包括参与Th1/Th2反应、趋化作用、抗原提呈和干扰素信号转导的基因。因此，这些最初的微阵列实验为我们提供了几个“线索”，这些“线索”将有助于进一步表征LAgP单核细胞，它们在对抗口腔病原体的免疫反应中的作用，以及它们的生物学如何既促进免疫又允许这些慢性感染持续存在。我们现在建议使用更多的定量方法来准确地比较LAgP和NP单核细胞中的基因表达。此外，还将进行生物检测，以评估基因表达变化的功能后果。LAgP单核细胞表型可能与LAgP患者的基因分型密切相关。然而，口腔细菌可以调节单核细胞生物学，这表明LAgP单核细胞与AA或PG之间的相互作用可能导致基因表达的变化。来解决这个问题。NP单核细胞将与AA或PG一起培养，并将使用微阵列方法将这些细胞中的基因表达谱与未接触细菌的NP单核细胞进行比较。总之，这些研究应该为我们提供更清楚的了解LAgP中宿主与病原体的相互作用，并潜在地提供改变这些相互作用的机制，从而控制这种慢性传染病。

DESCRIPTION (provided by applicant): Localized Aggressive Periodontitis (LAgP) is an inflammatory disorder of the periodontal tissues that primarily affects molars and incisors. LAgP is an infectious disease and has been linked to several oral pathogens, most notably Actinobacillus actinomycetemcomitans (Aa) and Porphyromonas gingivatis (Pg). However, the host response contributes to disease progression and may dictate the pattern and severity of the disease. Several lines of evidence suggest that LAgP monocytes exhibit a unique phenotype. For example, these cells exhibit exaggerated responses to gram negative LPS, reduced catabolism of the bioactive lipid platelet-activating factor (PAF), and produce soluble mediators that enhance the lgG2 antibody response, while non-periodontitis (NP) subjects monocytes do not have these effects. Although both LAgP and NP monocytes differentiate into monocyte-derived dendritic cells (DC), a higher percentage of LAgP monocytes undergo this process, suggesting that monocyte differentiation in LAgP is skewed to the DC phenotype. Based on these observations, we hypothesized that the gene expression profiles of LAgP and NP monocytes would differ and used microarray analyses to address this question. Our preliminary studies indicate that >600 genes are differentially expressed in the two groups of monocytes. Many of these are associated with innate and adaptive immunity, including genes involved in Th1/Th2 responses, chemotaxis, antigen presentation, and interferon signaling. Thus, these initial microarray experiments have provided us with several "leads" that will help in the further characterization of LAgP monocytes, their roles in the immune response against oral pathogens, and how their biology might both promote immunity and permit these chronic infections to persist. We now propose to use more quantitative methods to accurately compare gene expression in LAgP and NP monocytes. In addition, biological assays will be performed to assess the functional consequences of the changes in gene expression. It is possible that the LAgP monocyte phenotype is strictly related to the genotype of LAgP subjects. However, oral bacteria can modulate monocyle biology, suggesting that interactions between LAgP monocyles and Aa or Pg could generate the changes in gene expression. To address this issue. NP monocytes will be cultured together Aa or Pg and the microarray approach will be used Io compare gene expression profiles in these cells to NP monocytes that have not been exposed to bacteria. Together; these studies should provide us with a clearer understanding of host-pathogen interactions in LAgP and potentially with mechanisms for modifying these interactions and thereby controlling this chronic infectious disease.