The Role of B Cells and B Cell Toll-like Receptors in Periodontal Disease

描述（由申请人提供）：牙周病（PD）发病机制的特点是对口腔菌群的免疫反应长期升高。多种免疫细胞类型在PD中起作用，淋巴细胞浸润感染部位在疾病进展中相对较晚。在最严重的PD患者中，牙龈病变中的大多数细胞是B细胞。这些发现表明，B细胞在PD发病中起主导作用的时间相对较晚。然而，B细胞在PD中的作用尚未在体内得到严格的证实。我们最近的研究表明，PD患者的B细胞组成性地分泌细胞因子，同时发现人类牙周病变和PD患者血液中toll样受体（TLR） 2和tlr4阳性B细胞的百分比升高。功能分析表明，B细胞TLR2和TLR4的激活通常导致促炎和破骨细胞因子的产生。此外，TLR4配体减少tlr2介导的IL-10的产生，IL-10是一种重要的抗炎细胞因子。PD患者中TLR阳性B细胞比例升高的发现，这些B细胞对TLR配体的总体促炎反应，以及PD病变中B细胞的患病率表明，B细胞TLR通过调节炎症从而导致骨质流失，在PD中发挥重要作用。由于口腔菌群提供了无数的TLR配体，我们的初步数据预测B细胞TLR在体内通过细胞因子激活直接促进炎症。尽管对人类B细胞TLR功能的进一步研究可能具有机械和临床意义，但这一研究的下一个关键步骤是明确证明B细胞和B细胞TLR在PD中发挥作用。我们假设B细胞tlr促进炎症和骨质流失，从而加剧PD。我们将在PD小鼠灌胃模型中验证这一假设，以确定1。B细胞缺失；和2。TLR2或TLR4仅在B细胞上表达影响PD的发病机制。这些研究将明确证明B细胞在PD中的作用，从而显著扩展对黏膜炎症性疾病中基础B细胞生物学的认识。

DESCRIPTION (provided by applicant): Periodontal disease (PD) pathogenesis is characterized by a chronically elevated immune response to the oral flora. Multiple immune cell types play roles in PD, with lymphocytes infiltrating the site of infection relatively late in disease progression. In patients with the most severe PD, the majority of cells in the gingival lesions are B cells. These findings suggest that B cells play a dominant role relatively late in PD pathogenesis. However, the function of B cells in PD has not been rigorously established in vivo. Our recent demonstration that B cells from PD patients constitutively secrete cytokines was accompanied by the discovery of an elevated percentage of Toll-like receptor (TLR) 2 and TLR4-positive B cells in human periodontal lesions and PD patient blood. Functional analyses demonstrate that B cell TLR2 and TLR4 activation generally results in production of pro- inflammatory and osteoclastogenic cytokines. Additionally, TLR4 ligand decreases TLR2-mediated production of IL-10, an important anti-inflammatory cytokine. The discoveries of an elevated percentage of TLR-positive B cells in PD patients, the overall pro-inflammatory responses of these B cells to TLR ligands, and the prevalence of B cells in PD lesions indicate that B cell TLRs play important roles in PD by regulating inflammation thus bone loss. Because the oral flora provides innumerable TLR ligands, our preliminary data predict that B cell TLRs promote inflammation directly through cytokine activation in vivo. Although additional studies on human B cell TLR function are likely to be mechanistically and clinically important, the next critical step in this line of investigation is to unequivocally demonstrate B cells and B cell TLRs play a role in PD. We hypothesize that B cell TLRs promote inflammation and bone loss thus exacerbate PD. We will test this hypothesis in the oral gavage mouse model of PD to determine how 1. absence of B cells; and 2. TLR2 or TLR4 expression only on B cells affect PD pathogenesis. These studies will unequivocally demonstrate roles of B cells in PD to significantly expand the understanding of basic B cell biology in mucosal inflammatory diseases. PUBLIC HEALTH RELEVANCE: Periodontal Disease (PD) is a common infection linked to serious complications including cardiovascular disease. Novel PD treatments are needed to supplement current regimens, which have limited effectiveness in many patients. Although the immune system plays an important role in PD, the importance of one immune cell type, B cells, is poorly understood. New evidence from PD patients suggests that B cells play important roles in PD, but human subjects research, by its nature, cannot definitively link B cells to disease pathogenesis. The project proposes to test the role of B cells and their surface receptors in PD using model organisms with a long-term goal of identifying new treatments for PD.