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

B 细胞和 B 细胞 Toll 样受体在牙周病中的作用

• 批准号: 8112911
• 负责人: Barbara Nikolajczyk
• 金额: $ 24.49万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112911
• 关键词: Acute; Adoptive Transfer; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; B-Lymphocytes; Biological; Blood; CD19 gene; Cardiovascular Diseases; Cell Lineage; Cells; Cellular biology; Chronic; Connective Tissue Cells; Coupled; Cytokine Activation; Data; Disease; Disease Progression; Effectiveness; Gingiva; Goals; Hematopoietic stem cells; Human; Human Subject Research; Immune; Immune response; Immune system; Immunoglobulin G; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Interleukin-10; Investigation; Knockout Mice; Lesion; Ligands; Link; Lymphocyte; Measures; Mediating; Methods; Modeling; Monitor; Mus; Myelogenous; Nature; Onset of illness; Oral; Pathogenesis; Patients; Periodontal Diseases; Play; Prevalence; Production; Publishing; Receptor Activation; Regimen; Role; SCID Mice; Severities; Site; Specificity; Surface; T-Lymphocyte; TLR2 gene; TLR4 gene; Testing; Time; Tissues; Toll-Like Receptor 2; Toll-like receptors; Work; base; bone loss; cell type; cytokine; in vivo; monocyte; mouse model; neutrophil; novel; oral bacteria; oral pathogen; pathogen; receptor; receptor expression; receptor function; reconstitution; research study; response

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.

描述（由申请方提供）：牙周病（PD）发病机制的特征是对口腔植物群的免疫应答长期升高。多种免疫细胞类型在PD中发挥作用，其中淋巴细胞在疾病进展中相对较晚地浸润感染部位。在最严重的PD患者中，牙龈病变中的大多数细胞是B细胞。这些结果表明，B细胞在PD发病机制中发挥主导作用相对较晚。然而，B细胞在PD中的功能尚未在体内严格建立。我们最近的研究表明，PD患者的B细胞组成性分泌细胞因子，同时发现人牙周病变和PD患者血液中Toll样受体（TLR）2和TLR 4阳性B细胞的百分比升高。功能分析表明，B细胞TLR 2和TLR 4活化通常导致促炎性细胞因子和破骨细胞生成性细胞因子的产生。此外，TLR 4配体降低TLR 2介导的IL-10（一种重要的抗炎细胞因子）的产生。PD患者中TLR阳性B细胞百分比升高、这些B细胞对TLR配体的总体促炎反应以及B细胞在PD病变中的流行率的发现表明，B细胞TLR通过调节炎症从而骨丢失在PD中发挥重要作用。由于口腔植物群提供了无数的TLR配体，我们的初步数据预测，B细胞TLR直接通过体内细胞因子活化促进炎症。尽管对人B细胞TLR功能的其他研究可能在机制和临床上具有重要意义，但这一系列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促进炎症和骨丢失，从而加重PD。我们将在PD的经口灌胃小鼠模型中测试该假设以确定1.不存在B细胞;和2.仅在B细胞上表达的TLR 2或TLR 4影响PD发病机制。这些研究将明确证明B细胞在PD中的作用，以显著扩展对粘膜炎性疾病中基本B细胞生物学的理解。 公共卫生相关性：牙周病（PD）是一种常见的感染，与包括心血管疾病在内的严重并发症有关。需要新的PD治疗来补充目前的方案，这些方案在许多患者中的有效性有限。虽然免疫系统在PD中起着重要作用，但对一种免疫细胞类型B细胞的重要性了解甚少。来自PD患者的新证据表明，B细胞在PD中发挥重要作用，但人类受试者研究，就其性质而言，不能明确地将B细胞与疾病发病机制联系起来。该项目建议使用模型生物体测试B细胞及其表面受体在PD中的作用，其长期目标是确定PD的新治疗方法。