Roles for lymphocyte RANKL in periodontal complications of type 2 diabetes

牙周炎助长了肥胖相关的2型糖尿病（T2 D）的炎症，与低血糖相关， 控制，并增加T2 D发病率。迫切需要新的策略来对抗牙周炎的来源 感染和由此产生的炎症，这两种疾病在患有 2型糖尿病然而，牙周炎与T2 D之间关系的潜在机制仍然不清楚 阻碍了临床进展。牙周炎和T2 D之间的一个统一联系是改变的B细胞 功能，和最近的合作工作之间的博士芭芭拉Nikolajczyk和托马斯货车戴克表明， 2型糖尿病相关的B细胞变化促进牙周炎我们的工作进一步表明，T细胞不能驱动 在缺乏B细胞的情况下，T2 D宿主的慢性牙周炎，尽管有证据表明T细胞促进牙周炎 在贫瘠的土地上综上所述，这些发现支持了一种模型，其中B细胞支持T2 D增强的 牙周炎，而T细胞占主导地位的牙周炎在倾斜。B细胞和T细胞都是免疫调节的主要来源。 核因子κ B受体激活剂配体（RANKL），破骨细胞生成的关键驱动因子， 牙周骨质流失肥胖/T2 D增加RANKL的造血细胞产生，最可能通过 增加已知可驱动RANKL产生的多种细胞因子（TNFα、IL-1β和IL-6）的浓度。 这些数据，以及我们证明B细胞是T2 D增强的破骨细胞生成所必需的 和牙周炎，支持我们的中心假设：T2 D细胞因子特异性上调B细胞RANKL功能， 其独特地增强了T2 D的牙周并发症。需要进行连续性分析，以填补关键的 肥胖相关T2 D如何影响淋巴细胞RANKL诱导和功能的知识缺口，以及 与瘦型宿主相比，T2 D中破骨细胞生成RANKL的细胞来源是否不同。我们会利用损失- 在标准的T2 D小鼠模型中，结合标准的慢性T2 D小鼠模型， 牙周炎，以研究T2 D增强的牙周病的发展。我们将补充疾病 通过分析T2 D患者的牙龈，在小鼠中进行了病原学研究，以查询 慢性牙周炎该策略将识别T2 D增强的早期和慢性阶段的驱动因素。 牙周炎，以满足我们的长期目标：确定关键因素，促进牙周炎在T2 D相比， 非T2 D受试者，从而为未来的研究确定药物靶点。

Periodontitis fuels the inflammation of obesity-associated type 2 diabetes (T2D), associates with poor glycemic control, and increases T2D morbidity. New strategies are critically needed to counter sources of periodontal infection and the resulting inflammation, both of which are refractory to standard treatments in people with T2D. However, mechanisms underlying the relationship between periodontitis and T2D remain poorly understood, impeding clinical progress. One unifying link between periodontitis and T2D is altered B cell function, and recent collaborative work between Drs. Barbara Nikolajczyk and Thomas Van Dyke showed that T2D-associated changes in B cells promote periodontitis. Our work further indicates that T cells cannot drive chronic periodontitis in T2D hosts in the absence of B cells, despite evidence that T cells promote periodontitis in lean hosts. Taken together, these findings support a model in which B cells support T2D-potentiated periodontitis, while T cells dominate periodontitis in leans. Both B cells and T cells are major sources of receptor activator of nuclear factor kappa-B ligand (RANKL), a key driver of osteoclastogenesis and periodontal bone loss. Obesity/T2D increases hematopoietic cell production of RANKL, most likely through increasing concentrations of a number of cytokines (TNFα, IL-1β and IL-6) known to drive RANKL production. These data, together with our demonstration that B cells are required for T2D-potentiated osteoclastogenesis and periodontitis, support our central hypothesis: T2D cytokines specifically up regulate B cell RANKL function, which uniquely potentiates periodontal complications of T2D. Definitive analyses are needed to fill the critical gaps in knowledge of how obesity-associated T2D impacts lymphocyte RANKL induction and function, and whether cellular sources of osteoclastogenic RANKL differ in T2D compared to lean hosts. We will use loss- and gain-of-function approaches in a standard mouse model of T2D, coupled with a standard model of chronic periodontitis, to study development of T2D-potentiated periodontal disease. We will complement the disease etiology work in mice with analysis of gingiva from people with T2D to query mechanistic underpinnings of chronic periodontitis. This strategy will identify drivers of both early and chronic phases of T2D-potentiated periodontitis to meet our long-term objective: to identify key factors that promote periodontitis in T2D compared to non-T2D subjects, and thereby pinpoint drug targets for future studies.