Dendritic cells, Mucosal Immunity and C-type Lectins

树突状细胞、粘膜免疫和 C 型凝集素

• 批准号: 6852485
• 负责人: Edward A Clark
• 金额: $ 38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6852485
• 关键词: Bacteroides; Bacteroides gingivalis; Fusobacterium nucleatum; Streptococcus; antigen presenting cell; bacterial cytopathogenic effect; biological signal transduction; carbohydrate receptor; dendritic cells; genetically modified animals; gut associated lymphoid tissue; hematopoietic tissue; host organism interaction; human tissue; immunologic receptors; inflammation; laboratory mouse; lectin; microarray technology; monoclonal antibody; mucosal immunity; oral bacteria; oral mucosa; oral pharyngeal; phosphatidylcholines; protein tyrosine phosphatase; tissue /cell culture

DESCRIPTION (provided by applicant): The oral cavity, the gut-associated immune system and the skin have in residence both commensal and pathogenic bacteria. Significant progress has been made in defining how the innate immune system recognizes and responds to pathogenic bacteria via signaling through pattern recognition receptors (PRRs). However, relatively little is known about how the innate immune system responds to commensal bacteria and how encounters with commensals influence how the immune system responds to pathogens. This proposal will address this fundamental question using oral microflora and the C-type lectin receptor family as a model system. We have selected the C-type lectin family because members of this family of receptors appear to be able to both recognize and mediate either positive or negative responses to pathogens and because we have defined three new members of this family. The well-defined oral microflora is ideal for addressing this question. We have identified several new C-type lectins designated DCAL-1, DCAL-2 and DCAL-3. DCAL-2 is restricted in its expression to antigen presenting cells and has within its cytoplasmic tail an immunoreceptor tyrosine inhibitory motif (ITIM), suggesting that it functions to inhibit DC activation. We will first test if dendritic cells (DCs) are regulated differently by periopathogenic bacteria vs. commensal oral bacteria. We will compare the ability of oral flora to induce DC maturation, expression of inflammatory and non-inflammatory cytokines and chemokines, and expression of TLR and C-type lectin receptors. We predict that commensal bacteria, unlike periopathogenic bacteria, will trigger an anti-inflammatory program. Using microarrays we will test the hypothesis that pathogenic and commensal bacteria activate in DCs distinctive 'prewired signaling patterns' under the control of distinct drivers, which affect DC functions. Next we will test if DCAL-2 inhibits dendritic cell functions alters responses to periopathogenic bacteria. We will determine if certain bacteria including oral microflora bind to and signal DCs through DCAL-2. Finally we will test if DCAL-2 plays an important role in the resistance to pathogenic bacterial infection in vivo. We will prepare and then characterize DCAL-2-deficient mice and determine if these mice are more susceptible or resistant to infection by P. gingivalis as measured by alveolar bone loss and antibody responses. This work will lead to better understanding about how microflora can affect DCs.

描述(申请人提供)：口腔、肠道相关免疫系统和皮肤中既有共生菌又有致病菌。在确定先天性免疫系统如何通过模式识别受体(PRRs)发出信号来识别和响应病原菌方面已经取得了重大进展。然而，对于先天免疫系统如何应对共生菌，以及与共生菌的接触如何影响免疫系统对病原体的反应，人们知之甚少。这项建议将使用口腔微生物区系和C型凝集素受体家族作为模型系统来解决这一基本问题。我们之所以选择C型凝集素家族，是因为这个受体家族的成员似乎能够识别和介导对病原体的积极或消极反应，也因为我们已经定义了这个家族的三个新成员。明确的口腔微生物区系是解决这个问题的理想选择。我们已经鉴定了几个新的C型凝集素，分别命名为DCAL-1、DCAL-2和DCAL-3。DCAL-2仅限于抗原提呈细胞表达，其胞浆尾部含有免疫受体酪氨酸抑制基序(ITIM)，提示其具有抑制DC激活的功能。我们将首先测试树突状细胞(DC)是否受到病变周围细菌和共生口腔细菌的不同调控。我们将比较口腔菌群诱导DC成熟的能力，炎性和非炎性细胞因子和趋化因子的表达，以及TLR和C型凝集素受体的表达。我们预测，与周围致病细菌不同，共生细菌将触发抗炎计划。利用微阵列，我们将测试这一假设，即病原菌和共生菌在不同驱动器的控制下，在DC独特的“预连线信号模式”中激活，影响DC功能。接下来，我们将测试DCAL-2是否抑制树突状细胞功能，改变对周围致病细菌的反应。我们将确定包括口腔微生物在内的某些细菌是否通过DCAL-2与DC结合并发出信号。最后，我们将测试DCAL-2在体内对病原菌感染的抵抗力中是否发挥重要作用。我们将制备并鉴定DCAL-2缺陷小鼠，并通过牙槽骨丢失和抗体反应来确定这些小鼠是否更容易或更耐受牙龈假单胞菌感染。这项工作将有助于更好地理解微生物区系如何影响DC。