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: 7050592
• 负责人: Edward A Clark
• 金额: $ 37.11万
• 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/7050592
• 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（由申请人提供）：口腔，肠道相关的免疫系统和皮肤在居住中均具有共生和致病性细菌。在定义先天免疫系统如何通过模式识别受体（PRR）信号传导来识别和反应致病细菌方面取得了重大进展。然而，关于先天免疫系统如何对共生细菌的反应以及与Encensals的相遇如何影响免疫系统对病原体的反应方式相对较少。该提案将使用口腔微生物和C型凝集素受体家族作为模型系统解决这个基本问题。我们选择了C型凝集素家族，因为该受体家族的成员似乎能够识别并调节对病原体的正面或负面反应，并且因为我们定义了该家族的三个新成员。定义明确的口服微生物是解决此问题的理想选择。我们已经确定了几种指定DCAL-1，DCAL-2和DCAL-3的新的C型凝集素。 DCAL-2的表达限制在抗原呈递细胞中，并在其细胞质尾部具有免疫感受器酪氨酸抑制基序（ITIM），这表明它功能抑制DC激活。我们将首先测试是否通过围栏性细菌与共生口服细菌对树突状细胞（DC）进行不同的调节。我们将比较口腔菌群诱导直流成熟，炎症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的能力。我们预测，与围手术细菌不同，共生细菌将触发抗炎计划。使用微阵列，我们将测试以下假设：在不同驱动因素的控制下，DC中的致病性和共生细菌在DC独特的“前线信号传导模式”中激活，这会影响DC功能。接下来，我们将测试DCAL-2是否抑制树突状细胞功能会改变对毛细菌的反应。我们将确定包括口腔微生物（包括口腔微生物）与DCAL-2结合和信号DC的某些细菌。最后，我们将测试DCAL-2在体内对致病细菌感染的抗性中是否起重要作用。我们将准备并表征DCAL-2缺陷型小鼠，并确定这些小鼠是否更容易受到牙龈疟原虫感染的感染或抗性，这是通过肺泡骨损失和抗体反应测量的。这项工作将使人们更好地了解菌群如何影响DC。