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: 7223471
• 负责人: Edward A Clark
• 金额: $ 36.03万
• 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/7223471
• 关键词: Address; Adult; Affect; Alveolar Bone Loss; Anti-Inflammatory Agents; Anti-inflammatory; Antibody Formation; Antigen-Presenting Cells; Arts; Autoantibodies; Autoimmune Diseases; B-Lymphocytes; Bacteria; Bacterial Infections; Binding; Biological Models; C Type Lectin Receptors; C-Type Lectins; CD209 gene; Cell Maturation; Cell Survival; Cell physiology; Cells; Clinical; Communities; Condition; Crohn' s disease; Cytoplasmic Tail; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Family; Family member; Fusobacterium nucleatum; Genes; Gut associated lymphoid tissue; Human; Human body; Immune response; Immune system; Infection; Inflammatory; Inflammatory Response; Kilogram; Lead; Lectin; Lectin Receptors; Ligation; Light; Measures; Mediating; Memory B-Lymphocyte; Monoclonal Antibodies; Mouth Diseases; Mucosal Immunity; Mus; Mycobacterium tuberculosis; Nature; Oral; Oral cavity; Pattern; Pattern recognition receptor; Periodontitis; Play; Porphyromonas gingivalis; Preparation; Prevention; Production; Protein Tyrosine Phosphatase; Relative (related person); Resistance; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Skin; Stimulus; Streptococcus gordonii; Structure; System; Systemic Lupus Erythematosus; Testing; Time; Toll-like receptors; Tyrosine; Work; chemokine; commensal microbes; cytokine; dectin 1; immunogenic; in vivo; insight; member; oral bacteria; pathogen; pathogenic bacteria; programs; receptor; residence; response; scaffold; stem

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、肠道相关免疫系统和皮肤中同时存在着共生细菌和致病细菌。在定义先天免疫系统如何通过模式识别受体（PRR）信号传导来识别和响应病原菌方面，已经取得了重大进展。然而，关于先天免疫系统如何对共生细菌做出反应以及与共生细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。该提案将使用口腔微生物群和 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介导对病原体的阳性或阴性反应，并且因为我们已经定义了该家族的三个新成员。明确的口腔微生物群是解决这个问题的理想选择。我们已经鉴定了几种新的 C 型凝集素，命名为 DCAL-1、DCAL-2 和 DCAL-3。 DCAL-2 的表达仅限于抗原呈递细胞，并且在其细胞质尾部具有免疫受体酪氨酸抑制基序 (ITIM)，表明它具有抑制 DC 活化的功能。我们将首先测试病原细菌与口腔共生细菌对树突状细胞 (DC) 的调节是否不同。我们将比较口腔菌群诱导 DC 成熟、炎症和非炎症细胞因子和趋化因子表达以及 TLR 和 C 型凝集素受体表达的能力。我们预测，与周围病原细菌不同，共生细菌将触发抗炎程序。使用微阵列，我们将测试这样的假设：病原菌和共生细菌在不同驱动因素的控制下，在树突状细胞中激活独特的“预连线信号模式”，从而影响树突状细胞的功能。接下来我们将测试 DCAL-2 抑制树突状细胞功能是否会改变对周围病原细菌的反应。我们将确定某些细菌（包括口腔微生物群）是否与 DC 结合并通过 DCAL-2 发出信号。最后我们将测试DCAL-2是否在体内抵抗病原菌感染方面发挥重要作用。我们将准备并表征 DCAL-2 缺陷型小鼠，并根据牙槽骨丢失和抗体反应来确定这些小鼠是否更容易受到牙龈卟啉单胞菌感染或具有抵抗力。这项工作将有助于更好地了解微生物群落如何影响树突状细胞。