Epithelial BAFF and APRIL in Airway Inflammation, Immunity and Disease

上皮 BAFF 和 APRIL 在气道炎症、免疫和疾病中的作用

• 批准号: 7851231
• 负责人: Robert P Schleimer
• 金额: $ 36.66万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851231
• 关键词: Allergens; Allergic; Allergic Disease; Allergic rhinitis; Ambrosia; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Appearance; Aspergillus fumigatus; Asthma; Autoimmune Responses; Autopsy; B cell differentiation; B-Cell Activation; B-Lymphocytes; Biological Assay; Biology; Biopsy; Bone Marrow; Cell Maturation; Cell physiology; Cells; Chronic Obstructive Airway Disease; Clinical; Clinical Research; Collaborations; Collecting Cell; Cytokine Receptors; Data; Disease; Double-Stranded RNA; Engineering; Enzyme Activation; Enzyme Tests; Enzyme-Linked Immunosorbent Assay; Enzymes; Epithelial; Epithelial Cells; Epithelium; Event; Exposure to; Family member; Generations; Goals; Health; Host Defense Mechanism; Human; IgE; Immune; Immune response; Immunity; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin Switch Recombination; Immunoglobulins; Immunohistochemistry; Immunologic Deficiency Syndromes; In Situ; In Vitro; Infection; Inflammatory; Inflammatory Response; Knock-out; Ligands; Lung; Lymphoid Tissue; Mature B-Lymphocyte; Mediating; Modeling; Monitor; Mouse Strains; Mucous Membrane; Mus; Myeloid Cells; Nose; Operative Surgical Procedures; Organism; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Play; Pollen; Process; Production; Protease Inhibitor; Protocols documentation; Pulmonary Emphysema; Regulation; Research Personnel; Rest; Rhinitis; Role; Sampling; Seasons; Severities; Signal Transduction; Sinus; Source; Sterility; Stimulus; Structure; System; TALL-1 protein; TLR3 gene; TNF gene; Testing; Time; Tissues; Transcript; Transgenic Mice; Transgenic Organisms; Virus Diseases; Western Blotting; activation-induced cytidine deaminase; airborne allergen; airway epithelium; airway inflammation; airway obstruction; antigen challenge; arm; base; cell motility; chronic rhinosinusitis; cytokine; eosinophil; follow-up; human disease; human subject; in vivo; inhibitor/antagonist; laser capture microdissection; mast cell; mouse model; overexpression; pathogen; programs; receptor; research study; response

DESCRIPTION (provided by applicant): The goal of the project is to test the hypothesis that expression of the TNF family members BAFF and APRIL is important in the local immune and inflammatory responses that occur in the airways in health and disease. These factors are known to cause the proliferation, differentiation and immunoglobulin class switch recombination (CSR) of B lymphocytes. While it has been known for decades that B lymphocytes secrete immunoglobulins locally in the mucosae, until recently it was believed that the process of differentiation and CSR occurred in lymphoid tissues prior to B cell migration to the tissue. Several recent studies support the concept that these events occur extensively in the airways, although the local mechanism is not known. We have made the exciting finding that epithelial cells produce large quantities of BAFF and APRIL, and that BAFF is expressed in chronic rhinosinusitis (CRS) and allergen challenge models in humans, raising the hypothesis that epithelium plays a role in regulation of B cell responses in the airways. We propose experiments to test this hypothesis, using in vivo and in vitro approaches. Studies in Aim 1 will use an explant model to study the production and source of BAFF and APRIL by antigen challenged human mucosal tissue and will analyze the furin proteases involved in their expression. Studies in Aim 2 will test the role of BAFF and APRIL in human diseases, including rhinitis (in collaboration with Dr. Stephen Durham), COPD (in collaboration with Dr. James Hogg), asthma and CRS (in collaboration with investigators at Northwestern), using assays for the presence of these cytokines as well as assays to detect the local presence of B cells and the process of CSR (germline, circle and mature immunoglobulin transcripts and the necessary enzyme activation induced cytidine deaminase). In collaboration with Drs. Charles and Fabienne Mackay, studies in Aim 3 will use mouse models of systemic and airway sensitization and challenge with antigen, and challenge with RSV, to test the role of BAFF and APRIL in B cell responses in the airways. These studies will utilize assays for local B cell responses and inflammatory responses. Studies with knockout and transgenic mice will help pinpoint the cytokine and receptors responsible for important findings. We believe that the proposed studies have direct relevance in the mechanisms of host defense to pathogens and inflammatory airways diseases. Lay description: These studies will test new ideas about how our lungs and nose protect us from infections. We will also study what causes sinus disease, emphysema and asthma. We are testing the importance of two new factors called BAFF and APRIL in immunity and disease.

描述（由申请人提供）：该项目的目标是检验TNF家族成员BAFF和APRIL的表达在健康和疾病的气道中发生的局部免疫和炎症反应中是重要的这一假设。已知这些因子引起B淋巴细胞的增殖、分化和免疫球蛋白类别转换重组（CSR）。虽然几十年来已知B淋巴细胞在粘膜中局部分泌免疫球蛋白，但直到最近才认为分化和CSR过程发生在淋巴组织中，先于B细胞迁移到该组织。最近的几项研究支持这些事件广泛发生在气道的概念，尽管局部机制尚不清楚。我们已经取得了令人兴奋的发现，上皮细胞产生大量BAFF和APRIL，并且BAFF在人类慢性鼻窦炎（CRS）和过敏原激发模型中表达，提出了上皮在气道中调节B细胞应答中起作用的假设。我们提出了实验来验证这一假设，在体内和体外的方法。目标1中的研究将使用外植体模型研究抗原激发的人粘膜组织产生BAFF和APRIL的情况和来源，并分析参与其表达的弗林蛋白酶。目标2的研究将测试BAFF和APRIL在人类疾病中的作用，包括鼻炎（与Stephen达勒姆博士合作），COPD（与James Hogg博士合作），哮喘和CRS（与西北大学的研究人员合作），使用这些细胞因子存在的测定以及检测局部B细胞存在和CSR过程的测定。（生殖系、环状和成熟免疫球蛋白转录物和必需的酶活化诱导的胞苷脱氨酶）。与Charles和Fabienne Mackay博士合作，Aim 3中的研究将使用全身和气道致敏和抗原激发以及RSV激发的小鼠模型，以测试BAFF和APRIL在气道B细胞应答中的作用。这些研究将利用局部B细胞反应和炎症反应的测定。对基因敲除和转基因小鼠的研究将有助于确定重要发现的细胞因子和受体。我们相信，拟议的研究有直接的相关性，在宿主防御病原体和炎症性气道疾病的机制。这些研究将测试关于我们的肺和鼻子如何保护我们免受感染的新想法。我们还将研究是什么导致鼻窦疾病，肺气肿和哮喘。我们正在测试两种新的因子BAFF和APRIL在免疫和疾病中的重要性。