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

基本信息

批准号：
7863388
负责人：
Robert P Schleimer
金额：
$ 12.86万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/7863388
关键词：
Allergens Allergic 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 Upper arm Virus Diseases Western Blotting activation-induced cytidine deaminase airborne allergen airway epithelium airway inflammation airway obstruction antigen challenge 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

项目摘要

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）：该项目的目的是检验以下假设：TNF家族成员Baff和April在健康和疾病中气道中发生的局部免疫和炎症反应很重要。已知这些因素会导致B淋巴细胞的增殖，分化和免疫球蛋白类转换重组（CSR）。虽然数十年来，B淋巴细胞众所周知，淋巴细胞分泌粘膜局部的免疫球蛋白，但直到最近，人们相信在B细胞迁移到组织之前，淋巴组织中的分化和CSR的过程发生在淋巴组织中。最近的一些研究支持了这些事件在气道中广泛发生的概念，尽管局部机制尚不清楚。我们已经提出了令人兴奋的发现，即上皮细胞会产生大量的BAFF和4月，并且BAFF在人类中的慢性鼻孔炎（CRS）和过敏原挑战模型中表达，提出了上皮在气道中B细胞反应的调节中起作用的假设。我们提出了使用体内和体外方法检验该假设的实验。 AIM 1中的研究将使用epplant模型研究BAFF的生产和来源，而抗原挑战了人类粘膜组织，并将分析与其表达相关的脂肪蛋白蛋白酶。 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转录本和必要的酶激活诱导胞苷脱氨酶）。与Drs合作。 Charles和Fabienne Mackay，AIM 3中的研究将使用抗原的全身和气道敏感性和挑战的小鼠模型，并与RSV进行挑战，以测试Baff和April在气道中B细胞反应中的作用。这些研究将利用测定法进行局部B细胞反应和炎症反应。对基因敲除和转基因小鼠的研究将有助于查明负责重要发现的细胞因子和受体。我们认为，拟议的研究在宿主防御与病原体和炎症性气道疾病的机制中具有直接相关性。外行描述：这些研究将测试有关我们的肺和鼻子如何保护我们免受感染的新想法。我们还将研究导致鼻窦病，肺气肿和哮喘的原因。我们正在测试两个新因素在免疫和疾病中称为BAFF和APRIN的新因素的重要性。