Epithelial BAFF and APRIL in Airway Inflammation, Immunity and Disease

描述（由申请人提供）：该项目的目的是验证TNF家族成员BAFF和APRIL的表达在健康和疾病中气道局部免疫和炎症反应中起重要作用的假设。已知这些因素可引起B淋巴细胞的增殖、分化和免疫球蛋白类开关重组（CSR）。虽然几十年来人们已经知道B淋巴细胞在粘膜局部分泌免疫球蛋白，但直到最近，人们才认为分化和CSR过程发生在B细胞迁移到组织之前的淋巴组织中。最近的一些研究支持这一概念，即这些事件广泛发生在气道中，尽管局部机制尚不清楚。我们已经取得了令人兴奋的发现，上皮细胞产生大量的BAFF和APRIL，并且BAFF在人类慢性鼻窦炎（CRS）和过敏原挑战模型中表达，提出了上皮在气道中调节B细胞反应中起作用的假设。我们提出实验来验证这一假设，使用体内和体外的方法。Aim 1的研究将使用外植体模型研究抗原激发的人粘膜组织BAFF和APRIL的产生和来源，并分析参与其表达的furin蛋白酶。Aim 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 Durham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），使用检测这些细胞因子的存在以及检测局部存在的B细胞和CSR(种系细胞，循环和成熟的免疫球蛋白转录本和必要的酶激活诱导胞苷脱氨酶)。在与博士合作。Charles和Fabienne Mackay， Aim 3的研究将使用全身和气道致敏、抗原攻击和RSV攻击的小鼠模型来测试BAFF和APRIL在气道B细胞反应中的作用。这些研究将利用局部B细胞反应和炎症反应的测定。基因敲除和转基因小鼠的研究将有助于查明细胞因子和受体对重要发现的影响。我们认为，所提出的研究与宿主防御病原体和炎症性气道疾病的机制直接相关。这些研究将测试关于肺和鼻子如何保护我们免受感染的新想法。我们还将研究鼻窦疾病、肺气肿和哮喘的病因。我们正在测试BAFF和APRIL这两个新因子在免疫和疾病中的重要性。

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.