Epithelial BAFF and APRIL in Airway Inflammation, Immunity and Disease

描述(由申请人提供)：该项目的目标是测试假设，即在健康和疾病的呼吸道中，肿瘤坏死因子家族成员BAFF和APRIL的表达在局部免疫和炎症反应中是重要的。这些因素导致B淋巴细胞的增殖、分化和免疫球蛋白类开关重组(CSR)。虽然B淋巴细胞在粘膜局部分泌免疫球蛋白已知数十年，但直到最近才被认为是在B细胞迁移到组织之前在淋巴组织中发生分化和CSR的过程。最近的几项研究支持这一概念，即这些事件广泛发生在呼吸道中，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在慢性鼻-鼻窦炎(CRS)和过敏原激发模型中表达，提出了上皮在呼吸道B细胞反应调节中发挥作用的假设。我们建议进行实验，使用体内和体外的方法来验证这一假设。Aim 1的研究将使用外植体模型来研究抗原攻击的人粘膜组织产生BAFF和APRIL的原因，并将分析参与其表达的Furin蛋白水解酶。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)，使用这些细胞因子的存在分析以及检测B细胞的局部存在和CSR过程的分析(生殖系、环状和成熟的免疫球蛋白转录本和必要的酶激活诱导的胞苷脱氨酶)。在与Charles和Fabienne Mackay博士的合作下，Aim 3的研究将使用全身和呼吸道致敏以及用抗原和RSV挑战的小鼠模型，以测试BAFF和APRIL在呼吸道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分析。对基因敲除和转基因小鼠的研究将有助于确定导致重要发现的细胞因子和受体。我们认为，拟议的研究与宿主防御病原体和炎症性呼吸道疾病的机制有直接关系。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。我们还将研究是什么导致鼻窦疾病、肺气肿和哮喘。我们正在测试两种名为BAFF和APRIL的新因子在免疫和疾病方面的重要性。

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.