Structure and Function of the B Lymphocyte FCe Receptor

B 淋巴细胞 FCe 受体的结构和功能

• 批准号: 8867994
• 负责人: DANIEL H CONRAD
• 金额: $ 46.81万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-05-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867994
• 关键词: ADAM Family Protein; Allergic; Allergic Disease; Antibody Affinity; Antibody Formation; Antibody Response; Antigen-Antibody Complex; Antigens; Architecture; Asthma; Autoimmune Responses; B-Cell Activation; B-Lymphocytes; Cell physiology; Cells; Complex; Data; Defect; Disintegrins; Epithelial; Epithelial Cells; Exhibits; Financial compensation; Fractalkine; Funding; Grant; Half-Life; Health; Hematopoietic stem cells; Human; Humoral Immunities; Hypersensitivity; IgE; Immune; Immune response; Immune system; Immunoglobulin Class Switching; In Vitro; Injection of therapeutic agent; Lung; Lung Inflammation; Lymphoid; Lymphoid Tissue; Maintenance; Mediating; Membrane; Metalloproteases; Modeling; Mucous body substance; Mus; Nervous system structure; Pathology; Patients; Peptide Hydrolases; Phenotype; Plasma Cells; Play; Production; Proteins; Reporter; Research Design; Role; Signal Pathway; Site; Solid; Structure; Structure of germinal center of lymph node; TNF gene; Testing; Therapeutic Intervention; Work; airway hyperresponsiveness; allergic response; antigen processing; asthmatic; base; disorder control; immune function; inhibitor/antagonist; insight; interest; novel; overexpression; receptor; response; system architecture

DESCRIPTION (provided by applicant): This renewal builds on the progress in current funding. ADAM10 was shown to be quite important in humoral immune function. Mice in which their B cells lack ADAM10 (ADAM10B-/-) had defective lymphoid architecture. We will examine whether multiple antigen injections can overcome the defects seen. Newly data indicates that B cell TNF production is responsible for the altered germinal center architecture seen in the ADAM10B-/- mice and that this is due to increased expression of the TNF sheddase ADAM17. The opposite effects for ADAM10 will also be examined, namely what happens when ADAM10 is overexpressed in B cells. Early overexpression in hematopoietic stem cells was shown to block B cell production in the current funding period. Incorporation of a floxxed stop site in fron of the ADAM10 will allow delay of the overexpression until B cells develop. In addition, the ADAM17B-/- mouse should also have elevated ADAM10 expression and enhanced Ig production. Of particular interest is IgE production and we hypothesize that elevated IgE production will correlate with elevated B cell ADAM10. With respect to ADAM10 targets important in B cell function, based on preliminary data, we will concentrate on two substrates, CD23 and fractalkine. Finally, we will examine whether B cell exosomes play a role in the immunostimulatory activity of IgE-antigen complexes. In the second aim, mice with elevated B cell ADAM10 will be examined for enhanced lung inflammation in mouse asthma models and the effect of ADAM10 inhibitors will be examined to determine if this mechanism is solely ADAM10 related. The effect of ADAM10 inhibitors on the lymphoid architecture of the bronchial associated lymphoid tissues will be determined. Using IgE reporter mice, we will specifically determine the effect of ADAM10 inhibitors and ADAM10B-/- mice for germinal center and IgE plasma cell levels. We anticipate that when ADAM10 levels are inhibited we can specifically inhibit the IgE response. Using a model we have developed for suppression of an ongoing asthma response, ADAM10 inhibitors will be examined for their capacity to block this response. Mice lacking ADAM10 in their epithelial cells will be studied to determine whether ADAM10 inhibitors are working primarily by their effect on immune cells. Preliminary evidence indicates that a subpopulation of active allergic patients have elevated B cell ADAM10 levels when compared to controls. We will examine if the B cells from these patients have enhanced IgE production, using in vitro B cell stimulation models. Overall, the project will continue studies ino new promising avenues for understanding and harnessing ADAM10 to control the immune response. In addition, these two aims test the hypothesis that the ratio of ADAM10 to ADAM17 is important especially with respect to the allergic phenotype.

描述（由申请人提供）：本次更新建立在当前资金进展的基础上。 ADAM10被证明在体液免疫功能中非常重要。 B 细胞缺乏 ADAM10 (ADAM10B-/-) 的小鼠的淋巴结构有缺陷。我们将检查多次抗原注射是否可以克服所见的缺陷。新数据表明，B 细胞 TNF 的产生是 ADAM10B-/- 小鼠生发中心结构改变的原因，这是由于 TNF 脱落酶 ADAM17 表达增加所致。还将检查 ADAM10 的相反作用，即当 ADAM10 在 B 细胞中过度表达时会发生什么。在当前资助期间，造血干细胞的早期过度表达被证明会阻碍 B 细胞的产生。在 ADAM10 前面掺入 floxxed 终止位点将允许延迟过度表达，直到 B 细胞发育。此外，ADAM17B-/- 小鼠还应具有升高的 ADAM10 表达和增强的 Ig 产生。特别令人感兴趣的是 IgE 产生，我们假设 IgE 产生升高与 B 细胞 ADAM10 升高相关。对于 B 细胞功能中重要的 ADAM10 靶点，根据初步数据，我们将重点关注两种底物：CD23 和 fractalkine。最后，我们将检查 B 细胞外泌体是否在 IgE-抗原复合物的免疫刺激活性中发挥作用。在第二个目标中，将在小鼠哮喘模型中检查 B 细胞 ADAM10 升高的小鼠是否增强肺部炎症，并检查 ADAM10 抑制剂的作用以确定该机制是否仅与 ADAM10 相关。将确定 ADAM10 抑制剂对支气管相关淋巴组织的淋巴结构的影响。使用 IgE 报告小鼠，我们将具体确定 ADAM10 抑制剂和 ADAM10B-/- 小鼠对生发中心和 IgE 浆细胞水平的影响。我们预计，当 ADAM10 水平受到抑制时，我们可以特异性抑制 IgE 反应。使用我们开发的抑制持续哮喘反应的模型，将检查 ADAM10 抑制剂阻止这种反应的能力。将研究上皮细胞中缺乏 ADAM10 的小鼠，以确定 ADAM10 抑制剂是否主要通过其对免疫细胞的影响发挥作用。初步证据表明，与对照组相比，活动性过敏患者亚群的 B 细胞 ADAM10 水平升高。我们将使用体外 B 细胞刺激模型检查这些患者的 B 细胞是否增强了 IgE 的产生。总体而言，该项目将继续研究新的有前景的途径，以了解和利用 ADAM10 来控制免疫反应。此外，这两个目标检验了以下假设：ADAM10 与 ADAM17 的比例很重要，尤其是对于过敏表型而言。