Development of B cell memory in allergic asthma

项目摘要/摘要 过敏性哮喘是一种无法治愈的慢性肺部炎症性疾病。重复性过敏原暴露在 呼吸道导致病原性免疫记忆的产生和过敏原特异性的过度产生 过敏患者中介导炎症、呼吸道收缩和呼吸窘迫的免疫球蛋白抗体 哮喘。记忆B细胞是免疫记忆的关键组成部分。表型和功能的异质性 提供不同的抗体反应，并影响它们的运输、组织保持和能力 有系统地传播。在过敏性肺部炎症的小鼠模型中，我们观察到稳定的肺- 致敏肺中定位的多核细胞和产生致病抗体反应的证据。我们 假设在局部抗原致敏后，肺获得了让人想起 次级淋巴组织，能够维持长寿的记忆B细胞，并产生新的MBCs 可以在其他组织中循环和扩散，以调节全身过敏性炎症。在这项研究中，我们 将1)探索记忆B细胞(MBCs)在过敏性肺中的发展，包括深入表征 有助于过敏原特异性IgE反应的关键MBC亚群，以及2)这些MBC如何传播 从系统上讲。我们还将探索拦截致病MBCs系统性传播的策略 阻止过敏性炎症的发展。这些研究将促进我们对 记忆B细胞以及帮助设计新的过敏性哮喘治疗策略。

Project Summary/Abstract Allergic asthma is a chronic inflammatory disease of the lungs without cure. Repetitive allergen exposure in the airway leads to the generation of pathogenic immune memory and the excessive production of allergen specific IgE antibodies that mediate inflammation, airway constriction and respiratory distress in patients with allergic asthma. Memory B cells are a key component of immune memory. The phenotypic and functional heterogeneity of MBCs affords their differential antibody responses as well as impact their trafficking, tissue retention and ability to disseminate systemically. In a mouse model of allergic lung inflammation, we have observed stable lung- localized MBCs and evidence for the generation of pathogenic antibody responses in sensitized lungs. We hypothesize that after local antigen sensitization, the lung acquires immune functions reminiscent of those in secondary lymphoid tissues, capable of maintaining long-lived memory B cells as well as generating new MBCs that can recirculate and disseminate in other tissues to mediate systemic allergic inflammation. In this study, we will 1) probe the development of memory B cells (MBCs) in allergic lungs including in-depth characterization of the critical MBC subset that contributes to allergen specific IgE response, and 2) how these MBCs disseminate systemically. We will also 3) explore strategies to intercept the systemic dissemination of pathogenic MBCs to halt the progression of allergic inflammation. These studies will advance our fundamental understanding of memory B cells as well as help devise new therapeutic strategies for allergic asthma.