Development of B cell memory in allergic asthma

过敏性哮喘中 B 细胞记忆的发展

• 批准号: 10503760
• 负责人: Yee Ling Wu
• 金额: $ 45.43万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503760
• 关键词: Address; Affinity; Agonist; Airway Disease; Allergens; Allergic; Allergic inflammation; Anatomy; Antibodies; Antibody Affinity; Antibody Formation; Antibody Response; Antigens; Archives; B cell repertoire; B-Cell Antigen Receptor; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Bacterial Infections; Biology; Blood Circulation; CCL20 gene; CCR6 gene; Cell Adhesion Molecules; Cells; Characteristics; Development; Disease Progression; Effector Cell; Exposure to; Extrinsic asthma; Gene Expression Profile; Generations; Genetic Transcription; Goals; Heterogeneity; Homing; Human; IgE; IgG1; Immune response; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunoglobulin-Secreting Cells; Immunologic Memory; Infection; Inflammation; Intercept; Lung; Lymphoid Tissue; Mediating; Memory B-Lymphocyte; Microscopy; Mucous Membrane; Mus; Output; Parabiosis; Pathogenicity; Patients; Phenotype; Plasma Cells; Population; Positioning Attribute; Prevalence; Production; Pulmonary Inflammation; Respiratory distress; Seeds; Signal Transduction; Site; Spleen; Structure of germinal center of lymph node; Testing; Tissues; Virus Diseases; anti-CD20; chemokine receptor; chronic inflammatory disease; chronic inflammatory lung disease; constriction; experimental study; immune function; lymphoid organ; lymphoid structures; mouse model; novel therapeutic intervention; response; sensitizing antigen; trafficking; transcriptomics

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.

项目概要/摘要 过敏性哮喘是一种无法治愈的慢性肺部炎症性疾病。反复接触过敏原 气道导致致病性免疫记忆的产生和过敏原特异性的过度产生 IgE 抗体介导过敏患者的炎症、气道收缩和呼吸窘迫 哮喘。记忆 B 细胞是免疫记忆的关键组成部分。表型和功能异质性 MBC 的数量提供了不同的抗体反应，并影响其运输、组织保留和能力 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 局部 MBC 和致敏肺部产生致病性抗体反应的证据。我们 假设局部抗原致敏后，肺获得了类似于肺的免疫功能 次级淋巴组织，能够维持长寿的记忆 B 细胞并产生新的 MBC 它可以在其他组织中再循环和传播以介导全身过敏性炎症。在这项研究中，我们 将 1) 探索过敏性肺部中记忆 B 细胞 (MBC) 的发育，包括深入表征 有助于过敏原特异性 IgE 反应的关键 MBC 子集，以及 2) 这些 MBC 如何传播 系统地。我们还将 3) 探索拦截致病性 MBC 系统性传播的策略 阻止过敏性炎症的进展。这些研究将增进我们对以下问题的基本理解： 记忆 B 细胞还有助于制定过敏性哮喘的新治疗策略。