The Origin and Memory of Human IgE Responses

人类 IgE 反应的起源和记忆

• 批准号: 9375287
• 负责人: MARIA A CUROTTO DE LAFAILLE
• 金额: $ 25.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9375287
• 关键词: Affinity; Allergens; Allergic; Allergic Disease; Antibodies; Antigens; Apoptotic; Atopic Dermatitis; B-Lymphocytes; Binding; Biological; Biological Markers; Blood; Blood Circulation; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Chronic; DNA sequencing; Epigenetic Process; Extrinsic asthma; Generations; Genes; Genetic Transcription; Grant; Half-Life; Human; IgE; IgG1; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Switch Recombination; Incidence; Individual; Infection; Inflammatory; Mediating; Memory; Memory B-Lymphocyte; Modeling; Molecular Profiling; Mus; Parasites; Pathogenicity; Patients; Phase; Phenotype; Plasma; Plasma Cells; Play; Process; Production; Proliferating; Public Health; Regulation; Risk; Role; Sequence Analysis; Serum; Structure of germinal center of lymph node; T memory cell; T-Lymphocyte; Therapeutic; anti-IgE; base; crosslink; human subject; interest; mast cell; memory CD4 T lymphocyte; mouse model; novel; novel therapeutics; permissiveness; premature; receptor; response

Project Summary IgE antibodies play a central role in allergic diseases due to their ability to bind to high-affinity receptors on mast cells and induce degranulation upon allergen crosslinking1, 2. In spite of its powerful inflammatory effects, IgE is the antibody with the lowest serum concentration and the shortest half-life, and IgE-producing B lymphocytes are extremely rare in humans and mice, suggesting that IgE production is strongly regulated. The increased incidence of allergic diseases and its detrimental effects on public health brought renewed interest in understanding the regulation of IgE production. Furthermore, the positive effect of anti-IgE treatment on allergic asthma and other chronic allergic diseases validated IgE as a therapeutic target3. Studies from mouse models uncovered several mechanisms that restrain IgE production4, 5. The germinal center (GC) phase of IgE cells is prematurely terminated, and IgE GC cells do not generate IgE memory cells or long-lived IgE plasma cells6. Instead, the sequential switching of IgG cells to IgE originates most antigen-specific high affinity IgE plasma cells6, 7, 8. These findings have brought about a new understanding on the memory of IgE response, that is, that IgE memory is contained within IgG cells that under appropriate activation, can give rise to IgE plasma cells. Based on this novel model, we hypothesize that the potential for pathogenic IgE production resides in allergen- specific “permissive” IgG memory cells that can be activated by “permissive” CD4 memory T cells to switch to IgE. We propose to determine phenotypic, transcriptional, epigenetic and functional differences between total and antigen-specific IgG memory cells and CD4 memory T cells from atopic and non-atopic individuals. Through these studies we hope to identify “permissive” memory B and T cells, and determine the risk of individuals producing pathogenic IgE. Understanding the regulation of IgE production in human subjects is of great importance to developing new therapies for allergic diseases.

项目概要 IgE 抗体由于能够与过敏性疾病中的高亲和力受体结合，因此在过敏性疾病中发挥着核心作用。 肥大细胞并在过敏原交联时诱导脱颗粒1, 2。尽管其具有强大的炎症作用， IgE是血清浓度最低、半衰期最短的抗体，产生IgE的B 淋巴细胞在人类和小鼠中极为罕见，这表明 IgE 的产生受到强烈调节。这 过敏性疾病发病率的增加及其对公众健康的不利影响重新引起了人们的兴趣 了解 IgE 产生的调节。此外，抗 IgE 治疗对过敏的积极作用 哮喘和其他慢性过敏性疾病验证了 IgE 作为治疗靶点3。小鼠模型研究 发现了几种抑制 IgE 产生的机制4, 5。IgE 细胞的生发中心 (GC) 阶段是 过早终止，并且 IgE GC 细胞不会产生 IgE 记忆细胞或长寿命 IgE 浆细胞6。 相反，IgG 细胞顺序转换为 IgE 产生了大多数抗原特异性高亲和力 IgE 血浆 cells6,7,8。这些发现给IgE反应的记忆带来了新的认识，即 IgE 记忆包含在 IgG 细胞内，在适当的激活下，可以产生 IgE 浆细胞。 基于这个新模型，我们假设致病性 IgE 产生的潜力在于过敏原 - 特定的“允许的”IgG 记忆细胞可以被“允许的”CD4 记忆 T 细胞激活以切换到 免疫球蛋白E。我们建议确定总的表型、转录、表观遗传和功能差异 以及来自特应性和非特应性个体的抗原特异性 IgG 记忆细胞和 CD4 记忆 T 细胞。 通过这些研究，我们希望识别出“允许的”记忆 B 细胞和 T 细胞，并确定记忆的风险 产生致病性 IgE 的个体。了解人类受试者 IgE 产生的调节至关重要 开发过敏性疾病的新疗法非常重要。