Characterizing the IgG1 Memory B cells that are precursors of pathogenic IgE

表征作为致病性 IgE 前体的 IgG1 记忆 B 细胞

• 批准号: 10537860
• 负责人: Jamie Redes
• 金额: $ 4.66万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-03 至 2025-08-02
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537860
• 关键词: Address; Adoptive Cell Transfers; Affect; Affinity; Allergens; Allergic Reaction; Allergy to peanuts; Anaphylaxis; Antibodies; Antigens; B cell differentiation; B-Lymphocyte Subsets; B-cell receptor repertoire sequencing; Binding; Biological; Blood Circulation; CD80 gene; CRISPR/Cas technology; Cell Degranulation; Cell surface; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Characteristics; Child; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cues; Data; Detection; Disease; Exposure to; Flow Cytometry; Food; Food Hypersensitivity; Functional disorder; Genetic Engineering; Genetic Transcription; Growth; Gut Mucosa; Heterogeneity; Human; Hypersensitivity; IgE; IgG1; Immunity; Immunize; Immunoglobulin Class Switching; Immunoglobulin G; Immunotherapeutic agent; Immunotherapy; Impairment; Individual; Laboratories; Lead; Life; Lymphoid Tissue; Mediating; Memory; Memory B-Lymphocyte; Milk; Mission; Modeling; Molecular; Mus; National Institute of Allergy and Infectious Disease; Outcome; Outcome Study; Pathogenicity; Pathway interactions; Patients; Phenotype; Plasma; Plasma Cells; Play; Population; Prevalence; Probability; Process; Production; Public Health; Quality of life; Research; Research Personnel; Risk; Role; Signal Transduction; Structure of germinal center of lymph node; Surface; System; Techniques; Testing; Therapeutic Intervention; Tissue Stains; Tissues; Trust; Variant; Work; base; career; cytokine; differential expression; egg; food allergen; improved; in vivo; mast cell; mouse model; new therapeutic target; novel; pathogen; response; selective expression; single-cell RNA sequencing; training opportunity

PROJECT SUMMARY: IgE-mediated food allergy affects approximately 1 in 13 children in the USA and has continued to grow in prevalence in recent decades. For many, current immunotherapies are ineffective, making this is a lifelong disease with significant impairment in quality of life. Although IgE is central to the pathophysiology of food allergy, the mechanisms maintaining high affinity (pathogenic) IgE are not well understood. Previous work from our laboratory has shown that IgE memory in mice is contained within a population of antigen-specific IgG memory B cells (MBC) that can undergo class switching to IgE. However, strategies targeting a broad subset of IgG-expressing cells for treatment of food allergy is complicated by the need to retain protective immunity against pathogens. Therefore, it is important to identify the specific IgG MBC that have the ability to generate high affinity IgE responses. This proposal seeks to use mouse models of peanut allergy to identify immunophenotypic markers that can distinguish IgG MBC subsets with the ability to produce high affinity IgE plasma cells (PC). In addition, this application will address the plasticity of this cell fate and the external signals that are required for IgG MBC differentiation into IgE PC. Ultimately, we want to understand what it takes for an IgG MBC to become a pathogenic-IgE producing plasma cell and reveal targets that could be amenable to therapeutic intervention to improve the quality of life of patients who suffer from food allergies.

项目概要： 在美国，IgE介导的食物过敏影响大约1/13的儿童， 近几十年来的流行。对许多人来说，目前的免疫疗法是无效的，这是一个终身的 严重损害生活质量的疾病。虽然IgE是食物病理生理学的核心 在过敏中，维持高亲和力（致病性）IgE的机制还不清楚。以前的工作 来自我们实验室的研究表明，小鼠的IgE记忆包含在抗原特异性 IgG记忆B细胞（MBC），可经历IgE的类别转换。然而，针对广泛的 用于治疗食物过敏的IgG表达细胞的亚群由于需要保留保护性抗体而变得复杂。 对病原体的免疫力。因此，重要的是鉴定具有这种能力的特异性IgG MBC， 以产生高亲和力IgE应答。这项提议旨在使用花生过敏的小鼠模型， 鉴定可以区分IgG MBC亚群的免疫表型标志物，其具有产生高表达的能力。 亲和力IgE浆细胞（PC）。此外，本申请将解决这种细胞命运的可塑性和细胞周期的变化。 IgG MBC分化为IgE PC所需的外部信号。最终，我们希望 了解IgG MBC成为产生病原性IgE的浆细胞所需的条件，并揭示 这些目标可以通过治疗干预来改善患者的生活质量， 患有食物过敏症。