B cell memory in human food allergy

人类食物过敏中的 B 细胞记忆

• 批准号: 10306255
• 负责人: MARIA A CUROTTO DE LAFAILLE
• 金额: $ 75.97万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-09 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10306255
• 关键词: Affect; Affinity; Allergens; Allergic; Allergic Disease; Anaphylaxis; Antibodies; Antibody Response; Asthma; Atopic Dermatitis; B-Cell Activation; B-Lymphocytes; Basic Science; Blood; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Characteristics; Child; Childhood; Clinical Research; Cytometry; Data; Development; Diphtheria Toxoid; Disease; Environment; Evolution; Food; Food Hypersensitivity; Food Supply; Food production; Generations; Goals; Human; Hypersensitivity; IL4R gene; IgE; IgG1; Immune; Immunoglobulin Class Switching; Immunoglobulin G; In Vitro; Individual; Inflammatory; Institutes; Life; Mediating; Mediator of activation protein; Memory; Memory B-Lymphocyte; Milk; Modeling; Molecular Profiling; Mus; Pathogenicity; Phenotype; Plasma Cells; Population; Proteins; Publishing; Research; Resolution; Risk; Role; Tetanus; Transcript; Vaccine Antigen; Viral Antigens; Viral Vaccines; atopy; base; clinical care; comparative; design; experimental study; food allergen; inflammatory disease of the intestine; influenzavirus; longitudinal analysis; new therapeutic target; novel therapeutics; patient population; response; single-cell RNA sequencing; targeted treatment; tool; transcriptomics

Summary High affinity IgE antibodies are essential mediators of food allergy, a main cause of life-threatening anaphylaxis. Most food allergies develop in childhood and affect children disproportionally. A long-standing question in the allergy field is why allergies to some foods spontaneously cure, while others persist. A key to understanding the evolution of food allergy may reside in the mechanisms that maintain the B cell memory of high affinity IgE responses. Experimental studies from our group demonstrated that IgE cells exist mostly as plasma cells and not IgE memory cells, and that high affinity pathogenic IgE antibodies derive from the sequential switching of affinity matured IgG1 memory B cells. While the origin of human high affinity IgE is not definitely proved, an increasing body of work supports a precursor role of IgG memory cells in the generation of human pathogenic IgE plasma cells. We hypothesize that the existence of high affinity food-specific IgG cells and their ability to undergo class switching to IgE are critical for allergy persistence. Preliminary studies from our group suggest that atopic individuals harbor B lymphocytes with a distinct profile that increases their response to activation and differentiation into IgE plasma cells. We postulate that the atopic immune environment marks allergen-specific IgG memory cells with a ‘pro-allergic’ signature, and that the presence of these pro-allergic memory cells is necessary for the development and persistence of food allergy. We propose to investigate the existence of pro- allergic memory B lymphocytes in food allergic children, in children that outgrew their food allergy, in tolerant never-allergic children, and in children with non-allergic inflammatory disease. We will determine if memory B cells that recognize food allergens have a specific phenotype that distinguish them from memory B cells that recognize virus and vaccines antigens in allergic and non-allergic children. We expect that the findings from this study will provide tools to predict food-allergy risk and persistence, and help to design new therapies for allergic diseases.

概括 高亲和力 IgE 抗体是食物过敏的重要介质，是危及生命的过敏反应的主要原因。 大多数食物过敏发生在儿童时期，对儿童的影响尤为严重。一个长期存在的问题 过敏领域就是为什么对某些食物的过敏会自行治愈，而另一些则持续存在。理解的关键 食物过敏的进化可能在于维持高亲和力 IgE 的 B 细胞记忆的机制 回应。我们小组的实验研究表明，IgE 细胞主要以浆细胞形式存在， 不是 IgE 记忆细胞，并且高亲和力致病性 IgE 抗体源自连续切换 亲和力成熟的 IgG1 记忆 B 细胞。虽然人类高亲和力 IgE 的起源尚未得到明确证实，但 越来越多的工作支持 IgG 记忆细胞在人类致病性细胞生成中的先导作用 IgE 浆细胞。我们假设高亲和力食物特异性 IgG 细胞的存在及其能力 进行 IgE 类别转换对于过敏持续存在至关重要。我们小组的初步研究表明 特应性个体拥有具有独特特征的 B 淋巴细胞，可增强其对激活和 分化为 IgE 浆细胞。我们假设特应性免疫环境标记了过敏原特异性 具有“促过敏”特征的 IgG 记忆细胞，这些促过敏记忆细胞的存在是 对于食物过敏的发生和持续是必要的。我们建议调查是否存在亲 食物过敏儿童中的过敏记忆 B 淋巴细胞，在长大后不再对食物过敏的儿童中，在耐受中 从不过敏的儿童，以及患有非过敏性炎症性疾病的儿童。我们将确定内存B是否 识别食物过敏原的细胞具有特定的表型，将其与记忆 B 细胞区分开来。 识别过敏和非过敏儿童的病毒和疫苗抗原。我们期望本次调查的结果 研究将提供预测食物过敏风险和持续性的工具，并帮助设计新的过敏疗法 疾病。