Role of Memory IgG B Cells in the Development of Tolerance in Food Allergy

记忆 IgG B 细胞在食物过敏耐受性发展中的作用

基本信息

批准号：
10377446
负责人：
Sarita U Patil
金额：
$ 25.2万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-24 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377446
关键词：
Address Affect Affinity Allergens Allergic Allergic Disease Allergy to peanuts Antibodies Antibody Repertoire Antigens B-Lymphocytes B-cell receptor repertoire sequencing Basophils Biological Assay Biological Markers Cells Clinical Clinical Trials Clonal Evolution Clonality Development Epitopes Evolution Food Hypersensitivity Frequencies Human Humoral Immunities IgE Immune Tolerance Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin Switch Recombination Immunotherapy Lead Libraries Life Link Mass Spectrum Analysis Measures Mediating Memory Memory B-Lymphocyte Modality Oral Characters Outcome Pathogenicity Patients Population Positioning Attribute Prevalence Process Proteomics Public Health Publishing Reaction Recombinant Antibody Risk Role Serum Specificity Surface Techniques Testing Time Treatment Efficacy base clinical efficacy deep sequencing early detection biomarkers food allergen novel therapeutic intervention novel therapeutics oral immunotherapy patient subsets prevent technique development tool treatment strategy

项目摘要

Only a subset of patients with IgE-mediated food allergy develop clinical tolerance after oral immunotherapy (OIT), which has been attributed to the development of protective, functionally suppressive antibodies. However, those who lose tolerance are often seen to have an early transient increase in allergen- specific IgE. Previously, we have described the induction of allergen-specific memory B cells early in OIT, and these specific IgG B cells could serve as a reservoir of IgE memory via sequential class-switching. Therefore, the relative contribution of specific IgG B cells giving rise to protective IgG or IgA antibodies versus pathogenic IgE is critical to the development of immunological tolerance in OIT. Understanding the contributions of that B cell fate decision could lead to the development of new therapeutic modalities for allergic diseases. In OIT, we recently published that suppression of basophil sensitivity is a biomarker of tolerance. Functional suppression of basophils and not bulk levels of allergen-specific IgG is correlated with tolerance, suggesting that the antibody repertoire induced by OIT may be highly relevant to the development of tolerance. We have developed a highly specific fluorescent multimer to identify and characterize allergen-specific B cells in peanut OIT in order to define the clonal contributions of these B cells. Using these tools, we propose to track clonal evolution from the memory IgG B cells induced by OIT to the post-serum effector antibodies to explain how antibody evolution from specific IgG B cells influences clinical outcomes in OIT. Based on these findings, we hypothesize that allergen-specific memory IgG B cells can give rise to either protective or pathogenic antibodies that determine long-lived tolerance after OIT. Our approach combines the isolation of antigen-specific B cells for single-cell BCR sequencing, BCR repertoire analysis, and serum proteomics to dissect the clonality of serum antibodies to the peanut allergen, Ara h 2, over the course of OIT. We are uniquely positioned to conduct this study in that we have both serum and BCR repertoires from previously characterized OIT-treated patients. We will address our hypothesis in the following specific aims: (1) Evaluate the development of protective, functionally suppressive allergen-specific IgG in sustained tolerance after OIT; and (2) Evaluate the role of sequential switching in the loss of tolerance after OIT. We anticipate that the proposed studies will elucidate the connection between long-lasting clinical efficacy of OIT on a clonal level with protective and pathogenic antibodies, highlighting the critical role of memory allergen-specific IgG B cells and leading to new strategies for the treatment of food allergies. The development of techniques to track antigen-specific B cell fate, using BCR sequencing, proteomics and recombinant antibodies, will provide a powerful platform to further refine our understanding of how humoral immunity drives allergic disease in humans.

只有一小部分 IgE 介导的食物过敏患者在口服后产生临床耐受性。免疫疗法（OIT），归因于保护性、功能性抑制的发展抗体。然而，那些失去耐受性的人通常会发现过敏原早期短暂增加。特异性 IgE。之前，我们已经描述了 OIT 早期过敏原特异性记忆 B 细胞的诱导，并且这些特定的 IgG B 细胞可以通过顺序类别转换充当 IgE 记忆库。所以，特定 IgG B 细胞产生保护性 IgG 或 IgA 抗体与致病性抗体的相对贡献 IgE 对于 OIT 免疫耐受的发展至关重要。了解 B 的贡献细胞命运的决定可能会导致过敏性疾病新治疗方式的开发。在 OIT 中，我们最近发表了抑制嗜碱性粒细胞敏感性是耐受性的生物标志物。嗜碱性粒细胞的功能抑制而不是过敏原特异性 IgG 的大量水平与耐受性相关，表明 OIT 诱导的抗体库可能与耐受性的发展高度相关。我们开发了一种高度特异性的荧光多聚体，用于识别和表征过敏原特异性 B 细胞花生 OIT 中，以确定这些 B 细胞的克隆贡献。使用这些工具，我们建议跟踪从 OIT 诱导的记忆 IgG B 细胞到血清后效应抗体的克隆进化来解释特定 IgG B 细胞的抗体进化如何影响 OIT 的临床结果。基于这些发现，我们假设过敏原特异性记忆 IgG B 细胞可以产生决定 OIT 后长期耐受性的保护性抗体或致病性抗体。我们的方法结合了抗原特异性 B 细胞的分离，用于单细胞 BCR 测序、BCR 库分析，以及血清蛋白质组学分析整个过程中针对花生过敏原 Ara h 2 的血清抗体的克隆性的OIT。我们拥有独特的优势来开展这项研究，因为我们拥有来自以下来源的血清和 BCR 库：先前对接受 OIT 治疗的患者进行了表征。我们将在以下具体目标中解决我们的假设：（1）评估持续耐受中保护性、功能性抑制性过敏原特异性 IgG 的发展在OIT之后； (2) 评估顺序切换在 OIT 后耐受性丧失中的作用。我们预计拟议的研究将阐明长期临床治疗之间的联系 OIT 在克隆水平上对保护性和致病性抗体的功效，强调了 OIT 的关键作用记忆过敏原特异性 IgG B 细胞并导致治疗食物过敏的新策略。这开发利用 BCR 测序、蛋白质组学和追踪抗原特异性 B 细胞命运的技术重组抗体，将提供一个强大的平台，进一步完善我们对体液如何免疫力会导致人类过敏性疾病。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

EAACI task force report: A consensus protocol for the basophil activation test for collaboration and external quality assurance.

EAACI 工作组报告：用于协作和外部质量保证的嗜碱性粒细胞激活测试的共识协议。

DOI：
10.1111/all.15907
发表时间：
2024
期刊：
Allergy
影响因子：
12.4
作者：
Pascal,M;Edelman,SM;Nopp,A;Möbs,C;Geilenkeuser,WJ;Knol,EF;Ebo,DG;Mertens,C;Shamji,MH;Santos,AF;Patil,S;Eberlein,B;Mayorga,C;Hoffmann,HJ
通讯作者：
Hoffmann,HJ

Immunodominant conformational and linear IgE epitopes lie in a single segment of Ara h 2.

DOI：
10.1016/j.jaci.2021.12.796
发表时间：
2022-07
期刊：
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
影响因子：
14.2
作者：
Hazebrouck, Stephane;Patil, Sarita U.;Guillon, Blanche;Lahood, Nicole;Dreskin, Stephen C.;Adel-Patient, Karine;Bernard, Herve
通讯作者：
Bernard, Herve

Immunotherapy-induced neutralizing antibodies disrupt allergen binding and sustain allergen tolerance in peanut allergy.

DOI：
10.1172/jci164501
发表时间：
2023-01-17
期刊：
JOURNAL OF CLINICAL INVESTIGATION
影响因子：
15.9
作者：
LaHood, Nicole A.;Min, Jungki;Keswani, Tarun;Richardson, Crystal M.;Amoako, Kwasi;Zhou, Jingjia;Marini-Rapoport, Orlee;Bernard, Herve;Hazebrouck, Stephane;Shreffler, Wayne G.;Love, J. Christopher;Pomes, Anna;Pedersen, Lars C.;Mueller, Geoffrey A.;Patil, Sarita U.
通讯作者：
Patil, Sarita U.

Basophil activation test in food allergy: is it ready for real-time?