牛奶过敏患者口服免疫疗法诱导的脱敏、缓解及自然转归过程中过敏原特异性B细胞反应

Allergen-specific B cell responses in oral immunotherapy-induced desensitization, remission, and natural outgrowth in cow's milk allergy.

作者信息

Satitsuksanoa Pattraporn, van de Veen Willem, Tan Ge, Lopez Juan-Felipe, Wirz Oliver, Jansen Kirstin, Sokolowska Milena, Mirer David, Globinska Anna, Boonpiyathad Tadech, Schneider Stephan R, Barletta Elena, Spits Hergen, Chang Iris, Babayev Huseyn, Tahralı İlhan, Deniz Gunnur, Yücel Esra Özek, Kıykım Ayca, Boyd Scott D, Akdis Cezmi A, Nadeau Kari, Akdis Mübeccel

机构信息

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland.

Functional Genomics Center Zürich, ETH Zürich, Zürich, Switzerland.

出版信息

Allergy. 2025 Jan;80(1):161-180. doi: 10.1111/all.16220. Epub 2024 Jul 11.

DOI:10.1111/all.16220

PMID:38989779

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11724240/

Abstract

BACKGROUND

Antigen-specific memory B cells play a key role in the induction of desensitization and remission to food allergens in oral immunotherapy and in the development of natural tolerance (NT). Here, we characterized milk allergen Bos d 9-specific B cells in oral allergen-specific immunotherapy (OIT) and in children spontaneously outgrowing cow's milk allergy (CMA) due to NT.

METHODS

Samples from children with CMA who received oral OIT (before, during, and after), children who naturally outgrew CMA (NT), and healthy individuals were received from Stanford biobank. Bos d 9-specific B cells were isolated by flow cytometry and RNA-sequencing was performed. Protein profile of Bos d 9-specific B cells was analyzed by proximity extension assay.

RESULTS

Increased frequencies of circulating milk allergen Bos d 9-specific B cells were observed after OIT and NT. Milk-desensitized subjects showed the partial acquisition of phenotypic features of remission, suggesting that desensitization is an earlier stage of remission. Within these most significantly expressed genes, IL10RA and TGFB3 were highly expressed in desensitized OIT patients. In both the remission and desensitized groups, B cell activation-, Breg cells-, BCR-signaling-, and differentiation-related genes were upregulated. In NT, pathways associated with innate immunity characteristics, development of marginal zone B cells, and a more established suppressor function of B cells prevail that may play a role in long-term tolerance. The analyses of immunoglobulin heavy chain genes in specific B cells demonstrated that IgG2 in desensitization, IgG1, IgA1, IgA2, IgG4, and IgD in remission, and IgD in NT were predominating. Secreted proteins from allergen-specific B cells revealed higher levels of regulatory cytokines, IL-10, and TGF-β after OIT and NT.

CONCLUSION

Allergen-specific B cells are essential elements in regulating food allergy towards remission in OIT-received and naturally resolved individuals.

摘要

背景

抗原特异性记忆B细胞在口服免疫疗法中诱导对食物过敏原的脱敏和缓解以及自然耐受（NT）的形成过程中发挥关键作用。在此，我们对口服过敏原特异性免疫疗法（OIT）以及因NT而自然摆脱牛奶过敏（CMA）的儿童中的牛奶过敏原Bos d 9特异性B细胞进行了表征。

方法

从斯坦福生物样本库获取接受口服OIT（治疗前、治疗期间和治疗后）的CMA儿童、自然摆脱CMA的儿童（NT）以及健康个体的样本。通过流式细胞术分离Bos d 9特异性B细胞，并进行RNA测序。通过邻近延伸分析对Bos d 9特异性B细胞的蛋白质谱进行分析。

结果

在OIT和NT后观察到循环牛奶过敏原Bos d 9特异性B细胞的频率增加。牛奶脱敏的受试者表现出部分获得缓解的表型特征，这表明脱敏是缓解的早期阶段。在这些表达最显著的基因中，IL10RA和TGFB3在脱敏的OIT患者中高表达。在缓解组和脱敏组中，B细胞活化、Breg细胞、BCR信号传导和分化相关基因均上调。在NT中，与先天免疫特征、边缘区B细胞发育以及更成熟的B细胞抑制功能相关的通路占主导，这可能在长期耐受中发挥作用。对特异性B细胞中免疫球蛋白重链基因的分析表明，脱敏时IgG2占主导，缓解时IgG1、IgA1、IgA2、IgG4和IgD占主导，NT中IgD占主导。过敏原特异性B细胞分泌的蛋白质显示，OIT和NT后调节性细胞因子、IL-10和TGF-β水平升高。