{"title":"The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans","authors":"","doi":"10.1016/j.jaci.2024.04.018","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Autoimmune cytopenias (AICs) regularly occur in profoundly IgG-deficient patients with common variable immunodeficiency (CVID). The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear.</p></div><div><h3>Objective</h3><p>We sought to determine reactivity, clonality, and provenance of AIC-associated IgM autoantibodies in patients with CVID.</p></div><div><h3>Methods</h3><p>We used glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan-binding profiles were used to identify autoreactive clones across B-cell subsets, specifically circulating marginal zone (MZ) B cells, for sorting and <em>IGH</em> sequencing. The locations, transcriptomes, and responses of tonsillar MZ B cells to different T<sub>H</sub>- cell subsets were determined by confocal microscopy, RNA-sequencing, and cocultures, respectively.</p></div><div><h3>Results</h3><p>Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen–recognizing B-cell receptors were highly enriched among CVID+AIC circulating MZ B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL-10/IL-21–secreting FOXP3<sup>−</sup>CD25<sup>hi</sup> T follicular helper (Tfh) cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3<sup>+</sup> regulatory T cells, and rare FOXP3<sup>−</sup>CD25<sup>+</sup> cells that represented likely CD25<sup>hi</sup> Tfh cells all localized outside of germinal centers. In CVID+AIC lymph nodes, cellular positions were similar but CD25<sup>hi</sup> Tfh cells greatly outnumbered regulatory cells.</p></div><div><h3>Conclusions</h3><p>Our findings indicate that glycan-reactive IgM autoantibodies produced outside of germinal centers may contribute to the autoimmune pathogenesis of CVID.</p></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Allergy and Clinical Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0091674924004184","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background
Autoimmune cytopenias (AICs) regularly occur in profoundly IgG-deficient patients with common variable immunodeficiency (CVID). The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear.
Objective
We sought to determine reactivity, clonality, and provenance of AIC-associated IgM autoantibodies in patients with CVID.
Methods
We used glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan-binding profiles were used to identify autoreactive clones across B-cell subsets, specifically circulating marginal zone (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes, and responses of tonsillar MZ B cells to different TH- cell subsets were determined by confocal microscopy, RNA-sequencing, and cocultures, respectively.
Results
Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen–recognizing B-cell receptors were highly enriched among CVID+AIC circulating MZ B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL-10/IL-21–secreting FOXP3−CD25hi T follicular helper (Tfh) cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3+ regulatory T cells, and rare FOXP3−CD25+ cells that represented likely CD25hi Tfh cells all localized outside of germinal centers. In CVID+AIC lymph nodes, cellular positions were similar but CD25hi Tfh cells greatly outnumbered regulatory cells.
Conclusions
Our findings indicate that glycan-reactive IgM autoantibodies produced outside of germinal centers may contribute to the autoimmune pathogenesis of CVID.
期刊介绍:
The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.