Multivariate analysis of glycogenes reveals coordinated regulation of immunoglobulin glycosylation in an immortalized human B cell system
While neutralizing ability has traditionally been considered the most important antibody function, appreciation has grown for Fc-mediated 'extra-neutralizing' functions, which are shaped by IgG glycosylation. However, there remain fundamental questions as to how B lymphocytes induce and re...
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| Veröffentlicht in: | bioRxiv |
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| Hauptverfasser: | , , , , , , |
| Format: | Journal Article |
| Sprache: | Englisch |
| Veröffentlicht: |
United States
02.10.2025
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| ISSN: | 2692-8205, 2692-8205 |
| Online-Zugang: | Volltext |
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| Zusammenfassung: | While neutralizing ability has traditionally been considered the most important antibody function, appreciation has grown for Fc-mediated 'extra-neutralizing' functions, which are shaped by IgG glycosylation. However, there remain fundamental questions as to how B lymphocytes induce and regulate antibody glycosylation and thus functional capability. Understanding how transcriptional and cell state regulation shape glycosylation could reveal levers to tune protective humoral profiles in a disease- and antigen-specific manner. Prior studies have explored a limited panel of glycogenes and measured bulk glycosylation changes. Here, employing an in vitro antigen-specific B cell culture system, we systematically characterize transcriptional and humoral responses to cytokine perturbations. After exposure to a broad panel of cytokines (IL-4, IL-6, IL-10, IL-17, TNFa, IFNg, APRIL, and BAFF) across multiple concentrations and timepoints, transcriptomic profiling and lectin-based IgG glycome assays are employed to associate cytokine stimuli with both glycogene expression and IgG glycosylation. Supervised and unsupervised machine learning models identify cytokine-specific glycogene "signatures" as well as distinct immunoglobulin glycosylation profiles. We find that cytokines induce rapid transcriptional responses, with glycogene signatures outperforming single-gene changes in distinguishing stimulation conditions. We further demonstrate the ability to induce both pro- and anti-inflammatory IgG glycosylation profiles, particularly in terms of IgG galactosylation. This work demonstrates the utility of this system to parse the cytokine-driven regulation of B lymphocyte glycogenes, establishing a framework for dissecting how environmental cues shape antibody glycosylation, with relevance for autoimmune disease, infection, and vaccine responses. |
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| Bibliographie: | ObjectType-Working Paper/Pre-Print-3 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
| ISSN: | 2692-8205 2692-8205 |
| DOI: | 10.1101/2025.09.30.679651 |