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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| Vydané v: | bioRxiv |
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| Hlavní autori: | , , , , , , |
| Médium: | Journal Article |
| Jazyk: | English |
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United States
02.10.2025
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| ISSN: | 2692-8205, 2692-8205 |
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| Abstract | 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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| AbstractList | 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. 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.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. |
| Author | Wiggins, Christine D Koup, Richard A Sangés Ametllé, Marina Boswell, Kristin L Watkins, Timothy A Wu, Claire Lauffenburger, Douglas A |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/41256685$$D View this record in MEDLINE/PubMed |
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