What is it about?
Sialylation, a terminal and charged modification to complex carbohydrates attached to antibodies, has been shown to promote anti-inflammatory functions of the antibody class IgG. It was previously assumed that this modification was performed by antibody-secreting B-lineage cells before IgG release into the bloodstream. Here, we report that IgG sialylation occurs in endothelial cells, which line the vasculature. These cells use the antibody recycling receptor called FcRn to promote sialylation. Furthermore, we show that inflammatory signals can decrease endothelial cell-mediated IgG sialylation while pregnancy conversely upregulates sialylation, thereby providing a mechanistic framework to explain decades of work that aligns decreases in IgG sialylation with inflammation and increases in IgG sialylation during pregnancy-induced immune differences that are critical to protect a developing fetus.
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Why is it important?
Decades of literature report that IgG sialylation serves as a functional switch between inflammation and autoimmunity, such as rheumatoid arthritis, and conditions of heightened immune regulation, such as pregnancy. Our work provides a novel model that brings together these large datasets while introducing a previously unknown role for the vasculature in regulating immune homeostasis. Moreover, this pathway introduces the concept that the composition of complex carbohydrates on glycoproteins are not determined by the cell which originally synthesized the glycoprotein. Instead, those carbohydrates can be modified elsewhere in the body to modulate the function of the protein itself.
Perspectives
This work marks the culmination of nearly a decade of research from the Cobb laboratory that has suggested B cell lineage-independent antibody sialylation – an idea which contradicts the presumed mechanisms of how protein glycosylation is regulated. Previously, our model relied exclusively on the negative: B cell-mediated sialylation was inefficient and disposable. Now, we have a mechanistic explanation for our model by not only identifying the location of B cell-extrinsic antibody sialylation (i.e. endothelial cells), but also demonstrating the regulatory power of both inflammation and pregnancy in driving changes in this new endothelial cell IgG sialylation pathway. As such, our findings synergize with multiple decades of correlative human data. We feel that our findings illustrate the need to look at biological questions through a lens that emphasizes cooperation between cells and pathways while transcending single cell transcriptomics and proteomics to understand the complexities of biology not encoded by a template.
Brian Cobb
Read the Original
This page is a summary of: Endothelial cells sialylate IgG within the FcRn-mediated recycling pathway, Proceedings of the National Academy of Sciences, December 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2511216122.
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