Progressive IgG Agalactosylation in Severe COVID-19: What Drives G0 Enrichment? Comment on Vinicki et al. Longitudinal Changes in IgG N-glycome Are Associated with Disease Severity and Mortality in COVID-19 Patients. Viruses 2026, 18, 960

Progressive enrichment of agalactosylated IgG G0 glycoforms has been repeatedly associated with severe and fatal COVID-19. Similar hypogalactosylated IgG phenotypes have also been described in persistent viral infection, post-infectious immune-mediated disease, and autoimmunity, suggesting that these conditions converge on a broader pathological immune response pattern. Evidence from autoimmune and inflammatory conditions indicates that persistent inflammatory signaling can remodel B-cell and germinal-center glycosylation pathways, thereby reducing IgG Fc galactosylation. Despite the substantial literature documenting these changes across different pathological conditions, the upstream processes that initiate and sustain progressive G0 enrichment remain largely unresolved, and no unifying upstream mechanism has been established across these conditions. We suggest that xenosialylation may represent one upstream amplification mechanism. Exogenous N-glycolylneuraminic acid (Neu5Gc) can be incorporated into human glycoconjugates, while humans possess heterogeneous anti-Neu5Gc repertoires. During intense antiviral antibody production, Neu5Gc-bearing IgG could be recognized by pre-existing and/or evolving anti-Neu5Gc responses, promoting immune-complex formation, clearance, and inflammatory amplification. The model predicts a temporal sequence linking Neu5Gc-bearing antigen-specific IgG, anti-Neu5Gc repertoire engagement, xenoimmune inflammation, and subsequent G0 enrichment, providing a directly testable mechanistic framework.