Asymmetrically glycosylated IgG1 antibodies are universal and drive human disease.

IgG antibodies have a conserved N-linked glycan on residue Asn297 of the homodimeric Fc region that modulates antibody-mediated effector functions. These effects on the immune response are reflected in correlations between IgG glycans and numerous infectious and autoimmune diseases. However, current studies fail to characterize these Asn297-linked glycans comprehensively, relying on glycan release methods. Here, we develop an intact LC/MS method to glycoprofile polyclonal IgG antibodies while preserving the Fc glycan spatial pairing. We analyze plasma samples from healthy and virally infected individuals and find that all individuals have asymmetrically glycosylated IgGs-the glycans on each of the Fc protomers are not identical. We find that the previously observed association between IgG afucosylation and severe dengue disease is due to asymmetric monofucosylation of IgGs, not symmetric afucosylation. Finally, we engineer monofucosylated IgG1s which are indistinguishable from afucosylated IgG1s in binding to FcγRIIIA in vitro and inducing effector functions in vivo.