Year: 2025
Type: article
Abstract: 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. Authors show that all individuals have asymmetrically glycosylated IgGs—the glycans on each of the Fc protomers are not identical. Asymmetrically monofucosylated IgGs drive dengue disease and are functionally similar to afucosylated IgGs.
Source: Nature Communications
Authors: Tala Azzam, Stylianos Bournazos, Hasret Gunduz, Trevor Adams, Maria W. Flowers, Emily G. Niejadlik, Veasna Duong, Trenton J. Brown, Anne M. Roberts, Diego E. Sastre, Fikri Y. Avci, Wilbur A. Lam, Tineke Cantaert, Blaine R. Roberts, Betty Diamond, Jeffrey V. Ravetch, Jonathan J. Du, Eric J. Sundberg
Institutions: Emory University, Rockefeller University, Northwell Health, Feinstein Institute for Medical Research, Institut Pasteur du Cambodge, Pasteur Network, Georgia Institute of Technology, Centre National de la Recherche Scientifique, Institut Pasteur, Université Paris Cité, Génomique évolutive, modélisation et santé, The University of Sydney
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1049758315, Etiology and outcome of MIS-C (PRISM), G1164093520, G1522207996, G1941721978, G2980824148, G325969733, G339059223, G3556973499, G3953115687, G3958856016, G442117160, G4916442533, G5150330411, G5219120389, G605904739, Mechanisms of Antibody-Dependent Enhancement of Dengue Disease, Engineering mono-fucosylated IgGs to fine-tune antibody-mediated effector functions, Deciphering the IgG glycosylation code of Alzheimer's Disease, To B or not to B: Investigation of B cell responses during secondary flavivirus infection, Differentiation of immune cells and fibrobalsts in inflamed tissue in RA and SLE, G9000134163, G9000164145, Atlanta Center for Microsystems Engineered Point-of-Care Technologies (ACME POCT), G985056232
OpenAlex ID: W4417265007