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.
Authors
- Blaine R. Roberts
- Jeffrey V. Ravetch (ORCID: https://orcid.org/0000-0003-2024-9041)
- Hasret Gunduz (ORCID: https://orcid.org/0000-0002-8103-7846)
- A Roberts (ORCID: https://orcid.org/0000-0001-8730-942X)
- Stylianos Bournazos (ORCID: https://orcid.org/0000-0001-5466-5620)
- Fikri Y. Avci (ORCID: https://orcid.org/0000-0002-1902-7532)
- Trenton J Brown
- Eric J. Sundberg (ORCID: https://orcid.org/0000-0003-0478-3033)
- Veasna Duong (ORCID: https://orcid.org/0000-0003-0353-1678)
- Maria W. Flowers (ORCID: https://orcid.org/0000-0002-1814-7049)
- Wilbur Aaron Lam (ORCID: https://orcid.org/0000-0002-0325-7990)
- Diego E. Sastre (ORCID: https://orcid.org/0000-0003-2010-5398)
- Tineke Cantaert (ORCID: https://orcid.org/0000-0002-8911-1502)
- Jonathan J. Du (ORCID: https://orcid.org/0000-0002-7750-4413)
- Trevor M. Adams (ORCID: https://orcid.org/0000-0002-6661-1694)
- Betty Diamond (ORCID: https://orcid.org/0000-0002-3250-3804)
- Tala Azzam (ORCID: https://orcid.org/0000-0001-8739-7861)
- Emily G. Niejadlik
Institutions
- Centre National de la Recherche Scientifique (FR)
- The University of Sydney (AU)
- Northwell Health (US)
- Georgia Institute of Technology (US)
- Feinstein Institute for Medical Research (US)
- Emory University (US)
- Institut Pasteur (FR)
- Université Paris Cité (FR)
- Institut Pasteur du Cambodge (KH)
- Rockefeller University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-12
- DOI
- https://doi.org/10.1038/s41467-025-67070-3
- Primary Topic
- Monoclonal and Polyclonal Antibodies Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Wellcome Trust
- National Institutes of Health
- National Institute on Aging
- National Institute of Allergy and Infectious Diseases