Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity
Mads Delbo Larsen, Erik L. de Graaf, Myrthe E. Sonneveld, H. Rosina Plomp, Jan Nouta, Willianne Hoepel, Hung‐Jen Chen, Federica Linty, Remco Visser, Maximilian Brinkhaus, Tonći Šuštić, Steven W. de Taeye, Arthur E. H. Bentlage, S Toivonen, Carolien A. M. Koeleman, Susanna Sainio, Neeltje A. Kootstra, Philip J. M. Brouwer, Chiara E. Geyer, Ninotska I. L. Derksen, Gertjan Wolbink, Menno P.J. de Winther, Rogier W. Sanders, Marit J. van Gils, Sanne de Bruin, Alexander P. J. Vlaar, Amsterdam UMC COVID-19, biobank study group, Theo Rispens, Jeroen den Dunnen, Hans L. Zaaijer, Manfred Wuhrer, C. Ellen van der Schoot, Gestur Vidarsson, Michiel A. van Agtmael, Anna Geke Algera, Frank van Baarle, Diane Bax, Diederik van de Beek, Martijn Beudel, Harm Jan Bogaard, Peter I. Bonta, Marije K. Bomers, Lieuwe D. J. Bos, Michela Botta, Godelieve de Bree, Matthijs C. Brouwer, Justin de Brabander, Sanne de Bruin, Marianna Bugiani, Esther Bulle, Osoul Chouchane, Alex Cloherty, Paul Elbers, Lucas M. Fleuren, Suzanne E. Geerlings, Bart F. Geerts, Theo Geijtenbeek, Armand R. J. Girbes, Bram Goorhuis, Martin P. Grobusch, Florianne Hafkamp, Laura A. Hagens, Jörg Hamann, Vanessa Harris, Robert Hemke, Sabine Hermans, Leo Heunks, Markus W. Hollmann, Janneke Horn, Joppe W. Hovius, Menno D. de Jong, Rutger Koning, Niels van Mourik, Jeaninne Nellen, Esther J. Nossent, Frederique Paulus, Edgar J.G. Peters, Tom van der Poll, Bennedikt Preckel, Jan M. Prins, Jorinde Raasveld, Tom Rijnders, Michiel Schinkel, Marcus J. Schultz, Alex Schuurmans, Kim Sigaloff, Marry R. Smit, Cornelis Stijnis, Willemke Stilma, Charlotte E. Teunissen, Patrick Thoral, Anissa M. Tsonas, Marc van der Valk, Denise P. Veelo, Alexander P. J. Vlaar, Heder de Vries, Michèle van Vugt, W. Joost Wiersinga, Dorien Wouters
Abstract
Immunoglobulin G (IgG) antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc tail, which is essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anticancer therapeutic antibodies for their increased activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG (approximately 6% of total IgG in humans) are specifically formed against enveloped viruses but generally not against other antigens. This mediates stronger FcγRIIIa responses but also amplifies brewing cytokine storms and immune-mediated pathologies. Critically ill COVID-19 patients, but not those with mild symptoms, had high concentrations of afucosylated IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), amplifying proinflammatory cytokine release and acute phase responses. Thus, antibody glycosylation plays a critical role in immune responses to enveloped viruses, including COVID-19.