Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity

Larsen, Mads Delbo; de Graaf, Erik L.; Sonneveld, Myrthe E.; Plomp, H. Rosina; Nouta, Jan; Hoepel, Willianne; Chen, Hung-Jen; Linty, Federica; Visser, Remco; Brinkhaus, Maximilian; Šuštić, Tonći; de Taeye, Steven W.; Bentlage, Arthur E. H.; Toivonen, Suvi; Koeleman, Carolien A. M.; Sainio, Susanna; Kootstra, Neeltje A.; Brouwer, Philip J.M.; Geyer, Chiara Elisabeth; Derksen, Ninotska I. L.; Wolbink, Gertjan; de Winther, Menno; Sanders, Rogier W.; van Gils, Marit J.; de Bruin, Sanne; Vlaar, Alexander P. J.; Rispens, Theo; den Dunnen, Jeroen; Zaaijer, Hans L.; Wuhrer, Manfred; Ellen van der Schoot, C.; Vidarsson, Gestur

IgG antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc tail, essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anti-cancer therapeutic antibodies for their elevated activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG (~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 levels of afucosylated IgG antibodies against SARS-CoV-2, amplifying pro-inflammatory cytokine release and acute phase responses. Thus, antibody glycosylation plays a critical role in immune responses to enveloped viruses, including COVID-19.