Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity
Open accessPublished version of a preprint
Abstract
A single sugar makes all the difference: Antibodies are divided into several classes based on their nonvariable tail (Fc) domains. These regions interact with disparate immune cell receptors and complement proteins to help instruct distinct immune responses. The Fc domain of immunoglobulin G (IgG) antibodies contains a conserved N-linked glycan at position 297. However, the particular glycan used at this position is highly variable. IgG lacking core fucosylation at this position initiates enhanced antibody-dependent cellular cytotoxicity by increased affinity to the Fc receptor FcRIIIa. Larsen et al. report that COVID-19 patients with severe symptoms have increased levels of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG afucosylation compared with patients with mild disease. These findings suggest that treatment of COVID-19 patients with fucosylated anti–SARS-CoV-2 antibodies may circumvent pathologies associated with severe COVID-19. Science , this issue p. eabc8378
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Antibodies that promote inflammation might contribute to cytokine storm and severe disease.
“On the other hand, antibodies promoting inflammatory responses may contribute to a cytokine storm resulting in severe disease32,33.”
From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [33]
The possible role of IgG with reduced Fc fucosylation and stronger FcγRIII binding in severe COVID-19 suggests that vaccine-induced antibody quality may matter for minimizing ADE risk.
“However, the potential role of IgG with reduced Fc fucosylation and enhanced binding to FcγRIII in the development of severe COVID-19 suggests that the quality of antibodies induced by vaccination may also be important in minimizing the risk of ADE32,33.”
From Immunological mechanisms of vaccine-induced protection against COVID-19 in humans (2021) · cites this paper as [33]
ADCC-mediating antibodies have been detected in plasma of COVID-19 convalescent donors.
“ADCC-mediating antibodies have been detected in plasma of COVID-19 convalescent donors (16, 67, 68).”
From SARS-CoV-2 variants of concern partially escape humoral but not T cell responses in COVID-19 convalescent donors and vaccine recipients (2021) · cites this paper as [68]
The presence of IgG antibodies with an afucosylated IgG-Fc tail during acute COVID-19 is associated with severe outcomes.
“Interestingly, the presence of IgG antibodies with an afucosylated IgG-Fc tail during acute COVID-19 infection have also been associated with severe COVID-19 outcomes, perhaps owing to their stronger pro-inflammatory activity via FcγRIIIa153.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [153]
Afucosylated IgG-Fc antibodies may be associated with severe COVID-19 because of stronger pro-inflammatory activity via FcγRIIIa.
“Interestingly, the presence of IgG antibodies with an afucosylated IgG-Fc tail during acute COVID-19 infection have also been associated with severe COVID-19 outcomes, perhaps owing to their stronger pro-inflammatory activity via FcγRIIIa153.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [153]
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References 41 · Cited by 408
Research works printed but not linked: 3
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- Authors
- Larsen, M. D., de Graaf, E. L., Sonneveld, M. E., Plomp, H. R., Nouta, J., Hoepel, W., Chen, H.-J., Linty, F., Visser, R., Brinkhaus, M., Šuštić, T., de Taeye, S. W., Bentlage, A. E. H., Toivonen, S., Koeleman, C. A. M., Sainio, S., Kootstra, N. A., Brouwer, P. J. M., Geyer, C. E., Derksen, N. I. L., Wolbink, G., de Winther, M., Sanders, R. W., van Gils, M. J., de Bruin, S., Vlaar, A. P. J., COVID-19, A. U., biobank study group, Rispens, T., den Dunnen, J., Zaaijer, H. L., Wuhrer, M., Ellen van der Schoot, C., Vidarsson, G., van Agtmael, M., Algera, A. G., van Baarle, F., Bax, D., van de Beek, D., Beudel, M., Bogaard, H. J., Bonta, P. I., Bomers, M., Bos, L., Botta, M., de Bree, G., Brouwer, M. C., Brabander, J., de Bruin, S., Bugiani, M., Bulle, E., Chouchane, O., Cloherty, A., Elbers, P., Fleuren, L., Geerlings, S., Geerts, B., Geijtenbeek, T., Girbes, A., Goorhuis, B., Grobusch, M. P., Hafkamp, F., Hagens, L., Hamann, J., Harris, V., Hemke, R., Hermans, S. M., Heunks, L., Hollmann, M. W., Horn, J., Hovius, J. W., de Jong, M., Koning, R., van Mourik, N., Nellen, J., Nossent, E. J., Paulus, F., Peters, E., van der Poll, T., Preckel, B., Prins, J. M., Raasveld, J., Rijnders, T., Schinkel, M., Schultz, M., Schuurmans, A. R., Sigaloff, K., Smit, M., Stijnis, C. S., Stilma, W., Teunissen, C., Thoral, P., Tsonas, A., van der Valk, M., Veelo, D., Vlaar, A. P. J., de Vries, H., van Vugt, M., Wiersinga, W. J., Wouters, D., & Zwinderman, A. H. (.
- Affiliations
- Sanquin (NL)
- Department of Experimental Immunohematology, Sanquin Research, Amsterdam, Netherlands.
- Leiden University Medical Center (NL)
- Amsterdam University Medical Centers (NL)
- Finnish Red Cross (FI)
- Reade (NL)
- Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
- Cornell University (US)
- Department of Medical Microbiology, Amsterdam UMC, Amsterdam Infection and Immunity Institute, University of Amsterdam, Amsterdam, Netherlands.
- Department of Rheumatology and Clinical Immunology, Amsterdam UMC, Amsterdam Rheumatology and Immunology Center, Amsterdam, Netherlands.
- Amsterdam UMC Location University of Amsterdam (NL)
- Corresponding author
- Larsen, Mads Delbo
- Sonneveld, Myrthe E.
- Vidarsson, Gestur
- ORCID
- Larsen, Mads Delbo
- de Graaf, Erik L.
- Sonneveld, Myrthe E.
- Plomp, H. Rosina
- Hoepel, Willianne
- Chen, Hung-Jen
- 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.
- Rispens, Theo
- den Dunnen, Jeroen
- Zaaijer, Hans L.
- Wuhrer, Manfred
- Vidarsson, Gestur
- Beudel, Martijn
- Bogaard, Harm Jan
- Bonta, Peter I.
- Bomers, Marije
- Bos, Lieuwe
- Botta, Michela
- Brouwer, Matthijs C.
- Brabander, Justin
- Bugiani, Marianna
- Bulle, Esther
- Chouchane, Osoul
- Elbers, Paul
- Fleuren, Lucas
- Geerlings, Suzanne
- Geerts, Bart
- Girbes, Armand
- Grobusch, Martin P.
- Hafkamp, Florianne
- Hagens, Laura
- Harris, Vanessa
- Hemke, Robert
- Hermans, Sabine M.
- Heunks, Leo
- Hollmann, Markus W.
- Horn, Janneke
- Hovius, Joppe W.
- Koning, Rutger
- Nossent, Esther J.
- Paulus, Frederique
- Peters, Edgar
- Prins, Jan M.
- Raasveld, Jorinde
- Schinkel, Michiel
- Schultz, Marcus
- Sigaloff, Kim
- Smit, Marry
- Stijnis, Cornelis S.
- Stilma, Willemke
- Teunissen, Charlotte
- Thoral, Patrick
- Tsonas, Anissa
- Veelo, Denise
- Wiersinga, W. Joost
- Zwinderman, A. H. (Koos)
- Venue
- Science
- Published
- 2021-02-26
- Volume
- 371
- Issue
- 6532
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7919849
- OpenAlex
- W3117759033
- Cited by
- 408
- References
- 41
- Citations by year
- 2026: 32 · 2025: 58 · 2024: 62 · 2023: 63 · 2022: 95 · 2021: 86 · 2020: 12
- FWCI
- 31.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Science (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Leiden Repository (Leiden University) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Funders
- Landsteiner Foundation for Blood Transfusion Research (1229, 1908)
- H2020 European Research Council (722095)
- Seventh Framework Programme (278535)
- ZonMW (10430 01 201 0008, 10430 01 201 0021)
- Amsterdam Infection and Immunity Institute (24175, 24184)
- Netherlands Organization for Scientific Research
- Marie Skłodowska-Curie (847551)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Keywords
- antibody glycosylation, FcγRIIIa, enveloped viruses, SARS-CoV-2, COVID-19 severity, cytokine storm, inflammatory cytokines, acute phase response, humoral immune response
- MeSH terms
- COVID-19, SARS-CoV-2, Adult, Aged, Antibodies, Viral, Cells, Cultured, Cytomegalovirus, Female, Fucose, Glycosylation, HIV, Humans, Immunoglobulin G, Immunoglobulin Fc Fragments, Inflammation, Macrophages, Male, Middle Aged, Severity of Illness Index, Interleukin-6, Critical Illness, Parvovirus B19, Human, Hepatitis B Vaccines, Vaccines, Subunit, Young Adult, Spike Glycoprotein, Coronavirus
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