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 Patients with severe COVID-19 show heightened afucosylated antiviral antibody responses. INTRODUCTION Antibody function is often considered static and mostly determined by isotype and subclass. The conserved N-linked glycan at position 297 in the Fc domain of immunoglobulin G (IgG) is essential for an antibody’s effector functions. Moreover, this glycan is highly variable and functionally relevant, especially for the core fucose moiety. IgG lacking core fucosylation (afucosylated IgG) causes increased antibody-dependent cellular cytotoxicity (ADCC) through highly increased IgG-Fc receptor IIIa (FcγRIIIa) affinity. Despite constant levels of total plasma IgG-Fc fucosylation above 90%, specific IgG responses with low core fucosylation have been sporadically reported. These are directed against alloantigens on blood cells and glycoproteins of HIV and dengue virus. In this study, we investigated the induction of afucosylated IgG to various antigens and delineated its dynamics and proinflammatory potential in COVID-19. RATIONALE Afucosylated IgG responses have only been found in various alloimmune responses against cellular blood groups and two enveloped viruses. Therefore, we tested the hypothesis that foreign surface–exposed, membrane-embedded proteins induce a specific B cell response that results in afucosylated IgG. We compared immune responses to natural infections by enveloped viruses and nonenveloped viruses, protein subunit vaccination, and live attenuated virus vaccinations. We also assessed the relation to the clinical outcome of such a response in COVID-19. RESULTS Analogous to blood cell alloantigens, the response to all enveloped viruses showed clear signatures of afucosylation of the antigen-specific IgG. By contrast, IgG against the nonenveloped virus, parvovirus B19, were highly fucosylated. The extent of afucosylated IgG responses varied, both between individuals and between antigens. The viral context was essential to induce afucosylated IgG because induction did not occur after subunit vaccination against hepatitis B virus. However, afucosylated IgG responses were found in response to attenuated viruses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific afucosylated IgG were also found in critically ill COVID-19 patients but not in individuals with mild symptoms. Over the 2 weeks after seroconversion, the amount of fucosylated anti–SARS-CoV-2 IgG increased markedly, in most reaching relative levels similar to those found in total IgG. Afucosylated IgG promoted interleukin-6 (IL-6) release in macrophages cultured in vitro, which is in line with an observed association of SARS-CoV-2–specific IgG afucosylation with IL-6 and C-reactive protein (CRP) in these patients. CONCLUSION This work suggests that providing foreign B cell antigens in the context of host cells may be required to trigger an afucosylated IgG immune response. The strength of this response is highly variable for different antigens and between individuals. An afucosylated IgG response is a potent immune response, honed for the destruction of target cells by FcγRIII-expressing natural killer (NK) and myeloid cells. This may sometimes be desirable—for example, against HIV—and can be achieved in vaccines by providing the target as a surface protein, as is the case with attenuated viral vaccines or mRNA vaccines. However, for SARS-CoV-2, this afucosylated IgG response may promote the exacerbation of COVID-19 under conditions with high viral loads at the time of seroconversion. Afucosylated IgG response requires membrane context and results in strong FcγRIII-mediated activity. Only membrane association on host cells endows foreign antigens to trigger the B cell receptor in the context of other self receptors, leading to an afucosylated IgG response. The elevated FcγRIII binding and activity of afucosylated IgG can in some cases be protective, but for SARS-CoV-2, this triggers excessive inflammation during a natural infection. 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.
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