High titers and low fucosylation of early human anti–SARS-CoV-2 IgG promote inflammation by alveolar macrophages

Abstract

Patients diagnosed with coronavirus disease 2019 (COVID-19) become critically ill primarily around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG in serum of critically ill COVID-19 patients induces excessive inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more pro-inflammatory because of different glycosylation, particularly low fucosylation, of the antibody Fc tail. Notably, low fucosylation of anti-spike IgG was normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ Receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated human macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Finally, we demonstrate that the inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk kinase.

Structurally and functionally distinct early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response

“…Additional studies will be required to dissect which cells within the lung are the source of the factors that we observed in response to polyclonal afucosylated immune complexes. Alveolar macrophage (AMs) may have a central role as they are the predominant immune cell population within the lung under normal, unperturbed conditions, express high levels of FcγRIIIa/CD16a and can produce many of these specific factors in response to afucosylated immune complexes ex vivo 21 .…”

Physiological and Pathological Inflammation Induced by Antibodies and Pentraxins

“…While under homeostatic conditions most antibodies display similar antibody glycosylation patterns, the glycosylation of particular antibody clones can change under specific inflammatory conditions. For example, IgG glycosylation can be changed upon infection with enveloped viruses such as Dengue, HIV-1, or SARS-CoV-2 [ 70 , 76 ], which can have major effects on different antibody effector functions, including ADI [ 70 , 76 ].…”

“…This change in glycosylation is known to increase the binding affinity to FcγRs, particularly FcγRIII [ 102 ]. Strikingly, this aberrant glycosylation of anti-spike dramatically amplifies pro-inflammatory cytokine production by alveolar macrophages, thereby contributing to the observed “cytokine storm” that is noticed in these patients [ 76 ]. Moreover, this macrophage (over)activation subsequently permeabilizes pulmonary endothelium, leading to flooding of the lungs, and induces microvascular thrombosis, two hallmarks of severe COVID-19 [ 76 , 103 ].…”

“…CRP could also play a role in severely ill COVID-19 patients, since CRP levels in these patients are exceptionally high [ 70 ] and severe tissue damage in the lungs will lead to ample binding of CRP. In these patients, this would then act on top of the inflammation that is already induced by pathogenic IgG [ 76 ].…”

“…While ADI provides a powerful mechanism to counteract infections, over-activation of this mechanism can lead to chronic inflammation. One example of how ADI contributes to chronic inflammation is when antibodies become intrinsically more pro-inflammatory, caused by changes in the antibody glycosylation as described for various diseases, including COVID-19 [ 70 , 76 ], RA [ 42 , 106 ], and multiple myeloma [ 136 ]. Therefore, targeting of antibody glycosylation may be a promising therapeutic option.…”