Proinflammatory IgG Fc structures in patients with severe COVID-19

Chakraborty, Saborni; Gonzalez, Joseph; Edwards, Karlie; Mallajosyula, Vamsee; Buzzanco, Anthony S.; Sherwood, Robert; Buffone, Cindy; Kathale, Nimish; Providenza, Susan; Xie, Markus M.; Andrews, Jason R.; Blish, Catherine A.; Singh, Upinder; Dugan, Haley; Wilson, Patrick C.; Pham, Tho D.; Boyd, Scott D.; Nadeau, Kari C.; Pinsky, Benjamin A.; Zhang, Sheng; Memoli, Matthew J.; Taubenberger, Jeffery K.; Morales, Tasha; Schapiro, Jeffrey M.; Tan, Gene S.; Jagannathan, Prasanna; Wang, Taia T.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections can cause Coronavirus Disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that severe COVID-19 patients produced a unique serologic signature, including increased IgG1 with afucosylated Fc glycans. This Fc modification on SARS-CoV-2 IgGs enhanced interactions with the activating FcγR, FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including IL-6 and TNF. These results show that disease severity in COVID-19 correlates with the presence of afucosylated IgG1, a pro-inflammatory IgG Fc modification.