Anti-SARS-CoV-2 IgG from severely ill COVID-19 patients promotes macrophage hyper-inflammatory responses

Hoepel, Willianne; Chen, Hung-Jen; Allahverdiyeva, Sona; Manz, Xue; Aman, Jurjan; Bonta, Peter; Brouwer, Philip; de Taeye, Steven; Caniels, Tom; van der Straten, Karlijn; Golebski, Korneliusz; Griffith, Guillermo; Jonkers, René; Larsen, Mads; Linty, Federica; Neele, Annette; Nouta, Jan; van Baarle, Frank; van Drunen, Cornelis; Vlaar, Alexander; de Bree, Godelieve; Sanders, Rogier; Willemsen, Lisa; Wuhrer, Manfred; Bogaard, Harm Jan; van Gils, Marit; Vidarsson, Gestur; de Winther, Menno; den Dunnen, Jeroen

For yet unknown reasons, severely ill COVID-19 patients often become critically ill around the time of activation of adaptive immunity. Here, we show that anti-Spike IgG from serum of severely ill COVID-19 patients induces a hyper-inflammatory response by human macrophages, which subsequently breaks pulmonary endothelial barrier integrity and induces microvascular thrombosis. The excessive inflammatory capacity of this anti-Spike IgG is related to glycosylation changes in the IgG Fc tail. Moreover, the hyper-inflammatory response induced by anti-Spike IgG can be specifically counteracted in vitro by use of the active component of fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk. One sentence summary Anti-Spike IgG promotes hyper-inflammation.