Autoantibodies stabilize neutrophil extracellular traps in COVID-19

The release of neutrophil extracellular traps ( NETs ) by hyperactive neutrophils is recognized to play an important role in the thromboinflammatory milieu inherent to severe presentations of COVID-19. At the same time, a variety of functional autoantibodies have been observed in individuals with severe COVID-19 where they likely contribute to immunopathology. Here, we aimed to determine the extent to which autoantibodies might target NETs in COVID-19 and, if detected, to elucidate their potential functions and clinical associations. We measured global anti-NET activity in 171 individuals hospitalized with COVID-19 alongside 48 healthy controls. We found high anti-NET activity in the IgG and IgM fractions of approximately 40% and 50% of patients, respectively. There was a strong correlation between anti-NET IgG and anti-NET IgM, with high anti-NET antibody levels in general associating with circulating markers of NETs such as myeloperoxidase-DNA complexes and calprotectin. Clinically, anti-NET antibodies tracked with impaired oxygenation efficiency and elevated levels of circulating D-dimer. Furthermore, patients who required mechanical ventilation had higher levels of anti-NET antibodies than those who did not require oxygen supplementation. Mechanistically, anti-NET antibodies of the IgG isotype impaired the ability of DNases in healthy serum to degrade NETs. In summary, these data reveal high levels of anti-NET antibodies in individuals hospitalized with COVID-19, where they likely impair NET clearance and thereby potentiate SARS-CoV-2 mediated thromboinflammation.