Autoantibodies stabilize neutrophil extracellular traps in COVID-19.

Yu Zuo,Alyssa Harbaugh,Melanie Zuo,Yogendra Kanthi,Claire K Hoy,Srilakshmi Yalavarthi,Jacqueline A Madison,Hui Shi,Sherwin A Navaz,Jason S Knight,Kelsey Gockman

doi:10.1172/jci.insight.150111

Abstract

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 anti-NET antibodies in 328 individuals hospitalized with COVID-19 alongside 48 healthy controls. We found high anti-NET activity in the IgG and IgM fractions of 27% and 60% of patients, respectively. There was a strong correlation between anti–NET IgG and anti–NET IgM. Both anti–NET IgG and anti–NET IgM tracked with high levels of circulating NETs, impaired oxygenation efficiency, and high circulating D-dimer. Furthermore, patients who required mechanical ventilation had a greater burden of anti-NET antibodies than did those not requiring oxygen supplementation. Levels of anti–NET IgG (and, to a lesser extent, anti–NET IgM) demonstrated an inverse correlation with the efficiency of NET degradation by COVID-19 sera. Furthermore, purified IgG from COVID-19 sera with high levels of anti-NET antibodies impaired the ability of healthy control serum to degrade NETs. In summary, many individuals hospitalized with COVID-19 have anti-NET antibodies, which likely impair NET clearance and may potentiate SARS-CoV-2–mediated thromboinflammation.

Highlights

While it has been more than a year since the initial outbreak, coronavirus disease 2019 (COVID-19) — caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — remains a global health challenge with alarming death tolls [1]
Utilizing a unique ELISA platform that we developed (Figure 1A), we measured anti–neutrophil extracellular traps (NETs) IgG and IgM antibodies in 328 patients hospitalized with COVID-19 alongside 48 healthy controls
Elevated levels of anti–NET IgG and IgM were detected in patients with COVID-19 as compared with healthy controls (Figure 1, B and C)

Summary

Introduction

While it has been more than a year since the initial outbreak, coronavirus disease 2019 (COVID-19) — caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) — remains a global health challenge with alarming death tolls [1]. Severe acute COVID-19 is characterized by a thromboinflammatory state driven by a complex interplay between innate and adaptive immune responses [1]. This state manifests clinically as acute respiratory distress syndrome and, in some patients, widespread thrombotic microangiopathy. Our group and others have described high levels of NETs circulating in the blood of hospitalized COVID-19 patients, where they correlate with disease severity [6, 9,10,11,12]. We have found that neutrophil hyperactivity at the time of hospital admission predicts a more severe hospital course [13] and that NET levels are especially high in patients who experience thrombotic complications [14]

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