Autoantibodies to ACE2 and immune molecules are associated with COVID-19 disease severity

Abstract

Background

Increased inflammation caused by SARS-CoV-2 infection can lead to severe coronavirus disease 2019 (COVID-19) and long-term disease manifestations. The mechanisms of this variable long-term immune activation are poorly defined. One feature of this increased inflammation is elevated levels of proinflammatory cytokines and chemokines. Autoantibodies targeting immune factors such as cytokines, as well as the viral host cell receptor, angiotensin-converting enzyme 2 (ACE2), have been observed after SARS-CoV-2 infection. Autoantibodies to immune factors and ACE2 could interfere with normal immune regulation and lead to increased inflammation, severe COVID-19, and long-term complications.

Methods

Here, we deeply profiled the features of ACE2, cytokine, and chemokine autoantibodies in samples from patients recovering from severe COVID-19. We measured the levels of immunoglobulin subclasses (IgG, IgA, IgM) in the peripheral blood against ACE2 and 23 cytokines and other immune molecules. We then utilized an ACE2 peptide microarray to map the linear epitopes targeted by ACE2 autoantibodies.

Results

We demonstrate that ACE2 autoantibody levels are increased in individuals with severe COVID-19 compared with those with mild infection or no prior infection. We identify epitopes near the catalytic domain of ACE2 targeted by these antibodies. Levels of autoantibodies targeting ACE2 and other immune factors could serve as determinants of COVID-19 disease severity, and represent a natural immunoregulatory mechanism in response to viral infection.

Conclusions

These results demonstrate that SARS-CoV-2 infection can increase autoantibody levels to ACE2 and other immune factors. The levels of these autoantibodies are associated with COVID-19 disease severity.

Plain language summary

Antibodies are small proteins that are produced by your immune system to protect you when an unwanted foreign invader such as bacteria, viruses and toxins enters your body. When these antibodies target proteins on our own cells instead of the invader, we call them autoantibodies. Autoantibodies that target host immune molecules, as well as ACE2, a receptor molecule that interacts with the SARS-CoV-2 virus, have been observed after COVID-19. We found that patients who had severe COVID-19 displayed higher levels of these autoantibodies compared to those who had mild infection or were uninfected. These findings suggest that these autoantibody levels could serve as indicators of COVID-19 severity.

Abstract

Geanes et al. demonstrate that COVID-19 severity is associated with increased levels of IgG, IgA, IgM antibodies to ACE2 and other immune molecules. These findings expand the understanding of immune mechanisms in COVID-19 and suggest that the evaluation of autoantibody levels to immune factors may serve as a potential biomarker for COVID-19 severity.