Autoantibodies against Angiotensin-converting enzyme 2 and immune molecules are associated with COVID-19 disease severity.

Increased inflammation caused by SARS-CoV-2 infection can lead to severe coronavirus disease 2019 (COVID-19) and long-term disease manifestations referred to as post-acute sequalae of COVID (PASC). The mechanisms of this variable long-term immune activation are poorly defined. 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. Here, we deeply profiled the features of ACE2, cytokine, and chemokine autoantibodies in samples from patients recovering from severe COVID-19. We identified epitopes in the catalytic domain of ACE2 targeted by these antibodies, that could inhibit ACE2 function. 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.