Angiotensin-converting enzyme 2 (ACE2) is a vital component of the renin-angiotensin-aldosterone system (RAAS). Its crucial function is the catalytic conversion of the vasoconstrictor angiotensin II into angiotensin. Angiotensin II is pro-inflammatory, and ACE2 counters this harmful aspect of the RAAS. ACE2 is also the primary receptor engaged by the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein, enabling cell entry. ACE2 autoantibodies have been causally linked to adverse COVID-19 outcomes by causing endothelial dysfunction and complement activation. These autoantibodies, possibly pathogenic during acute COVID-19, might also involve phenomena such as vaccine adverse effects or post-acute sequelae of SARS-CoV-2 infection (PASC).
More Information
The exact causes of severe COVID-19, or the long-lasting effects of SARS-CoV-2 infection, are not yet well defined. One possible contributing mechanism could be the persistent overactivation of the immune system, driving inflammation and cellular injury and disrupting host tissue homeostasis. While inflammatory signaling is critical for viral clearance, heightened or prolonged inflammation could lead to increased tissue damage and adverse disease outcomes.
Acute cases of COVID-19 and associated disease outcomes have been shown to correlate with elevated expression levels of proinflammatory cytokines and chemokines. The enzyme angiotensin-converting enzyme 2 (ACE2) is the host viral receptor for SARS-CoV-2 and plays a crucial role in the renin-angiotensin system that can regulate systemic and local inflammation. ACE2 levels are inversely correlated with markers of inflammation, and mice with genetic knock-out of ACE2 present a hyperinflammation phenotype. It has been reported that SARS-CoV-2 infection can directly alter ACE2 levels, leading to increased inflammation. In addition to altering ACE2 levels and elevated levels of inflammation, individuals with prior SARS-CoV-2 infections produce autoantibodies targeting ACE2, type I interferons, and other immune molecules. These autoantibodies have been associated with more severe COVID-19 disease outcomes. Interestingly, increased autoantibodies to cytokines or other autoantigens have also been observed in other respiratory infections and critical illnesses involving inflammation. Thus, generating autoantibodies to pro-inflammatory immune molecules, including ACE2, could represent a common immunoregulatory mechanism for controlling inflammation. In the case of COVID-19, investigating the levels and activity of ACE2 and the creation of autoantibodies could provide insight into the extent of inflammatory responses and disease severity outcomes. Utilizing these profiles may provide a more accurate understanding of how to treat and predict COVID-19 and other respiratory disease severity before infection. There have been reports that both IgG and IgM isotypes of ACE2 autoantibodies are associated with COVID-19 disease severity. However, the characterization of the features and functions of ACE2 autoantibodies and their impact on COVID-19 disease outcomes within the same cohort has not yet been described.
Autoantibodies targeting ACE2 and other immune factors are higher in individuals with severe COVID-19. These levels may serve as determinants of COVID-19 disease severity and represent an essential immunoregulatory mechanism after viral infection.
