Autoantibodies targeting angiotensin-converting enzyme 2 are prevalent and not induced by SARS-CoV-2 infection

Clinical outcomes resulting from SARS-CoV-2 infection vary widely, ranging from asymptomatic cases to the development of mild to severe respiratory illness, and in some instances, chronic lingering disease and mortality. The underlying biological mechanisms driving this wide spectrum of pathogenicity among certain individuals and demographics remain elusive. Autoantibodies have emerged as potential contributors to the severity of COVID-19. Although preliminary reports have suggested the induction of antibodies targeting Angiotensin-Converting Enzyme II (ACE2) post-infection, this assertion lacks confirmation in large-scale studies. In this study, our objective is to comprehensively characterize and quantify the prevalence and expression levels of autoantibodies directed against ACE2 in a sizable cohort (n = 464). Our findings reveal that ACE2-reactive IgM antibodies are the most prevalent, with an overall seroprevalence of 18.8%, followed by IgG at 10.3% and IgA at 6.3%. Longitudinal analysis of individuals with multiple blood draws showed stable ACE2 IgG and IgA levels over time. Upon stratifying individuals based on molecular testing for SARS-CoV-2 or serological evidence of past infection, no significant differences were observed between groups. Functional assessment of ACE2 autoantibodies demonstrated that they are non-neutralizing and failed to inhibit spike-ACE2 interaction or affect the enzymatic activity of ACE2. Our results highlight that ACE2 autoantibodies are prevalent in the general population and were not induced by SARS-CoV-2 infection in our cohort. Notably, we found no substantiated evidence supporting a direct role for ACE2 autoantibodies in SARS-CoV-2 pathogenesis.