LAUSR

Diverse autoantibodies were suggested to contribute to severe outcomes of COVID‐19, but their functional implications are largely unclear. ACE2, the SARS‐CoV‐2 receptor and a key regulator of blood pressure, was described to be one of many targets of autoantibodies in COVID‐19. ACE2 in its soluble form (sACE2) is highly elevated in the blood of critically ill patients, raising the question of whether sACE2:spike complexes induce ACE2 reactivity. Screening 247 COVID‐19 patients, we observed elevated sACE2 and anti‐ACE2 IgG that were poorly correlated. Interestingly, levels of IgGs recognizing ACE2, IFNα2, and CD26 strongly correlated in severe COVID‐19, with 15% of sera showing polyreactivity versus 4.1% exhibiting target‐directed autoimmunity. Promiscuous autoantibodies failed to impair the activity of ACE2 and IFNα2, while only specific anti‐IFNα2 IgG compromised cytokine function. Our study suggests that the detection of autoantibodies in COVID‐19 is often attributed to a promiscuous reactivity, potentially misinterpreted as target‐specific autoimmunity with functional impact.