text: Development of ACE2 autoantibodies after SARS CoV 2 infection Activation of the immune system is implicated in the Post Acute Sequelae after SARS CoV 2 infection PASC but the mechanisms remain unknown Angiotensin converting enzyme 2 ACE2 cleaves angiotensin II Ang II resulting in decreased activation of the AT1 receptor and decreased immune system activation We hypothesized that autoantibodies against ACE2 may develop after SARS CoV 2 infection as anti idiotypic antibodies to anti spike protein antibodies We tested plasma or serum for ACE2 antibodies in 67 patients with known SARS CoV 2 infection and 13 with no history of infection None of the 13 patients without history of SARS CoV 2 infection and 1 of the 20 outpatients that had a positive PCR test for SARS CoV 2 had levels of ACE2 antibodies above the cutoff threshold In contrast 26 32 81 in the convalescent group and 14 15 93 of patients acutely hospitalized had detectable ACE2 antibodies Plasma from patients with antibodies against ACE2 had less soluble ACE2 activity in plasma but similar amounts of ACE2 protein compared to patients without ACE2 antibodies We measured the capacity of the samples to inhibit ACE2 enzyme activity Addition of plasma from patients with ACE2 antibodies led to decreased activity of an exogenous preparation of ACE2 compared to patients that did not have antibodies Many patients with a history of SARS CoV 2 infection have antibodies specific for ACE2 Patients with ACE2 antibodies have lower activity of soluble ACE2 in plasma Plasma from these patients also inhibits exogenous ACE2 activity These findings are consistent with the hypothesis that ACE2 antibodies develop after SARS CoV 2 infection and decrease ACE2 activity This could lead to an increase in the abundance of Ang II which causes a proinflammatory state that triggers symptoms of PASC 