Evidence of Persisting Autoreactivity in Post-Acute Sequelae of SARS-CoV-2 Infection

Woodruff, M.; Walker, T.; Truong, A.; Han, J.; Dixit, A.; Ramonell, R.; Runnstrom, M.; Rudoloph, M.; Khosroshahi, A.; Lee, F. E.-H.; Sanz, I.

Recent studies have demonstrated the significant breadth of emerging autoreactivity in severe SARS-CoV-2 infection. Importantly, we have identified a relaxation of peripheral tolerance within early antibody secreting cells that emerge in patients with COVID-19 as important drivers of those responses. While often viral-specific, these extrafollicular-derived cells also display cross reactivity to autoantigens present in the inflammatory lung environment, and despite resolution of most autoreactivity within 6 months, they persisted in some patients. These results raise questions regarding autoreactive antibodies that arise during acute SARS-CoV-2 infection and their persistence in patients with symptoms in Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Through clinical autoreactive antibody screening of 95 patients with PASC and no history of autoimmune disease, we identify significant autoreactive profiles in patients with ongoing symptoms post-recovery, with 80% of patients returning positive tests for at least one autoantigen, and 40% showing breaks in tolerance to 2 or more. Anti-nuclear antigen positivity was most common, displaying positivity in 63% of patients, however, positive tests were broad and included reactivities against carbamylated protein responses, RNA polymerase III, and phospholipids. We also identify patients with reactivity against dsDNA in the PASC cohort -- a reactivity not observed in acute infection even in the critically ill. These results demonstrate evidence of serum autoantibodies in patients who present to PASC clinics with persistent symptoms up 14 months following SARS-CoV-2 infection, and further confirm the growing linkage between COVID-19 and observed clinical autoreactivity -- even into the recovery phase of disease.