Inflammation and autoreactivity define a discrete subset of patients with post-acute sequelae of COVID-19, or long-COVID

Abstract

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.

Clinical, imaging, serological, and histopathological features of pulmonary post-acute sequelae after mild COVID-19 (PASC)

“…Presence of autoantibodies was not associated with specific clinical characteristics, results from pulmonary function test or histopathological findings. Thus, they might reflect extrafollicular B cell activation upon contact with SARS-CoV-2 [24].…”

Inflammation, immunity, and antigen persistence in post-acute sequelae of SARS-CoV-2 infection

“…atMBCs are also associated with the production of autoantibodies in several autoimmune diseases, and were observed to be expanded in the peripheral blood of individuals with PASC prior to the onset of symptoms [13] . Cheon and colleagues [44•] also observed elevated frequencies of activated resident memory-like CD27 + CD69 + B cells in the BAL fluid of aged convalescent subjects, and several studies have shown or suggested a potential relationship between peripheral autoantibody levels and PASC 46 , 47• . Further investigation will be required to determine whether atMBCs and circulating autoantibodies detected in PASC patients contribute to symptoms, or are a consequence of PASC itself.…”

The pathogenesis of neurologic symptoms of the postacute sequelae of severe acute respiratory syndrome coronavirus 2 infection

“…The few studies that have specifically examined autoantibodies in patients with PASC are suggestive that postinfectious autoimmune processes persist. In one cohort of 95 patients with PASC, 80% of the patients had autoantibodies 110 days after infection with SARS-CoV-2 and 40% of the patients had antibodies to two or more immune specificities [46 ▪ ]. Another study of 31 patients, composed primarily of patients with neurological symptoms, found antibodies to β2 adrenoceptor, muscarinic M2 receptor, angiotensin II AT1 receptor, and angiotensin 1–7 MAS receptor [47 ▪ ].…”