Clonal landscape of autoantibody-secreting plasmablasts in COVID-19 patients

Although severe COVID-19 is often associated with elevated autoantibody titers, the underlying mechanism has been unclear. Here, we investigated repertoires and reactivities of immunoglobulins derived from blood plasmablasts (PBs) in COVID-19 patients. This uncovered robust clonal expansion of PBs secreting cardiolipin (CL)-reactive autoantibodies in humoral response to SARS-CoV-2. About half of the expanded CL-reactive clones were also reactive to SARS-CoV-2 antigens and derived from SARS-CoV-2-specific primary responses as well as seasonal coronavirus-reactive memory responses. One such clone, CoV1804, was reactive to both CL and viral nucleocapsid (N), and exhibited anti-nucleolar activity in human cells. Repertoire analysis identified antibodies sharing genetic features with CoV1804 in COVID-19 patient-derived immunoglobulins from our and other cohorts, thereby constituting a novel public antibody. These public autoantibodies had numerous mutations that enhanced anti-N reactivity. On the other hand, anti-CL reactivity fluctuated through somatic hypermutation, which instead resulted in the acquisition of additional self-reactivities, including anti-nucleolar activity in the progeny. Thus, potentially CL-reactive precursors may have developed multiple reactivities to different self-antigens through clonal expansion driven by viral antigens. Our results unraveled a unique process of autoantibody production during COVID-19 and provide novel insights into the origin of virus-induced autoantibodies.