Unique extrafollicular B cell expansion in COVID-19 patients who developed prothrombotic platelet-activating antibodies 2427

Description Despite vaccine development, COVID-19 morbidity and mortality remain high, with thrombotic complications contributing significantly to severe cases. Our lab has identified a subset of hospitalized COVID-19 patients who develop prothrombotic platelet-activating antibodies, some of which target the receptor-binding domain of the SARS-CoV-2 spike protein. To explore the origins of these antibodies, we performed single-cell RNA and VDJ sequencing on B cells from hospitalized COVID-19 patients. We found no major differences in overall B cell populations between patients who developed platelet-activating antibodies (PEA+) and those who did not (PEA-). However, distinct expansions of B cell clones were observed between the two groups. Further, the PEA+ expanded clones showed lower mutation frequencies in their heavy chain complementarity-determining regions, a strong IFN-γ signaling signature, and markers of DN2 B cells—an extrafollicular subset linked to autoimmune diseases. Furthermore, PEA+ and PEA- B cells generated transcriptionally distinct atypical memory B cell subclusters. Together, these findings suggest that prothrombotic antibody generation in hospitalized COVID-19 patients involves an extrafollicular pathway driven by IFN-γ signaling, leading to autoreactive antibodies with reduced mutation frequencies. Funding Sources NIH R01HL161127; NIH R01HL148120; NIH P01HL167668 Topic Categories Immune Mechanisms of Human Disease (HUM)