This study investigated the cellular origins of autoantibodies (autoAbs) in SARS-CoV-2 infection using the INCOV cohort (n=12, age- and sex-matched participants with varying autoAb levels), integrating single-cell RNA-seq, ATAC-seq, plasma proteomics, proteome-wide autoAb profiling, and in vitro assays.
CD11c+ atypical memory B cells (double-negative 2, DN2s) were identified as key precursors of autoAb-producing cells; autoAb abundance inversely correlated with neutralizing IgG, and in vitro TLR7/8 stimulation preferentially drove atypical memory B cells toward autoAb-secreting differentiation. DN2s showed the strongest enrichment for autoimmune trait heritability among all B cell subsets.
The discovery cohort is very small (n=12), limiting statistical power and generalizability. The study is observational and in vitro findings may not fully reflect in vivo biology. Causal directionality between DN2 expansion and autoAb production cannot be firmly established from this design.
Clinicians should be aware that autoantibody production in COVID-19 may be driven by a distinct DN2 B cell subset, which could represent a future therapeutic target—particularly for patients at risk of Long COVID or autoimmune sequelae. Monitoring autoAb levels alongside neutralizing IgG may help stratify disease severity risk.
