Tu109 - Transcriptomic Signatures of ANA+ and ANA- B Cells Reveal Shifts from Active Disease to Remission in Systemic Lupus Erythematosus

Abstract Text: In systemic lupus erythematosus (SLE), IgG antibodies target nuclear antigens (ANA). Healthy individuals (HC) possess ANA+ mature B cells, without producing pathogenic antibodies. This study aimed to identify differential activation and regulatory mechanisms of ANA+ B cells in patients with SLE and HC by single-cell RNA sequencing. We included patients with active disease (SLE-A) and in remission (SLE-R) to gain insight into the immune homeostasis of remission.
We identified seven B cell clusters indicating distinct activation states within conventional B cell subsets. Compared to SLE-R and HC, SLE-A predominantly consisted of activated B cell and age-associated B cell (ABCs) clusters with fewer quiescent Naïve and Marginal Zone B cells. SLE-R displayed both activated and quiescent clusters, but with fewer activated memory and ABCs compared to SLE-A, shifting to a B cell composition that is closer, but not identical, to HC. HC exhibited only quiescent clusters.
Gene set enrichment analysis (GSEA) confirmed the presence of an interferon signature in both SLE-A and SLE-R. GSEA also revealed TNF-α signaling in activated clusters, which correlated inversely with interferon. The upregulation of the Fc receptor pathway in ANA+ B cells from SLE-R and HCs, but not in SLE-A, suggests differential regulation. In patients with SLE, preferential accumulation of ANA+ B cells within activated memory and ABCs was observed, supporting the notion that antigen-experienced ANA+ B cells are selectively activated in SLE. These results provide new insights into the complex B cell landscape in SLE, highlighting potential targets for therapeutic intervention during different disease states.