Transcriptomic characterization of transitional B cells reveals four subsets with perturbed activation profiles in...

We previously demonstrated that patients with scleroderma or systemic sclerosis (SSc) have elevated autoreactive transitional B cells, including against topoisomerase I (anti-topoisomerase I autoantibody [ATA⁺]). This suggests that defective transitional B cell tolerance could drive autoimmunity in SSc. To investigate this, we used single-cell transcriptomic and B cell receptor (BCR) sequencing on sorted transitional B cells from treatment-naive SSc patients and healthy controls (HCs). Four transitional B cell clusters were identified as T1, T2, CD27⁺, and marginal zone precursors (MZPs). T1 B cells were significantly expanded in SSc with a 2-fold increase compared with HCs. Additionally, pro-survival genes (IL4R, TCL1A, and S100A10) and IFN-responsive genes (IFITM1 and IFITM2) were upregulated in SSc. BCR analysis revealed increased complementarity determining region 3 (CDR3) hydrophobicity and altered κ/λ ratios with proximal Jκ gene usage in the SSc patients. Collectively, our findings support divergent transitional B cell development and activation in SSc with an AKT-driven pathway likely promoting autoreactive transitional B cell survival.