The disease-residual transcriptomic profile of B cells drives distinct Dsg-specific antibody regeneration in pemphigus

Summary: Abstract Body: B cells are critical effectors in the onset and relapse of pemphigus. To unravel the characteristics of pathogenic B cells responsible for disease relapse, we constructed a comprehensive B cell blueprint using single-cell transcriptomics and B cell receptor (BCR) repertoire analysis in patients with pemphigus vulgaris (PV). The study included pemphigus vulgaris (PV) patients during remission with anti-Dsg1 or anti-Dsg3 antibodies (Dsg+ PV), patients who had undergone seroconversion to negativity (Dsg- PV), PV patients during active disease (Act PV), and healthy controls. Through integrated analyses, we characterized the cellular composition, transcriptomic landscape, and BCR features of B cell subtypes across different disease groups. Notably, we identified immunoglobulin class switching differences among Act PV, Dsg+ PV and Dsg- PV. By combining single-cell sequencing with flow cytometry, we observed an enrichment of age-associated B cells (ABCs) in Dsg+ PV, along with dysregulated regulatory B cells (Bregs). BCR lineage tracing and pseudotime trajectory analysis revealed that plasma cells in PV patients exhibit distinct developmental origins based on specific autoantibody profiles. ABCs are located at the terminal end of the B cell developmental trajectory in Dsg+ PV and share some BCR clones with plasma cells. Furthermore, we identified a unique disease-residual transcriptomic profile (DRTP) that underpins ABCs perturbations in patients with high Dsg-specific antibody during remission. Our findings suggest that PV patients with high Dsg-specific antibody titers during remission retain a DRTP, which drives ABCs developmental programs and potentially contributes to disease relapse. Zhi Hu¹, Ming Zhao¹ 1. Affiliated Hospital for Skin Diseases of Chinese Academy of Medical Sciences, Nanjing, Jiangsu, China. Adaptive and Auto-Immunity