Abstract
Plasma cells (PC) participate in the pathogenesis of systemic lupus erythematosus (SLE) through sustained autoantibody and inflammatory cytokine secretion. Current PC-depleting therapies risk eliminating protective long-lived PCs, highlighting the need to identify pathogenic subsets for selective targeting. Here, using single-cell RNA sequencing, B cell receptor repertoire analysis, and genetic models, we identify disease- and organ-specific PCs in lupus-prone mice. We find a substantial expansion of autoreactive CD19- PCs, particularly class-switched CXCR3⁺ and phosphatidylcholine-specific B-1-derived subsets, which exhibit unique gene expression profiles. We show that CD19- PCs originate from CD19+ PCs in a unidirectional manner. Peripheral blood from SLE patients shows elevated frequencies of CD19- PCs, implicating these cells in sustaining pathogenic activity. Our findings highlight the emergence of autoreactive CD19- PCs as a critical feature of lupus pathogenesis in mice and underscore the need for therapeutic approaches that extend beyond CD19-targeting to improve treatment strategies in SLE.