Distinct Autoreactive CD19– Plasma Cell Subsets Accumulate in Lupus

Plasma cells (PCs) play a pathogenic role in autoimmune diseases by secreting autoantibodies and inflammatory cytokines. While PC elimination therapies exist, they risk depleting protective long-lived plasma cells. Using single cell RNA sequencing, including B cell receptor repertoire analysis, and genetic models, we identified disease- and organ-specific PC subsets in systemic lupus erythematosus (SLE) mice. We uncovered a substantial expansion of autoreactive CD19– PCs, particularly switched CXCR3+ and phosphatidylcholine-specific B-1-derived subsets, which exhibit unique gene expression profiles in SLE. Notably, our findings suggest that CD19– PCs originate from CD19+ PCs in a unidirectional manner, complicating the effectiveness of CD19-targeted therapies in advanced disease stages. This study highlights the crucial role of timing in anti-CD19 therapy and the necessity to broaden therapeutic targets beyond CD19+ PCs. The emergence of CD19– subpopulations underscore the need for novel therapeutic strategies that target these elusive PCs, offering new avenues for intervention in SLE treatment. BM (healthy/sick: each n= 6), spleen (healthy/sick: each n= 6) and kidney (sick: n= 13) of SLE123 mice were collected and pooled. PCs from those tissues were enriched using anti-CD138 magnetic beads followed by cell sorting. Mice without proteinuria (9-12 weeks) were included as healthy control compared to mice with proteinuria (>24 weeks). Sequencing was performed using the 10X Genomics platform with the Single Cell 5’ Library & Gel Bead Kit v1.1 (single index) and Illumina NextSeq2000.