Kidney SPP1+ B Cells Promote Local Autoantibody Production in Lupus Nephritis

Background: Despite the established role of autoreactive B cells in systemic lupus erythematosus, kidney-specific mechanisms remain unclear. We analyze kidney-infiltrating B cells in lupus nephritis (LN) to reveal their activation, clonal selection, and differentiation pathways toward pathogenic plasma cells. Methods: Single-cell RNA and B cell receptor sequencing were performed on kidney biopsies from 40 LN patients and 6 healthy controls, with matched peripheral blood samples from 9 LN patients. Results: We analyzed 27,154 cells, identifying 10 B-cell subsets including naïve, activated, memory, plasmablasts, and plasma cells. Two novel subsets were found: interferon-stimulated gene-positive naïve B cells, and SPP1+ B cells enriched with MT1G genes. SPP1+ B cells, plasmablasts, and plasma cells were significantly enriched in LN kidneys. LN kidney-infiltrating B cells showed higher IGH mutation loads, preferential isotype switching (IGHG1-3), and pronounced clonal expansion compared to peripheral and healthy kidney cells, especially within SPP1+ subsets, plasmablasts, and plasma cells. In LN kidneys, we stratified plasma cells into clonally expanded (Clone) and non-expanded (Unique) populations. The Clone subset was enriched in severe pathological subtypes. Clonally expanded plasma cells display increased polyreactivity, with three known polyreactive IGHV genes (IGHV3-23, IGHV4-34, and IGHV1-69). Paired BCR analyses indicated minimal peripheral recruitment, with local expansion primarily from SPP1+ B cells. Transcriptomic analysis showed LN-derived SPP1+ B cells upregulated oxidative phosphorylation, and protein synthesis stress pathways, indicating a hypermetabolic state linked to antibody secretion. LN-derived SPP1+ B cells exhibited significantly enhanced IL-21 signaling compared to their healthy counterparts. Cell-cell interaction analysis identified IL-21 signaling between SPP1+ B cells and CXCL13+ T peripheral helper (Tph) cells, highlighting CD4+ T-cell-driven differentiation within LN kidneys. Conclusion: SPP1+ B cells in LN kidneys differentiate locally into plasma cells through IL21-mediated Tph cell interactions, contributing significantly to pathogenic autoantibody production. Funding: Government Support – Non-U.S.