Single-cell profiling unveils nephritis-related circulating immunological signatures in systemic lupus erythematosus patients.

Lupus nephritis (LN), the most severe complication of systemic lupus erythematosus (SLE), arises from systemic immune dysregulation and renal damage. While renal immune perturbations are well-studied, systemic signatures specific to LN pathogenesis remain unclear. Integrated single-cell RNA and immune repertoire analysis of 177,259 peripheral blood mononuclear cells (PBMCs) from healthy donors and SLE patients (including active LN and non-nephritis controls) revealed LN-specific circulating immune signatures, including κ light-chain preference in naive B cells and distinct clonal expansion in CD8+ effector T cells. These clonally expanded CD8+ effector T cells exhibited transcriptional variations indicating increased migratory capacity and exhaustion, along with preferential usage of TRBV genes (TRBV27/TRBV15/TRBV7-9), which have enhanced binding potential to an EBV epitope GLCTLVAM. Based on these findings, we developed a dual-biomarker model demonstrating reliable LN diagnosis (AUC = 0.895). Cross-tissue analysis confirmed concordance between peripheral and intrarenal immune perturbations, supporting non-invasive blood-based monitoring. Enhanced MIF-(CD74 + CXCR4) axis activity linked to lymphocyte activation/migration, while CD74+ memory B cells upregulated MHC-I antigen presentation. Renal immunostaining revealed CD74+ B cells proximal to CD8+ T cell infiltrates, suggesting CD74-mediated crosstalk facilitates intrarenal T cell activation. This study provides an integrated LN immune atlas, identifies translatable biomarkers and highlights CD74 as a potential therapeutic target.