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

## TL;DR

This study uses single-cell analysis to identify immune signatures in blood that are linked to kidney inflammation in lupus patients, offering non-invasive biomarkers and a new treatment target.

## Contribution

The study identifies LN-specific immune signatures in blood and proposes CD74 as a potential therapeutic target.

## Key findings

- LN-specific immune signatures include κ light-chain preference in B cells and clonal expansion in CD8+ T cells.
- A dual-biomarker model achieved reliable LN diagnosis with an AUC of 0.895.
- CD74+ B cells and T cell crosstalk suggest a role for CD74 in intrarenal T cell activation.

## Abstract

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.

Integrated single-cell RNA and immune repertoire analysis of PBMCs identifies key circulating immune perturbations in lupus nephritis, highlighting non-invasive biomarkers and CD74 as a potential therapeutic target.