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<p>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<sup>+</sup> effector T cells. These clonally expanded CD8<sup>+</sup> effector T cells exhibited transcriptional variations indicating increased migratory capacity and exhaustion, along with preferential usage of TRBV genes (<i>TRBV27/TRBV15/TRBV7-9</i>), 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<sup>+</sup> memory B cells upregulated MHC-I antigen presentation. Renal immunostaining revealed CD74<sup>+</sup> B cells proximal to CD8<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月5日

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  • Qun Liu,
  • Linjie Wu,
  • Sha Hao,
  • Yiyao Deng,
  • Xiaomin Liu,
  • Shunlai Shang,
  • Yena Zhou,
  • Jie Zhang,
  • Qinggang Li,
  • Ping Li,
  • Ying Zheng,
  • Xueyuan Bai,
  • Xu Wang,
  • Xiaowei Xie,
  • Chaomin Guo,
  • Liuyang Yang,
  • Huayu Lin,
  • Guangyan Cai,
  • Tao Cheng,
  • Xiangmei Chen

摘要

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.