Type I interferon dysregulation drives distinct pathogenic pathways in early- and late-onset lupus nephritis.

Abstract

Lupus nephritis (LN) is a leading cause of morbidity and mortality in systemic lupus erythematosus (SLE), affecting nearly half of the patients with SLE. Type I interferon (IFN) plays a central role in SLE and LN pathogenesis. This study explored the differential expression of type I IFN gene signatures (IFNGS) in renal tissues from early- and late-onset LN patients to uncover pathways linked to disease progression. Twenty-one patients with biopsy-confirmed LN were analysed. Based on the timing of LN onset, patients were classified into early-onset (n = 10) or late-onset (n = 11) groups. Clinical data, laboratory results and histological features were also obtained. RNA sequencing was performed on the renal biopsy samples to examine gene expression. Differentially expressed genes were identified using edgeR, and gene set enrichment analysis (GSEA) was used for IFNGS. Patients with early-onset LN exhibited significantly higher anti-dsDNA titres (63.4 U/ml, P = 0.024) and urinary N-acetyl-β-D-glucosaminidase levels (39.4 U/l, P = 0.005) than those with late-onset LN (7.3 U/ml and 11.4 U/l, respectively). Hierarchical clustering identified 100 genes (50 upregulated and 50 downregulated) that differentiated the groups. GSEA revealed enrichment of type I IFN pathways in early-onset LN with prominent neutrophil chemotaxis. Early-onset LN is characterized by elevated type I IFN activity and neutrophil-driven inflammation, reflecting a more aggressive phenotype. These findings highlight the potential therapeutic targets and emphasize the importance of personalized treatment. Early modulation of type I IFN may prevent fibrosis and improve renal outcomes in early-onset LN.