Human immunology · 2026
Serum sPD-1 and sTIM-3 as T-cell exhaustion biomarkers in systemic lupus erythematosus: The IL-6-associated exhaustion axis and the SLE Immune Exhaustion Index.
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Al-Karawi Abdullah Salim, Al-Budairi Ali Saad
Аннотация
BACKGROUND: T-cell exhaustion marked by soluble PD-1 (sPD-1) and soluble TIM-3 (sTIM-3) has been implicated in systemic lupus erythematosus (SLE), yet the cytokine mechanisms driving checkpoint-receptor upregulation, the relationship with complement consumption, and the clinical utility of these markers remain incompletely characterised.
METHODS: In a case-control with cross-sectional study of 120 participants (40 active SLE, 40 quiescent SLE, 40 healthy controls), serum sPD-1, sTIM-3, IL-6, ferritin, complement proteins (C3, C4, C1q), anti-dsDNA, CRP, ESR, and urinary protein-to-creatinine ratio (UPCR) were measured. A 12-parameter Spearman correlation matrix, principal component analysis (PCA) of 10 standardised biomarkers, ROC curve analysis with bootstrap 95% CIs and DeLong pairwise comparisons, lupus-nephritis (LN) subgroup analysis, and four pre-specified novel analyses were performed: (i) formal bootstrap mediation analysis of the IL-6 → sPD-1/sTIM-3 → SLEDAI-2K pathway; (ii) the sTIM-3/sPD-1 imbalance ratio; (iii) an Exhaustion-to-Complement Index (ECI); and (iv) multivariable logistic regression for LN prediction. The SLE Immune Exhaustion Index (SIEI) was evaluated by ROC analysis.
RESULTS: Four primary biomarkers were significantly elevated in active versus quiescent SLE and healthy controls (Kruskal-Wallis H 87.2-99.0; all p < 0.001), with strong positive correlations with SLEDAI-2K (rho = 0.647-0.747). PCA identified a single dominant axis (PC1 = 78.9% variance) driven by exhaustion and inflammatory markers opposing complement proteins. Individual ROC AUCs were: sPD-1 0.932, sTIM-3 0.966, IL-6 0.944, and ferritin 0.953; the SIEI achieved 0.974, significantly exceeding sPD-1 alone (p = 0.002) but not the other individual markers. Bootstrap mediation analysis confirmed that sPD-1 and sTIM-3 each mediated approximately one-third of the IL-6 effect on SLEDAI-2K (indirect effects 0.276 and 0.303; bootstrap 95% CI excluding zero; Sobel p < 0.001). The ECI correlated strongly with SLEDAI-2K (rho = 0.86, p < 0.001; within-cohort AUC = 0.985). The UPCR plus sPD-1 plus IL-6 model significantly improved LN prediction over UPCR alone (AUC 0.869 vs 0.699; bootstrap p = 0.020), with sPD-1 carrying the dominant predictive contribution.
CONCLUSIONS: Serum sPD-1 and sTIM-3 are closely associated with the IL-6-related, complement-consuming inflammatory network of SLE, in a pattern consistent with but not proving a mechanistic link. The SIEI is the first named, weighted composite exhaustion score in SLE, with within-cohort discrimination that requires prospective external validation. These findings support T-cell exhaustion as a serologically accessible disease axis with direct implications for disease monitoring and lupus-nephritis risk stratification.
METHODS: In a case-control with cross-sectional study of 120 participants (40 active SLE, 40 quiescent SLE, 40 healthy controls), serum sPD-1, sTIM-3, IL-6, ferritin, complement proteins (C3, C4, C1q), anti-dsDNA, CRP, ESR, and urinary protein-to-creatinine ratio (UPCR) were measured. A 12-parameter Spearman correlation matrix, principal component analysis (PCA) of 10 standardised biomarkers, ROC curve analysis with bootstrap 95% CIs and DeLong pairwise comparisons, lupus-nephritis (LN) subgroup analysis, and four pre-specified novel analyses were performed: (i) formal bootstrap mediation analysis of the IL-6 → sPD-1/sTIM-3 → SLEDAI-2K pathway; (ii) the sTIM-3/sPD-1 imbalance ratio; (iii) an Exhaustion-to-Complement Index (ECI); and (iv) multivariable logistic regression for LN prediction. The SLE Immune Exhaustion Index (SIEI) was evaluated by ROC analysis.
RESULTS: Four primary biomarkers were significantly elevated in active versus quiescent SLE and healthy controls (Kruskal-Wallis H 87.2-99.0; all p < 0.001), with strong positive correlations with SLEDAI-2K (rho = 0.647-0.747). PCA identified a single dominant axis (PC1 = 78.9% variance) driven by exhaustion and inflammatory markers opposing complement proteins. Individual ROC AUCs were: sPD-1 0.932, sTIM-3 0.966, IL-6 0.944, and ferritin 0.953; the SIEI achieved 0.974, significantly exceeding sPD-1 alone (p = 0.002) but not the other individual markers. Bootstrap mediation analysis confirmed that sPD-1 and sTIM-3 each mediated approximately one-third of the IL-6 effect on SLEDAI-2K (indirect effects 0.276 and 0.303; bootstrap 95% CI excluding zero; Sobel p < 0.001). The ECI correlated strongly with SLEDAI-2K (rho = 0.86, p < 0.001; within-cohort AUC = 0.985). The UPCR plus sPD-1 plus IL-6 model significantly improved LN prediction over UPCR alone (AUC 0.869 vs 0.699; bootstrap p = 0.020), with sPD-1 carrying the dominant predictive contribution.
CONCLUSIONS: Serum sPD-1 and sTIM-3 are closely associated with the IL-6-related, complement-consuming inflammatory network of SLE, in a pattern consistent with but not proving a mechanistic link. The SIEI is the first named, weighted composite exhaustion score in SLE, with within-cohort discrimination that requires prospective external validation. These findings support T-cell exhaustion as a serologically accessible disease axis with direct implications for disease monitoring and lupus-nephritis risk stratification.