Beyond the surface: soluble SIGLEC-1 as a clinically applicable type I IFN biomarker.

Abstract

Type I IFNs (IFN-I) are central to pathogenesis and monitoring of SLE, yet clinically accessible biomarkers remain limited. Building on prior validation of membrane-bound SIGLEC-1 (mbSIGLEC-1), we conducted a proof-of-concept study to evaluate soluble SIGLEC-1 (sSIGLEC-1) as a useful IFN-I biomarker in SLE. The study prospectively enrolled 61 SLE patients and 100 blood donors as controls. In SLE patients, disease activity indices (DAIs) and routine SLE and IFN biomarkers (IFNα, IP-10, mbSIGLEC-1) were assessed longitudinally. sSIGLEC-1 was measured using chemiluminescence immunoassay; a cohort-specific threshold was defined by ROC analysis. Cross-sectional correlations between DAIs and biomarkers were analysed in all patients, longitudinal analyses included 23 patients over 57 visits. Flare-predictive value was evaluated in 27 patients with quiescent disease over 180 days. We determined a threshold for sSIGLEC-1 at 4.55 ng/ml (sensitivity: 70.49%, specificity: 90%). Cross-sectionally, sSIGLEC-1 correlated with mbSIGLEC-1 (r = 0.67, P < 0.001), BILAG (r = 0.37, P = 0.004) and SLEDAI (r = 0.36, P = 0.005). sSIGLEC-1 and mbSIGLEC-1 showed high sensitivity in moderate (sSIGLEC-1: 76%; mbSIGLEC-1: 84%) and severe (both: 100%) disease activity. sSIGLEC-1 correlated positively with IFN-α (r = 0.35; P = 0.006) and IP-10 (r = 0.57; P < 0.001), with similar results for mbSIGLEC-1. Longitudinally, changes in BILAG correlated to changes in sSIGLEC-1 (r = 0.36; P = 0.014) and mbSIGLEC-1 (r = 0.38; P = 0.009). Analysing flare-predictive ability, neither sSIGLEC-1 nor mbSIGLEC-1 showed significant results. Our study supports sSIGLEC-1 as a reliable and scalable biomarker of IFN-I activity in SLE. Its performance and compatibility with routine assays make it a strong candidate for clinical translation and broader application in IFN-I-driven diseases.