Circulating soluble PD-1 in lupus nephritis: disease activity, renal progression, and preclinical therapeutic implications

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus and a leading cause of morbiFdity and mortality. While soluble PD-1 (sPD-1) has been implicated in SLE pathogenesis, its specific role in LN remains poorly characterized. We measured serum sPD-1 levels in a multicenter LN cohort and analyzed correlations with clinical and pathological features. Peripheral PD-1⁺ T cells and renal PD-L1 expression were assessed. Mechanistically, we examined whether sPD-1 may interfere with membrane PD-1/PD-L1 signaling. Therapeutic strategies using PD-L1-MSA fusion protein or engineered PD-1 exosomes to neutralize sPD-1 were tested in a pristane-induced LN mouse model. Elevated sPD-1 levels in patients correlate with increased disease severity and poor therapeutic response, while immunosuppression effectively reduces these levels. Functionally, our data support a model in which sPD-1 may interfere with PD-1/PD-L1 signaling, thereby potentially weakening inhibitory immune regulation. In pristane-induced LN mice, PD-L1-MSA fusion protein or engineered PD-1 exosomes improved renal pathology and serological parameters, consistent with a therapeutic effect of targeting the PD-1/PD-L1 axis. sPD-1 may serve as a biomarker for LN activity and progression and as a potential therapeutic target. Targeting the PD-1/PD-L1 axis may ameliorate renal injury in LN and warrants further investigation as a therapeutic approach.