Soluble PD-1 Drives Disease Activity in Lupus Nephritis and Presents a Promising Therapeutic Target

Lupus nephritis (LN) stands as one of the most severe organ manifestations of systemic lupus erythematosus (SLE), representing a leading cause of significant morbidity and mortality. The clinical management of LN is often challenged by the limitations of existing biomarkers in accurately reflecting real-time disease activity, predicting treatment response, and delineating underlying pathological processes. While the programmed cell death 1 (PD-1) pathway is a critical checkpoint for maintaining immune tolerance, recent evidence has pointed to a potential role for its soluble form, soluble PD-1 (sPD-1), in the pathogenesis of SLE. However, the specific involvement of sPD-1 in the development and progression of LN, particularly its correlation with clinical and histopathological features, remains largely unexplored and poorly defined. Elucidating the function of sPD-1 in LN could provide crucial insights into disease mechanisms and uncover new diagnostic and therapeutic avenues.

This study comprehensively investigated the role of sPD-1 in LN through a multi-faceted approach. The serum levels of sPD-1 were quantified using enzyme-linked immunosorbent assay (ELISA) in a cohort of LN patients and healthy controls. Detailed clinical data, including disease activity indices (e.g., SLEDAI), renal function parameters (e.g., proteinuria, serum creatinine), and histopathological classifications from renal biopsies, were collected for correlation analysis with sPD-1 levels. Treatment response was evaluated following standard broad-spectrum immunosuppressive therapy, and serial measurements of sPD-1 were taken to track dynamic changes. Furthermore, peripheral blood mononuclear cells (PBMCs) from patients were analyzed by flow cytometry to assess the frequency of PD-1⁺ T cells. Immunohistochemistry and immunofluorescence were performed on renal biopsy sections to evaluate the expression and localization of PD-L1 within the kidney. To establish causality and explore therapeutic potential, a pristane-induced lupus nephritis mouse model was utilized. Two distinct therapeutic strategies were tested in this model: a PD-L1–MSA (monoclonal antibody scaffold) fusion protein and engineered exosomes displaying PD-1. Their efficacy was assessed by monitoring changes in proteinuria, serum autoantibodies, renal histopathology, and inflammatory cytokine profiles.

Our findings revealed a significant elevation of serum sPD-1 levels in patients with active LN compared to controls. This elevation demonstrated strong positive correlations with established markers of disease activity, histological severity (as per the ISN/RPS classification), and progressive renal impairment. Notably, patients with a poor response to conventional immunosuppressive therapy exhibited persistently higher baseline sPD-1 levels. Following effective treatment, a significant decrease in serum sPD-1 concentrations was observed, paralleling clinical improvement. Concurrently, we found an increased population of PD-1⁺ T cells in the peripheral blood of LN patients and a marked upregulation of PD-L1 expression on renal tubular epithelial cells and infiltrating immune cells in the kidney. Mechanistically, we propose that sPD-1, unlike its membrane-bound counterpart (mPD-1) which transmits inhibitory signals, acts as a molecular decoy. It competitively binds to PD-L1, thereby hijacking the ligand and preventing its interaction with the inhibitory mPD-1 receptor on T cells. This disruption is postulated to lead to the collapse of peripheral immune tolerance and uncontrolled T cell activation. In the interventional studies, both the PD-L1–MSA fusion protein and the engineered PD-1 exosomes effectively reduced circulating sPD-1 levels in the murine LN model. This reduction was associated with a significant amelioration of disease, including reduced proteinuria, improved renal histology (decreased glomerulonephritis and immune complex deposition), and attenuation of systemic inflammation.

This study identifies serum sPD-1 as a robust and dynamic biomarker that reflects disease activity, severity, and treatment response in lupus nephritis. Beyond its diagnostic utility, our data illuminate a novel pathogenic mechanism whereby sPD-1 functions as a competitive inhibitor that disrupts the PD-1/PD-L1 regulatory axis. Furthermore, we demonstrate the compelling therapeutic promise of targeting this pathway. Strategies designed to neutralize or clear sPD-1, such as PD-L1–MSA fusion proteins or engineered PD-1 exosomes, show significant efficacy in ameliorating LN in a preclinical model, positioning them as promising novel therapeutic modalities for this serious condition.