Analysis of Peripheral Blood Mononuclear Cells Single-Cell RNA Sequencing Shows IFN Signaling Activation Contributes to the Pathogenesis of Childhood Nephrotic Syndrome

Background: IdiopathicNephrotic syndrome (INS) is a prevalent glomerular disease, especially in children. Previous understanding of INS pathogenesis has emphasized T-cell changes and their correlation with cytokine shifts. Accumulating evidence indicates that B-cell dysfunction is also involved in the process. Nevertheless, a gap remains in the comprehensive understanding of the mechanisms and cellular interactions among immune cells in new-onset INS. Methods: Our study employed single-cell RNA sequencing (scRNA-seq) to characterize immuno-dysfunction in peripheral blood mononuclear cells (PBMCs) obtained from five new-onset INS patients before treatment and post-remission, alongside healthy controls. We identified differentially expressed genes and investigated cell-cell communications across different cell types. We also performed validations. Results: Through differentially expressed gene analysis across clusters, we observed the activation of interferon-stimulated genes (ISGs) and the enrichment of interferon (IFN)-related pathways. Specifically, we noted increased expression of B-cell activating factor (BAFF) in untreated patients, along with elevated expression of BAFF receptors, particularly B-cell maturation antigen (BCMA) in plasma cells, collaborated by flow cytometry in an independent INS cohort. Furthermore, we identified an increase in the serum level of IFN-γ rather than IFN-α. Conclusion: Our research provides the first comprehensive exploration of IFN-related pathways in the initiation of INS. These results suggest that IFN-γ activation stimulates the interaction between BAFF and B-cell receptors, triggering autoantibody release and contributing to INS pathogenesis. New insights into the pathogenesis of NS may pave the way for precise therapeutic interventions that target these pathways.