Single-Cell Multiomic Profiling of Peripheral Blood Mononuclear Cells Reveals Immune Heterogeneity and Therapeutic Target Expression in IgAN

Background: The composition and activation state of peripheral blood mononuclear cells (PBMCs) may reflect or contribute to the pathogenesis and activity of IgA nephropathy (IgAN). Several new targeted therapies for IgAN have recently been approved or are under investigation in RCTs. However, target expression in PBMCs remains poorly defined, though mapping it is key to understanding mechanisms and guiding therapy development. Methods: We used the 10x Genomics VDJ single-cell multiomic platform to analyze fresh unfrozen PBMCs from patients with IgAN (N=8) and non-IgAN CKD controls (N=5). The platform enables high-resolution profiling of gene expression, immune receptors, and surface proteins. We used it to identify which immune cell types express therapeutic targets in IgAN. Results: We profiled in total 91,000 PBMCs. BAFF was strongly enriched in several monocyte subclusters. BAFFR was expressed almost exclusively in B cells, particularly in naïve B cell populations and plasma cells. In contrast, APRIL showed expression in subsets of B cells—especially naïve B cells—and monocytes. Using antibodies targeting the respective surface proteins, we validated the observed gene expression at the protein level. Similarly, distinct expression patterns were noted for other therapeutic targets currently investigated in IgAN, including those involved in complement inhibition and CD38. Conclusion: High-resolution immune profiling of PBMCs in IgAN reveals distinct cellular niches for current and emerging therapeutic targets. Mapping the expression of therapeutic targets to specific immune subsets may help predict off-target effects, guide safety assessments, and inform patient stratification in future clinical trials and therapeutic decision-making.UMAP showing the different cell types and target gene expression.