Immunoprofiling by CyTOF Uncovers Disease-Defining Peripheral Immune Signatures and Mechanistic Links to Renal Injury in IgA Nephropathy

Introduction: The immunopathogenesis of IgA nephropathy (IgAN) involves mechanisms beyond B-cell dysregulation, yet the full spectrum and clinical relevance of peripheral immune alterations remain insufficiently defined. Methods: Peripheral blood from 7 IgAN patients and 3 healthy controls was analyzed by 30-marker mass cytometry (CyTOF), revealing 22 immune clusters across lymphoid and myeloid lineages. Independent flow cytometry validated CyTOF findings in 50 IgAN patients and 10 controls. Group differences were assessed by Mann‐Whitney U test and associations with clinical measures via Spearman correlation. Results: CyTOF mapping revealed 22 immune clusters spanning lymphoid and myeloid lineages. Among these, two subsets showed a significant increase in IgAN: switched memory B cells (CD19+CD20+CD27+IgD−CD38low) (median 1.75% vs. 0.91%, p = 0.004) and CD56+ CD8+ TEMRA cells (CD3+CD8+CD45RA+CCR7−CD56+) (median 1.66% vs. 0.21%, p = 0.02). These alterations were validated by flow cytometry in the independent cohort. Switched memory B-cell frequencies negatively correlated with serum C3 (p = 0.01) and positively correlated with proteinuria (p = 0.03) and Oxford T scores (p = 0.03), while CD56+ TEMRA frequencies correlated with serum creatinine (p = 0.02), uric acid (p = 0.03), and inversely with eGFR (p = 0.03). Conclusions: Our study delineates a peripheral immune signature of IgAN characterized by enhanced B-cell activation and cytotoxic T-cell responses, reflecting a dual-axis immune imbalance that may shape disease progression. These findings refine current immunopathogenic models and may guide future therapeutic research.