Dissociated FoxP3 Up-regulation With Functional Surface Marker Loss Defines a Convergent Treg Paradox Across Immunological Archetypes of IgA Nephropathy and IgA Vasculitis

BACKGROUND/AIM: Immunoglobulin A nephropathy (IgAN) and immunoglobulin A vasculitis (IgAV) exhibit remarkable clinical heterogeneity, yet its underlying immunological diversity remains poorly characterized. We investigated whether high-dimensional peripheral blood immunophenotyping could identify distinct immunological archetypes and shared regulatory T cell (Treg) dysregulation across the clinical spectrum of IgAN and IgAV. PATIENTS AND METHODS: Four patients with biopsy-proven IgAN or clinically confirmed IgAV were prospectively enrolled. Serial multicolor flow cytometry characterized T-cell subsets, Treg populations, and B-cell subpopulations relative to healthy controls. RESULTS: Individual-level profiling revealed four distinct immunological archetypes: activated T-cell, B-cell dominant, severe dysregulator, and quiescent each correlating with a specific clinical trajectory from decade-long stability to fatal outcome. Cross-case analysis revealed a convergent Treg paradox across all archetypes, characterized by increased intracellular forkhead box protein P3 (FoxP3) expression concurrent with depletion of key functional surface markers, including cluster of differentiation 25 (CD25), L-selectin (CD62L), and cluster of differentiation 127 (CD127). This paradox was consistently observed across all four archetypes regardless of disease severity or treatment status. CONCLUSION: IgAN and IgAV are not uniform immunological entities. The Treg Paradox, a dissociation between regulatory commitment and functional capacity may represent a shared pathogenic feature across clinically diverse phenotypes, warranting further validation as a potential basis for immunotype-guided precision therapy.