Dissociated FoxP3 Up-regulation With Functional Surface Marker Loss Defines a Convergent Treg Paradox Across...

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.

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.

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.

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.