Tonsillar Tfh cells contribute to the pathogenesis of IgA nephropathy in collaboration with memory B cells.

INTRODUCTION: Immunoglobulin A nephropathy (IgAN) is a chronic glomerular disease characterized by mesangial IgA deposition, which can progress to end-stage renal failure. Tonsillectomy is used as a therapeutic intervention to slow disease progression and provide early clinical benefit. However, the immune mechanisms within the palatine tonsils that contribute to IgAN pathogenesis remain incompletely understood. METHODS: To define the tonsillar immune environment that regulates pathological antibody production, we analyzed T and B lymphocyte subsets in relation to renal function. We also conducted functional studies to evaluate the production of galactose-deficient IgA (Gd-IgA) and anti-Tn (GalNAc-Ser/Thr) antibodies, both of which are implicated in the formation of pathogenic immune complexes. RESULTS: Interfollicular T follicular helper (IF-Tfh) cells (CD3+CD4+CD8-PD-1loCXCR5lo) were significantly expanded in IgAN tonsils compared with disease controls and strongly correlated with clinical markers of renal abnormalities. Transcriptomic analysis of IF-Tfh cells from IgAN tonsils revealed a distinct gene expression profile enriched for effector memory T cell-like features associated with kidney impairment. Functional studies demonstrated that IF-Tfh cells potently promoted class-switched memory B cells to produce Gd-IgA1 and anti-Tn (GalNAc-Ser/Thr) antibodies. CONCLUSION: These findings suggest that an IF-Tfh cell-dominant immune environment drives IgAN pathogenesis and may represent a target for noninvasive therapeutic approaches.