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-1 lo CXCR5 lo ) 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.