Extrafollicular Tph2-CD11c⁺CD21^- B cell interactions orchestrate immune dysregulation in IgG4-related disease

IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder characterized by IgG4-positive plasma cell infiltration and ectopic lymphoid structure formation. Although glucocorticoids are effective, relapse rates and adverse effects highlight the need for novel therapeutic targets. The immunological basis of IgG4-RD remains incompletely understood.

We analyzed peripheral blood mononuclear cells and inflammatory cells from the affected submandibular glands of patients with IgG4-RD using FACS. We assessed T peripheral helper (Tph) cell subsets and CD11c⁺CD21^- B cells and examined their associations with immunological and clinical parameters.

Tph2 cells in peripheral blood and submandibular glands were significantly increased in patients with IgG4-RD, and circulating Tph2 cells expressed granzyme B, indicating their cytotoxic potential. Their frequency correlated positively with serum IgG4, soluble IL-2 receptor levels, plasmablast expansion, eosinophil counts, number of affected organs, and IgG4-RD Responder Index. CD11c⁺CD21^- B cells were also expanded and enriched in IgG4-producing subsets. These cells showed strong correlations with serum IgG4 levels, the IgG4/IgG ratio, and disease activity, but were inversely related to T follicular helper cells. Notably, Tph2 cells exhibited a robust positive correlation with CD11c⁺CD21^- B cells, defining a distinct extrafollicular immune axis. Glucocorticoid treatment reduced Tph2 frequencies in parallel with serum IgG4 decline.

This study identifies a novel Tph2-CD11c⁺CD21^- B cell axis driving extrafollicular immune dysregulation in IgG4-RD. Tph2 cells link humoral activation with cytotoxicity, and CD11c⁺CD21^- B cells serve as producers of IgG4 associated with disease severity. Targeting this axis may provide therapeutic strategies for refractory or relapsing IgG4-RD beyond glucocorticoids.