Allergology international : official journal of the Japanese Society of Allergology · 2026
Extrafollicular Tph2-CD11c+CD21- B cell interactions orchestrate immune dysregulation in IgG4-related disease.
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Sakamoto Hiroshi, Kamekura Ryuta, Takayanagi Shin, Tanaka Akihisa, Yajima Ryoto, Yamamoto Keisuke, Okuni Tsuyoshi, Kurose Makoto, Yamamoto Motohisa, Takahashi Hiroki, Ichimiya Shingo, Takano Kenichi
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.