To validate the phenotype and function of plasmacytoid dendritic cells (pDCs) in IgG4-related disease (IgG4-RD) and to further investigate their pathogenic role in disease progression.

Forty-five treatment-naïve patients with IgG4-RD and healthy controls were enrolled. Flow cytometry was used to assess the proportion of peripheral blood pDCs and the expression of activation- and function-related molecules. Immunohistochemistry and immunofluorescence were performed to evaluate pDC infiltration in affected tissues and their spatial association with lymphocytes. Annexin V assays were used to detect spontaneous apoptosis and plasma-induced apoptosis of pDCs. Purified pDCs were co-cultured with B cells and naïve T cells to determine their effects on lymphocyte activation, proliferation, and differentiation.

The percentage of pDCs in peripheral blood mononuclear cells was significantly decreased in patients with IgG4-RD compared with healthy controls (0.14 ± 0.13% vs 0.30 ± 0.20%) and increased again after remission. Reduced pDC levels were negatively associated with inflammatory status and disease activity, and patients with lower pDC proportions showed higher serum IgG, IgG1, and IgE levels. Peripheral pDC apoptosis was not significantly increased, but pDCs exhibited an activated phenotype, with higher expression of HLA-DR, CD86, and TLR7. Increased CCR5 expression on peripheral pDCs, together with enhanced pDC infiltration in affected tissues, suggested chemotactic migration from blood to lesions. Immunofluorescence further showed that pDCs were located adjacent to CD19+ B cells and CD4+ T cells in affected tissues. In co-culture experiments, activated pDCs from IgG4-RD more potently promoted B-cell activation, proliferation, plasma cell differentiation, and IgG/IgG4 production than those from controls, and also enhanced T-cell proliferation and differentiation toward Treg cells.

Peripheral blood pDCs in IgG4-RD are aberrantly activated and may migrate to affected tissues through CCR5-mediated chemotaxis. By interacting with B cells and T cells, pDCs may amplify local immune responses and contribute to tissue fibrosis, highlighting pDCs as a potential therapeutic target in IgG4-RD.