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Objective  IgG4‐related disease (IgG4‐ RD ) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll‐like receptor ( TLR ) pathway. This study was undertaken to examine the expression of  TLR s in salivary glands ( SG s) from patients with IgG4‐ RD .    Methods   SG s from 15 patients with IgG4‐ RD , 15 patients with Sjögren's syndrome ( SS ), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically.  TLR  family gene expression ( TLR ‐1 through  TLR ‐10) was analyzed by  DNA  microarray in the submandibular glands ( SMG s). Up‐regulation of  TLR s was confirmed in  SG s from patients with IgG4‐ RD . Finally, the phenotype of human  TLR ‐7 (hu TLR ‐7)–transgenic C57 BL /6 mice was assessed before and after stimulation with  TLR  agonist.    Results  In patients with IgG4‐ RD ,  TLR ‐4,  TLR ‐7,  TLR ‐8, and  TLR ‐9 were overexpressed. Polymerase chain reaction validated the up‐regulation of  TLR ‐7 in IgG4‐ RD  compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of  TLR ‐7–positive cells in the  SG s of patients with IgG4‐ RD . Double immunohistochemical staining showed that  TLR ‐7 expression colocalized with  CD 163+ M2 macrophages. After in vitro stimulation with a  TLR ‐7 agonist,  CD 163+ M2 macrophages produced higher levels of interleukin‐33 ( IL ‐33), which is a Th2‐activating cytokine. In hu TLR ‐7–transgenic mice, the focus and fibrosis scores in  SMG s, pancreas, and lungs were significantly higher than those in wild‐type mice ( P  < 0.05). Moreover, the concentration of serum IgG, IgG1, and  IL ‐33 in hu TLR ‐7–transgenic mice was distinctly increased upon stimulation with a  TLR ‐7 agonist ( P  < 0.05).    Conclusion   TLR ‐7–expressing M2 macrophages may promote the activation of Th2 immune responses via  IL ‐33 secretion in IgG4‐ RD .

Activated M2 Macrophages Contribute to the Pathogenesis of IgG4‐Related Disease via Toll‐like Receptor 7/Interleukin‐33 Signaling