IgG4-related disease is a systemic disorder with unique clinicopathological features and uncertain etiological features and is frequently related to allergic disease. T helper 2 and regulatory T-cell
cytokines have been reported to be upregulated in the affected tissues; thus, the production of these
cytokines by T helper 2 and regulatory T cells has been suggested as an important factor in the pathogenesis of
IgG4-related disease. However, it is not yet clear which cells produce these
cytokines in
IgG4-related disease, and some aspects of the disorder cannot be completely explained by T-cell-related processes. To address this, we analyzed
paraffin-embedded sections of tissues from nine cases of IgG4-related
submandibular gland disease, five cases of submandibular
sialolithiasis, and six cases of normal submandibular gland in order to identify potential key players in the pathogenesis of
IgG4-related disease. Real-time polymerase chain reaction analysis confirmed the significant upregulation of
interleukin (IL)4,
IL10, and
transforming growth factor beta 1 (TGFβ1) in
IgG4-related disease. Interestingly, immunohistochemical studies indicated the presence of mast cells expressing these
cytokines in diseased tissues. In addition, dual immunofluorescence assays identified cells that were double-positive for each
cytokine and for KIT, which is expressed by mast cells. In contrast, the distribution of T cells did not correlate with
cytokine distribution in affected tissues. We also found that the mast cells were strongly positive for
IgE. This observation supports the hypothesis that mast cells are involved in
IgG4-related disease, as mast cells are known to be closely related to
allergic reactions and are activated in the presence of elevated non-specific
IgE levels. In conclusion, our results indicate that mast cells produce T helper 2 and regulatory T-cell
cytokines in tissues affected by
IgG4-related disease and possibly have an important role in disease pathogenesis.