T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease.

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 (TGFß1) 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.

The Role of Fetuin-A and Electrolytes in the Etiology of Sialolithiasis.

Objective The aim of this study was to investigate serum and saliva fetuin-A, protein, and electrolyte levels in patients with sialolithiasis. Study Design Prospective randomized controlled study. Setting Tertiary center. Subjects and Methods Twenty patients with recurrent sialadenitis secondary to submandibular salivary gland stones and 20 asymptomatic healthy volunteers without salivary gland stones were included in the study. Bimanual palpation and ultrasonography were performed in the patient and control groups. The electrolyte, protein, and fetuin-A levels of the serum and saliva were measured. Results The serum calcium, phosphorus, and potassium levels of the patients were significantly lower than those of the control group (respectively, P = .04, P = .01, P = .04). There was no statistically significant difference between the serum fetuin-A levels of the 2 groups ( P = .06). The saliva phosphorus values of the patients were higher than those of the control group ( P = .05), as were their saliva fetuin-A and total protein values ( P = .001, P = .01). A positive correlation was determined between the saliva fetuin-A levels and the saliva phosphorus and potassium levels of the patients ( P = .04, P = .02). The magnesium level, which has been argued to be a factor in the prevention of calcification, showed an increased correlation with the total protein in the patient group ( P = .02). Conclusion It is possible that the high levels of saliva fetuin-A, total protein, and phosphorus with insufficient of saliva magnesium levels may make a contribution to the formation of sialoliths.

Association of serum electrolytes and smoking with salivary gland stone formation.

To further define potential factors that may contribute to stone formation in salivary glands (sialolithiasis), a retrospective chart review was performed of patients diagnosed with sialolithiasis between March 1, 1998 and February 29, 2012. Information on salivary gland stone number, location and size, medical history, medications, and serum electrolyte levels were collected. Associations between electrolyte levels and stone characteristics (such as stone number and size) were examined. Fifty-nine patients were identified; their median age was 58 years (range 25-89 years) and most were male (95%). Salivary stones were most commonly located in the submandibular glands (83%). Thirty-five patients (59%) had a smoking history, with 16 (27%) reported as current smokers. There was a significant association between current smoker status and stone size (mean largest stone size 12.4±8.8mm vs. 7.5±4.8mm in current smokers vs. non-smokers; P=0.03). Serum sodium levels (r=0.32, P=0.014) and serum potassium levels (r=0.31, P=0.017) showed significant positive correlations with stone size. While the aetiology of sialolithiasis remains unclear, smoking (which can contribute to reduced saliva flow) and higher serum sodium levels (which can reflect volume depletion) are associated with larger salivary stones.