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Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease that affects exocrine glands, such as salivary and lacrimal glands. The Janus kinase (JAK) /signal transducer and activator of transcription (STAT) pathway are activated in various inflammatory diseases including pSS. This study aimed to investigate the expression of JAK1, JAK2, phosphorylated JAK1, and phosphorylated JAK2 in labial salivary gland (LSG) tissues from patients with pSS to evaluate the potential of JAK inhibitors as therapeutic agents for pSS. Immunohistochemical analysis was performed using LSG tissues of patients with pSS (n=10), non-SS (n=5), and healthy controls (n=5). In acinar epithelial cells, JAK1, JAK2, and phosphorylated JAK1 were expressed at significantly lower levels in LSG tissues of patients with pSS than in healthy controls. Significantly higher expression of phosphorylated JAK1 and phosphorylated JAK2 was observed in the ductal epithelial cells of patients with pSS compared to the controls. However, there was no significant association between the expression levels of phosphorylated JAK1 or JAK2 and the degree of inflammation. In addition, immunofluorescence analysis revealed JAK2 phosphorylation in many CD3 + T cells infiltrating the LSG tissues. These results suggested the activation of JAK/STAT signaling in both the ductal epithelial cells and the infiltrating CD3 + T cells in the LSG tissues of patients with pSS. Therefore, JAK inhibitors may be effective therapeutic agents for pSS by regulating both effector T cells and target cells.

Gene expression profiling of lip salivary gland (LSG) has shown that C-X-C motif chemokine 10 (CXCL10) and matrix metalloproteinase 9 (MMP9) expression is up-regulated in primary Sjögren's syndrome (pSS) patients. Although CXCL10 and MMP-9 are both associated with pSS pathogenesis, the potential relationship between these two factors has not been investigated. In this study, we used LSG sections from pSS patients and human salivary gland cell lines to investigate the relationship between CXCL10 and MMP-9. Immunofluorescence analyses revealed that CXCL10 and MMP-9 were co-expressed in the LSG of pSS patients, particularly in expanded ductal cells. Furthermore, RT-qPCR analyses on human salivary gland ductal NS-SV-DC cells confirmed that CXCL10 expression was induced by interferon (IFN)-γ, whereas that of MMP9 was stimulated by IFN-α, tumor necrosis factor-α, and interleukin 1β. Remarkably, MMP-9 inhibition in IFN-γ-stimulated NS-SV-DC cells significantly decreased CXCL10 mRNA and secreted protein levels. Further analyses established that MMP-9 inhibition in IFN-γ-stimulated NS-SV-DC cells decreased STAT1 phosphorylation and hence suppressed IFN-γ signaling. Collectively, these results suggest that in addition to its reported role in the destruction of acinar structures, MMP-9 is involved in the IFN-γ-induced production of CXCL10 in pSS lesions. We believe that our findings open the door to the development of novel treatments for pSS, based on the modulation of MMP-9 activity.

Sjogren’s syndrome (SS) is a chronic autoimmune disease targeting salivary and lacrimal glands. C-X-C motif chemokine ligand 10 (CXCL10) expression is upregulated in lip salivary glands (LSGs) of primary SS (pSS) patients, and CXCL10 involved in SS pathogenesis via immune-cell accumulation. Moreover, interferon (IFN)-γ enhances CXCL10 production via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. We investigated the effects of baricitinib, a selective JAK1/2 inhibitor, on both IFN-γ-induced CXCL10 production and immune-cell chemotaxis. We used immunohistochemical staining to determine the expression levels and localization of JAK1 and JAK2 in LSGs of SS patients (n = 12) and healthy controls (n = 3). We then evaluated the effect of baricitinib in an immortalized normal human salivary gland ductal (NS-SV-DC) cell line. Immunohistochemical analysis of LSGs from pSS patients revealed strong JAK1 and JAK2 expression in ductal and acinar cells, respectively. Baricitinib significantly inhibited IFN-γ-induced CXCL10 expression as well as the protein levels in an immortalized human salivary gland ductal-cell clone in a dose-dependent manner. Additionally, western blot analysis showed that baricitinib suppressed the IFN-γ-induced phosphorylation of STAT1 and STAT3, with a stronger effect observed in the case of STAT1. It also inhibited IFN-γ-mediated chemotaxis of Jurkat T cells. These results suggested that baricitinib suppressed IFN-γ-induced CXCL10 expression and attenuated immune-cell chemotaxis by inhibiting JAK/STAT signaling, suggesting its potential as a therapeutic strategy for pSS.

Background: Mechanisms underlying immune cells' recruitment and activation into the inflammatory lesions of lip salivary glands (LSGs) from primary Sjogren's syndrome (pSS) patients are incompletely understood. Chemokines play pivotal roles in these processes, so we investigated the clinical significance of chemokine receptor CXCR3 and its ligands in the autoimmune lesions of pSS. Methods: We histologically determined the grade of LSG samples from 22 pSS patients and subjected the samples to immunofluorescence analysis to determine the expressions of CXCR3 and its ligands: CXCL9, CXCL10, and CXCL11. To identify the immune cells expressing CXCR3 in the LSGs, we performed double immunofluorescence analysis using antibodies against CD3 (pan-T cells), CD80 (M1 macrophages), CD163 (M2 macrophage), and CD123 (plasmacytoid dendritic cells: pDCs). The relationship between the grade of lymphocytic infiltration and the number of positively stained cells was analyzed by Spearman's rank correlation test. Results: The expressions of CXCL9 and CXCL10 showed particularly intense staining in the LSG samples' ductal cells. The CXCR3 expression was detected mainly in CD80+ and CD163+ macrophages. The number of CXCR3+CD163+ macrophages inversely correlated with the LSG inflammatory lesions' severity (rs= −0.777, p

CXCL10, a CXC chemokine induced by interferon-gamma [IFN-γ], has been observed in a wide variety of chronic inflammatory disorders and autoimmune conditions. Although CXCL10 is known to be overexpressed in the salivary glands of individuals with primary Sjögren's syndrome (pSS), it is unclear which cells produce CXCL10 under what types of stimulations. Here, we investigated the precise molecular mechanisms by which CXCL10 was produced in human salivary gland ductal (NS-SV-DC) and acinar (NS-SV-AC) cell lines. Our results demonstrated that NS-SV-DC cells produced higher levels of CXCL10 compared to NS-SV-AC cells. In addition, our findings demonstrated that the regulator of the enhancement of CXCL10 was different between NS-SV-DC and NS-SV-AC cells, i.e., interferon-gamma (IFN-γ) had more potential than interferon-alpha (IFN-α), tumor necrosis factor (TNF)-α, and interleukin (IL)1-β in the induction of CXCL10 production in NS-SV-DC cells, whereas TNF-α had potential to induce CXCL10 production in NS-SV-AC cells. A Western blot analysis demonstrated that IFN-γ enhanced the production of CXCL10 via both the JAK/STAT1 pathway and the NF-κB pathway in NS-SV-DC cells, whereas TNF-α enhanced the production of CXCL10 via the NF-κB pathway in NS-SV-AC cells. The results of study suggest that the CXCL10 overexpression in the salivary glands is caused mainly by IFN-γ-stimulated salivary gland ductal cells. The enhanced production of CXCL10 by IFN-γ from ductal cells may result in the inflammation of pSS lesions.

Mechanisms underlying immune cells' recruitment and activation into the inflammatory lesions of lip salivary glands (LSGs) from primary Sjögren's syndrome (pSS) patients are incompletely understood. Chemokines play pivotal roles in these processes, so we investigated the clinical significance of chemokine receptor CXCR3 and its ligands in the autoimmune lesions of pSS.We histologically determined the grade of LSG samples from 22 patients with pSS and subjected the samples to immunofluorescence analysis to determine the expressions of CXCR3 and its ligands: CXCL9, CXCL10, and CXCL11. To identify the immune cells expressing CXCR3 in the LSGs, we performed double immunofluorescence analysis using antibodies against CD3 (pan-T cells), CD80 (M1 macrophages), CD163 (M2 macrophages), and CD123 (plasmacytoid dendritic cells: pDCs). The relationship between the grade of lymphocytic infiltration and the number of positively stained cells was analyzed by Spearman's rank correlation test.The expressions of CXCL9 and CXCL10 showed particularly intense staining in the LSG samples' ductal cells. The CXCR3 expression was detected mainly in CD80Our results suggest that the enhanced production of CXCL9 and CXCL10 from ductal cells results in the CXCR3

Cepharanthine, a biscolaurine alkaloid isolated from the plant Stephania cephalantha Hayata, has been reported to have potent anti-inflammatory properties. Here, we investigated the effects of cepharanthine on the expression of CXCL10 (a CXC chemokine induced by interferon-gamma [IFN-γ] that has been observed in a wide variety of chronic inflammatory disorders and autoimmune conditions) in IFN-γ-treated human salivary gland cell lines. We observed that IFN-γ-induced CXCL10 production in NS-SV-DC cells (a human salivary gland ductal cell line), but not in NS-SV-AC cells (a human salivary gland acinar cell line). Cepharanthine inhibited the IFN-γ-induced CXCL10 production in NS-SV-DC cells. A Western blot analysis showed that cepharanthine prevented the phosphorylation of JAK2 and STAT1, but did not interfere with the NF-κB pathway. Moreover, cepharanthine inhibited the IFN-γ-mediated chemotaxis of Jurkat T cells. These results suggest that cepharanthine suppresses IFN-γ-induced CXCL10 production via the inhibition of the JAK2/STAT1 signaling pathway in human salivary gland ductal cells. Our findings also indicate that cepharanthine could inhibit the chemotaxis of Jurkat T cells by reducing CXCL10 production.

This is a rare case report of a cerebellopontine angle (CPA) mass mimicking lingual nerve injury after a dental implant placement. Lingual nerve injury is a common complication following dental implant placement. CPA masses are likely to cause symptomatic trigeminal neuralgia, and thus can mimic and be easily confused with oral diseases. We experienced a case of CPA mass mimicking lingual nerve injury after dental implant placement. The patient was a 57-year-old Japanese female who complained of glossalgia. She underwent dental implant placement in the mandible before visiting our clinic. Panoramic x-ray radiography revealed no abnormalities; the salivary flow rate by gum test was 7.0 ml/10 min. She was diagnosed with lingual nerve injury and secondary burning mouth syndrome. Vitamin B12 and oral moisturizer did not provide relief; furthermore, numbness in the lower lip emerged. A Semmes Weinstein test demonstrated elevation of her sensitivity threshold. Finally, magnetic resonance imaging revealed a 20-mm diameter mass in the CPA. The patient is now being followed under conservative management. Our experience underscores the importance of including CPA mass in the differential diagnosis of dental diseases.

Background Burning mouth syndrome (BMS) is characterized by the following subjective complaints without distinct organic changes: burning sensation in mouth or chronic pain of tongue. BMS is also known as glossodynia; both terms are used equivalently in Japan. Although the real cause of BMS is still unknown, it has been pointed out that BMS is related to some autonomic abnormality, and that stellate ganglion near-infrared irradiation (SGR) corrects the autonomic abnormality. Frequency analysis of heart rate variability (HRV) is expected to be useful for assessing autonomic abnormality. Objectives This study investigated whether frequency analysis of HRV could reveal autonomic abnormality associated with BMS, and whether autonomic changes were corrected after SGR. Subjects and Methods Eight subjects received SGR; the response to SGR was assessed by frequency analysis of HRV. Results No significant difference of autonomic activity concerning low-frequency (LF) norm, high-frequency (HF) norm, and low-frequency/high-frequency (LF/HF) was found between SGR effective and ineffective groups. Therefore, we proposed new parameters: differential normalized low frequency (D LF norm), differential normalized high frequency (D HF norm), and differential low-frequency/high-frequency (D LF/HF), which were defined as differentials between original parameters just before and after SGR. These parameters as indexes of responsiveness of autonomic nervous system (ANS) revealed autonomic changes in BMS, and BMS seems to be related to autonomic instability rather than autonomic imbalance. Conclusions Frequency analysis of HRV revealed the autonomic instability associated with BMS and enabled tracing of autonomic changes corrected with SGR. It is suggested that frequency analysis of HRV is very useful in follow up of BMS and for determination of the therapeutic efficacy of SGR.

Xerostomia is the symptom of oral dryness resulting most frequently, but not exclusively, from salivary gland hypofunction. Because the prevalence of xerostomia may increase with age, it has multiple oral health consequences in aging populations. In the present study, we demonstrate that the in vivo administration of 5-aza-2′-deoxycytidine (5-Aza-CdR; decitabine), a DNA demethylating agent, to the murine aging model C57BL/6CrSlc mice (24 wks old) increased the volumes of salivary flow compared with those of control mice. Western blot analysis and immunohistochemical staining demonstrated the augmented expression of AQP5 protein in the salivary glands of 5-Aza-CdR-treated mice compared with those of control mice. In addition, AQP5 protein expression levels in 5-Aza-CdR-treated old mice (27 wks old) were much higher than those in untreated and young mice (6 wks old). Global methylation levels in the salivary glands were significantly lower in the 5-Aza-CdR-treated mice than in the untreated mice. Moreover, the induction of demethylation in the AQP5 promoter of 5-Aza-CdR-treated mice was stronger than in the control mice. Analysis of our data therefore suggests that a DNA demethylating agent may be a useful drug for restoring hyposalivation in elderly individuals, thereby leading to the resolution of xerostomia.