Role of CXCL10 in pathogenesis of Sjögren's syndrome

Sjögren's syndrome (SS) is a common autoimmune disease characterized by the destruction of acinar structure by marked lymphocytic infiltrates in the salivary and lacrimal glands, resulting in sicca symptoms. Gene expression profiling of lip salivary glands (LSGs) shows that C-X-C motif chemokine 10 (CXCL10) expression is upregulated in patients with primary SS (pSS). CXCL10 and its receptor, C-X-C receptor 3 (CXCR3), contribute to the pathogenesis of SS. We investigated the clinical significance of CXCL10 and CXCR3 in the autoimmune lesions of pSS and the molecular mechanisms of CXCL10 upregulation in the salivary gland cells. CXCL10 showed particularly intense staining in LSG ductal cells from pSS patients. CXCR3 expression was detected primarily in CD163+ macrophages. The number of CXCR3+CD163+ macrophages was inversely correlated with the severity of LSG inflammatory lesions. Our in vitro experiments demonstrated that human salivary gland ductal (NS-SV-DC) cells produced higher levels of CXCL10 than acinar (NS-SV-AC) cells. Furthermore, NS-SV-DC and NS-SV-AC cells had different regulators of CXCL10 enhancement: interferon (IFN)-γ had more potential than 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 the potential to induce CXCL10 production in NS-SV-AC cells. Our results suggest that CXCL10 overexpression in salivary glands is mainly caused by IFN-γ-stimulated salivary gland ductal cells. The enhanced production of CXCL10 by ductal cell IFN-γ results in the migration of CXCR3+ immune cells. CXCL10 plays an important role in SS pathogenesis, and CXCL10 regulation may be useful in the treatment of SS patients

Baricitinib Inhibits CXCL10 Production in Salivary Gland Cells

Sjögren'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 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 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

MMP-9 Inhibition Suppresses Interferon-γ-Induced CXCL10 Production in Human Salivary Gland Ductal 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

Management of tooth extraction in a patient with ELANE gene mutation-induced cyclic neutropenia

Introduction: Cyclic neutropenia (CyN) is a rare hematological disease, and patients with CyN often experience an early onset of severe periodontitis and are forced to undergo tooth extraction. Here, we report a case of a patient with CyN who showed different periodicity and oscillations of neutrophil count compared with her mother, despite sharing the same novel genetic mutation. Patient concerns: A 17-year-old Japanese girl who had been diagnosed with CyN shortly after birth presented to our hospital with a complaint of mobility of her teeth and gingivitis. Upon presentation, an intraoral examination was performed and revealed redness and swelling of the marginal and attached gingiva. Radiographs revealed extreme resorption of the alveolar bone and apical lesions in her mandibular lateral incisors. The patient's hematologic data demonstrated a lack of blood neutrophils (0/μL). The patient had no history of dental extraction, and her mother also had a history of CyN. Diagnoses: The patient was diagnosed with severe periodontitis that was associated with CyN. Gene testing showed a novel heterozygous mutation in exon 4 of the ELANE gene (c.538delC, p.Leu180Ser fsX11). Interventions: Based on the clinical findings, we planned to extract the patient's mandibular lateral incisors. Although the tooth extraction was scheduled considering the cyclic variation in neutrophil count, the patient's neutrophil count was 0/μL on the day before the planned extraction. Therefore, granulocyte-colony stimulating factor (G-CSF) was administered to increase the patient's neutrophil count. On the day of the patient's admission for the tooth extraction, she presented with fever (body temperature, 38.5°C), tonsillitis, and stomatitis. The extraction was subsequently delayed, and the patient was administered antibiotics and G-CSF for 4 days. At this time, the neutrophil count increased to 750/μL, and the tooth extraction was carried out safely. Outcomes: The postoperative course was uneventful, and the healing process at the extraction site was excellent. Conclusion: There is a possibility that the periodicity and oscillations of neutrophil count may change with growth in patients with CyN. Therefore, it is important to frequently examine and treat patients with fluctuating neutrophil levels for the management of invasive dental treatment in patients with CyN

Cepharanthine Inhibits IFN-γ-Induced CXCL10

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

Distinct Regulation of CXCL10 Production in Salivary Gland Cells

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

CXCR3+ macrophage in Sjögren's syndrome

Background: 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. 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<0.001). Conclusions: Our results suggest that the enhanced production of CXCL9 and CXCL10 from ductal cells results in the CXCR3+ macrophages' migration. There was an inverse correlation between these two parameters: i.e., the number of CXCR3+CD163+ macrophages decreased as the lymphocytic infiltration grade increased. Although CXCR3 is expressed in all of the innate immune cells, CXCR3+CD163+ M2 macrophages may contribute to the anti-inflammatory functions in pSS lesions

シンキン バイヨウ ケンサ ニオケル カンジダ ノ ケンシュツ ニ エイキョウ スル リンショウテキ ヨウイン ノ ケントウ : コウクウ カンソウ ノ カンレン ニツイテ

In order to analyze the clinical factors affecting the fungal culture test, we examined the oral mucosae of 89 individuals with various complaints: pain, xerostomia etc. The subjects, age ranged from 36 to 87 years (mean age: 64.8 ± 11.8). Based on the fungal culture, 56 patients were found Candida-positive, and the remaining 33 patients were Candida-negative. The mean ages of the Candida-positive and -negative groups, respectively, were 67.4 ± 12.0 and 60.5 ± 10.3 years old, with the Candida-positive group being significantly older than Candida-negative group. The Candida-positive group showed a smaller amount of salivary secretion (10.9 ± 5.3 ml/10 min) than the Candida-negative group (13.8 ± 6.0 ml/10 min); this difference was also statistically significant. Patients with Candida infection suffered from different diseases and conditions, including hypertension, gastrointestinal disease, and xerostomia. The above findings suggest that one of the factors in the fungal culture test is dry mouth. Specifically, old age, dry mouth, chronic disease or medication leading to dry mouth were the clinical factors affecting the fungal culture test. However, neither the Candida species detected in the fungal culture nor the clinical appearance of the oral mucosa influenced these clinical features

トクシマ ダイガク ビョウイン セイシンカ シンケイカ ニュウイン カンジャ ニ タイスル コウクウ ケア ノ イギ

For patients with mental diseases, safe food-intake and the maintenance of good oral hygiene become difficult due to a decline in the ability of daily livings. In addition, a majority of patients suffer from the lack of reflection of both deglutition and cough as well as clinical silent aspiration, resulting from the extrapyramidal symptom (EPS) caused by antipsychotics. In this clinical study, we evaluated the oral environment in 10 inpatients with psychiatry neurology, and examined the usefulness of professional oral care. They were divided into 2 groups: the physical restriction group (restriction group) and the non-physical restriction group (control group), followed by the estimation of the conditions of oral hygiene and the days accompanied by fever, one of the symptoms of aspiration-related pneumonia, before and after professional oral care intervention. As a result, restriction group had poor oral hygiene condition as compared to the control group. After professional oral care intervention, oral hygiene condition was significantly improved in the restriction group, and reached to the same levels as in the control group. The days with fever were 7.3 and 5.0 days per month in the restriction group before and after the intervention, respectively. In the control group, those were 0.6 and 0 day per month before and after intervention, respectively. The cause of the difference in days with fever between 2 groups was considered to be the effect of clinical silent aspiration by EPS induced by antipsychotics. The professional oral care contributed to the improvement of the oral hygiene in inpatients with psychiatry neurology, resulting in the reduction of aspiration-related pneumonia. Therefore, the role of dentistry in the field of psychiatry neurology would be inevitable in the future

イワユル ビョウビョウ レンケイ ガ ソウコウ シタ ショウガイシャ ニ タイスル シュウガクテキ シカ チリョウ ニツイテ

In recent years, the oral environments of disabled people are well maintained by dental specialists for the disabled; however, because serious conditions requiring dental therapy do occur in disabled patients, we created a referral system for multidisciplinary dentistry for the disabled. In this report, we describe the successful implementation of this referral system and the treatment outcomes of disabled patients who underwent therapy by dental specialists. The patients were 12 disabled people, comprising 9 males and 3 females, who had been undergoing dental treatment in Tokushima Red Cross Hinomine Rehabilitation Center for People with Disabilities and had visited Tokushima University Hospital between January 2010 and March 2013. Their ages ranged from 14 to 71 years old, with a mean of 32.5 years old. The most common types of disabilities were hypophrenia: 7 patients (58.3%); cerebral palsy: 4 patients (33.3%), autism: 3 patients (25.0%), malformation syndrome: 2 patients (16.7%), etc. were found. The most frequent complications were epilepsy: 5 patients (41.7%); cured patent ductus arteriosus, laryngomalacia, asthma, hypertension, and ventilatory impairment were found in 1 patient (8.3%). Regarding oral diseases, chronic periodontitis and dental caries: 11 cases (91.7%), impacted wisdom teeth and persistence of deciduous teeth: 2 cases (16.7%) and oral cancer: 1 case (8.3%), were found. Concerning treatment, tooth extraction: 11 cases (91.7%), crown restoration: 5 cases (41.7%), pulpectomy: 2 cases (16.7%) and tumor resection: 1 case (8.3%), were safely performed. The procedures were performed under intravenous sedation in 6 cases, and under general anesthesia in the other 6 cases. Our referral system may contribute to the development of low-risk dentistry for the disabled