Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jaci.2020.05.022

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/art.41052

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-019-51149-1

Language：English  

DOI： 10.1080/14397595.2018.1438093

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.2169/internalmedicine.8946-17

Language：English   Publishing type：Research paper (scientific journal)  

To examine genes expressed specifically in labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS) in comparison with those of patients with immunoglobulin (Ig)G4-related disease (IgG4-RD), and to identify the genes involved in the pathogenesis of SS. Gene expression in LSGs of SS patients, IgG4-RD patients and healthy controls (HC) was analysed by cDNA microarray. Quantitative polymerase chain reaction (qPCR) was used to validate the up-regulation of differentially expressed genes (DEGs) in SS. Protein production of the validated gene in LSGs was examined by immunofluorescence (IF) assay. The association of molecular functions of the gene with the pathological conditions in SS was examined using peripheral blood lymphocytes. Among 1320 DEGs up-regulated in SS, qPCR confirmed the up-regulation of NR4A2 in LSGs of SS compared with IgG4-RD. IF staining showed higher production of NR4A2 in nuclei of CD4⁺ T cells and interleukin (IL)-17-producing cells in LSGs of SS, compared with IgG4-RD. Over-expression of NR4A2 mRNA was observed in peripheral CD4⁺ T cells of SS patients, compared with HC. Nuclear NR4A2 expression in T helper type 17 (Th17)-polarized CD4⁺ T cells determined by cellular IF was significantly higher in SS than in HC. Importazole, an inhibitor of importin-β, inhibited nuclear transport of NR4A2 and Th17 polarization along with IL-21 expression in naive CD4⁺ T cells under Th17-polarizing conditions, but did not alter retinoic acid receptor-related orphan receptor C (RORC) expression. NR4A2 seems to promote Th17 polarization via increased expression and intranuclear localization in CD4⁺ T cells of SS patients, which could play a critical role in the pathogenesis of SS.

DOI： 10.1111/cei.13000

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-017-01661-z

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0173017

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DOI： 10.1038/srep42413

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DOI： 10.1136/annrheumdis-2016-209139

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DOI： 10.1007/82_2016_40

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3109/14397595.2016.1148225

Language：English  

Objectives: Küttner tumour (KT), so-called chronic sclerosing sialoadenitis, is characterised by concomitant swelling of the submandibular glands secondary to strong lymphocytic infiltration and fibrosis independent of sialolith formation. However, recent studies have indicated that some patients with KT develop high serum levels of IgG4 and infiltration of IgG4-positive plasma cells, namely IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease. The aim of this study was to clarify the clinical and pathological associations between KT and IgG4-DS. Materials and Methods: Fifty-four patients pathologically diagnosed with KT or chronic sialoadenitis were divided into two groups according to the presence or absence of sialolith (KT-S (+) or KT-S (-), respectively). Results: There were no significant differences in the clinical findings, including the mean age, sex and disease duration, between the two groups. All patients in the KT-S (+) group showed unilateral swelling without infiltration of IgG4-positive plasma cells or a history of other IgG4-related diseases (IgG4-RD), while those in the KT-S (-) group showed bilateral swelling (37.5%), strong infiltration of IgG4-positive plasma cells (87.5%) and a history of other IgG4-RD (12.5%). Conclusions: These results suggest an association between the pathogeneses of KT-S (-) and IgG4-DS, but not KT-S (+).

DOI： 10.1111/odi.12259

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English  

Objectives: Recently, the use of saliva as a diagnostic tool has gained considerable attention because it is non-invasive and easy to perform repeatedly. In this study, we focused on soluble molecules in saliva to establish a new diagnostic method for xerostomia. Materials and Methods: Saliva was obtained from 90 patients with Sjögren's syndrome (SS), 22 patients with xerostomia associated with neurogenic/neuropsychiatric disorders and drugs (XND), 30 patients with radiation-induced xerostomia (RX), and 36 healthy controls. Concentrations of helper T (Th) cytokines in saliva were measured by flow cytometric analysis. Concentrations of secretory IgA (SIgA) and chromogranin A (CgA) were measured by ELISA. Results: Unstimulated and stimulated whole saliva from patients with SS, XND, and RX was significantly reduced compared with controls. Th1 and Th2 cytokines from SS patients were significantly higher than controls. Furthermore, Th2 cytokines were closely associated with strong lymphocytic accumulation in salivary glands from SS patients, while Th1 and Th17 cytokines were negatively associated. SIgA levels were not significantly different between all patient groups and controls. CgA levels from XND patients were significantly higher than controls. Conclusions: The measurement of cytokines, CgA, and SIgA in saliva is suggested to be useful for the diagnosis of xerostomia and also to reveal disease status.

DOI： 10.1111/odi.12252

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DOI： 10.1016/j.clim.2014.10.008

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DOI： 10.1016/j.jaut.2013.07.007

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DOI： 10.1016/j.ijom.2014.06.014

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DOI： 10.1038/bmt.2012.100

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1136/annrheumdis-2012-201477

Language：English  

DOI： 10.1111/j.1601-0825.2012.01923.x

Language：English  

The aim of this study was to investigate the initiation and progression of autoimmune damage in the lesions of labial salivary glands (LSGs) from primary Sjögren's syndrome (SS) patients by examining the selective localization of T helper (Th) subsets such as Th1, Th2, Th17 regulatory T cells (T _regs) and follicular T helper cells (Tfh). The expression of cytokines and transcription factors associated with these Th subsets in the LSGs from 54 SS patients and 16 healthy controls was examined using real-time polymerase chain reaction (PCR) and immunostaining. Additionally, infiltrating lymphocytes without germinal centre (GC ^-) and with GC (GC ⁺) in the LSGs specimens from eight SS patients were extracted selectively by laser capture microdissection (LCM). The mRNA expression of these molecules was compared between the two sample groups of GC ^- and GC ⁺ by real-time PCR. The mRNA expression of cytokines and transcription factors of all T helper (Th) subsets in the LSGs from the SS patients was increased significantly in comparison with controls. In LSGs from the SS patients, Th2 and Tfh was associated closely with strong lymphocytic infiltration; however, Th1, Th17 and T _regs was not. In the selectively extracted lesions of LSGs, Th1 and Th17-related molecules were detected strongly in the GC ^-, while Th2 and Tfh-related molecules were detected in the GC ⁺. In contrast, no significant association with strong lymphocytic infiltration was observed in T _reg-related molecules. These results indicate that SS has selective localization of Th subsets such as Th1, Th2, Th17 and Tfh in the LSGs, which is associated closely with disease severity and/or status. SS might be initiated by Th1 and Th17 cells, and then progressed by Th2 and Tfh cells via GC formation.

DOI： 10.1111/j.1365-2249.2012.04606.x

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DOI： 10.1186/ar3924

Language：English   Publishing type：Research paper (scientific journal)  

To investigate the pathogenesis of localized autoimmune damage in Sjögren's syndrome (SS) by examining the expression patterns of cytokines, chemokines and chemokine receptors at sites of autoimmune damage. mRNA expression of these molecules in the labial salivary glands (LSGs) and peripheral blood mononuclear cells (PBMCs) from 36 SS patients was examined using a real-time polymerase chain reaction-based method. Subsets of the infiltrating lymphocytes and chemokines/chemokine receptors expression in the LSG specimens were examined by immunohistochemistry. Cytokines/chemokine concentrations in the saliva were analysed using flow cytometry or enzyme-linked immunosorbent assay. mRNA expression of T helper type 1 (Th1) cytokines, chemokines and chemokine receptors was higher in LSGs than in PBMCs. In contrast, mRNA expression of Th2 cytokines, chemokines [thymus and activation-regulated chemokine (TARC/CCL17), macrophage-derived chemokine (MDC/CCL22)] and chemokine receptor (CCR4) was associated closely with strong lymphocytic accumulation in LSGs. Furthermore, TARC and MDC were detected immunohistochemically in/around the ductal epithelial cells in LSGs, whereas CCR4 was detected on infiltrating lymphocytes. The concentrations of these cytokines/chemokines were significantly higher in the saliva from SS patients than those from controls, and the concentrations of Th2 cytokines/chemokines were associated closely with strong lymphocytic accumulation in LSGs. These results suggest that SS might be initiated and/or maintained by Th1 and Th17 cells and progress in association with Th2 cells via the interaction between particular chemokines/chemokine receptors. Furthermore, the measurement of cytokines/chemokines in saliva is suggested to be useful for diagnosis and also to reveal disease status.

DOI： 10.1111/j.1365-2249.2012.04587.x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/art.33320

Language：English   Publishing type：Research paper (scientific journal)  

Background: IgG4-related tubulointerstitial nephritis (TIN) shows characteristic serum IgG4 elevation and increased IgG4-positive plasma cells in the renal interstitium, and inclusion of TIN as an IgG4-related systemic disease has been suggested. IgG4 is the rarest IgG subclass and is a Th2-dependent isotype with low affinity for target antigen. Although the pathogenesis of this disease has not been elucidated, positive serum immune complex and hypocomplementemia in some patients with this disease suggest that immune complex mechanisms are involved in the causation of this disease. Method:We selected 20 cases of histological diagnosed TIN. These cases were etiologically different and included 4 cases of IgG4-related TIN.We extracted RNAfrom paraffin embedded biopsied kidney and evaluated expression levels of various cytokines for each case by real time PCR. Results: Comparison of cytokine production patterns among different disease-associated TINs revealed that IgG4-related TIN exhibited a quite distinct pattern. On the one hand, there was no expression of IL-2, IFN-γ, IL-17 and IL-6, whereas production of IL-4, IL-10 and TGF-β was, on the other hand, remarkably increased in IgG4-related TIN. Conclusion: Based on these cytokine production results, Th2 and Treg appear to play a central role in IgG4-related TIN.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10165-007-0010-3

Language：English  

DOI： 10.1111/j.1600-0714.2006.00442.x

Publisher：Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology  

Objectives: To investigate the use of an oral moisture meter to aid in the diagnosis of Sjögren's syndrome (SS) by measuring the moisture values and salivary flow rate (SFR) simultaneously. Methods: The SFR and moisture values of the dorsum of the tongue and buccal mucosa were measured in 40 patients with SS and 29 healthy controls using an oral moisture meter. In addition, a visual analogue scale (VAS) was used to determine the degree of subjective oral symptoms (xerostomia, decreased saliva production, drinking during eating, oral pain, dysphagia, and dysgeusia). Results: The moisture values of the dorsum of the tongue and buccal mucosa were significantly lower in SS patients than in healthy subjects (both p < 0.01). SFR, especially when measured by the spitting test, correlated positively with the moisture values of the dorsum of the tongue (p < 0.0001) and buccal mucosa (p < 0.0003). Furthermore, the sensitivity, specificity, and accuracy of the oral moisture meter measurements of the dorsum of the tongue and buccal mucosa were 92.5%, 68.9%, and 82.6%, and 70.0%, 82.8%, and 73.9%, respectively. The moisture values of the dorsum of the tongue had a moderate negative correlation with the VAS scores of secondary subjective oral symptoms of xerostomia (oral pain, dysphagia, and dysgeusia), whereas a weak negative correlation was observed for subjective oral symptoms directly related to xerostomia (xerostomia and decreased saliva production). Conclusions: The oral moisture meter accurately reflected the results of the SFR tests and chronic subjective oral symptoms, and therefore might be a diagnostic criterion for SS.

DOI： 10.1016/j.ajoms.2024.02.007

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Odontogenic tumors (OGTs), which originate from cells of odontogenic apparatus and their remnants, are rare entities. Primary intraosseous carcinoma NOS (PIOC), is one of the OGTs, but it is even rarer and has a worse prognosis. The precise characteristics of PIOC, especially in immunohistochemical features and its pathogenesis, remain unclear. We characterized a case of PIOC arising from the left mandible, in which histopathological findings showed a transition from the odontogenic keratocyst to the carcinoma. Remarkably, the tumor lesion of this PIOC prominently exhibits malignant attributes, including invasive growth of carcinoma cell infiltration into the bone tissue, an elevated Ki-67 index, and lower signal for CK13 and higher signal for CK17 compared with the non-tumor region, histopathologically and immunohistopathologically. Further immunohistochemical analyses demonstrated increased expression of ADP-ribosylation factor (ARF)-like 4c (ARL4C) (accompanying expression of β-catenin in the nucleus) and yes-associated protein (YAP) in the tumor lesion. On the other hand, YAP was expressed and the expression of ARL4C was hardly detected in the non-tumor region. In addition, quantitative RT-PCR analysis using RNAs and dot blot analysis using genomic DNA showed the activation of Wnt/β-catenin signaling and epigenetic alterations, such as an increase of 5mC levels and a decrease of 5hmC levels, in the tumor lesion. A DNA microarray and a gene set enrichment analysis demonstrated that various types of intracellular signaling would be activated and several kinds of cellular functions would be altered in the pathogenesis of PIOC. Experiments with the GSK-3 inhibitor revealed that β-catenin pathway increased not only mRNA levels of ankyrin repeat domain1 (ANKRD1) but also protein levels of YAP and transcriptional co-activator with PDZ-binding motif (TAZ) in oral squamous cell carcinoma cell lines. These results suggested that further activation of YAP signaling by Wnt/β-catenin signaling may be associated with the pathogenesis of PIOC deriving from odontogenic keratocyst in which YAP signaling is activated.

DOI： 10.1016/j.prp.2024.155420

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Language：Japanese   Publisher：日本口腔顎顔面外傷学会  

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ajoms.2024.01.006

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Language：English   Publisher：Cellular Signalling  

Previous studies have demonstrated that extracellular vesicles (EVs) from dental pulp stem cells (DPSCs), which release abundant hepatocyte growth factor (HGF) and transforming growth factor-β1 (TGF-β1), contribute to the pathogenesis of Sjögren's syndrome (SS). However, depending on the condition of DPSCs, this effect is often not achieved. In this study, we established induced pluripotent stem (iPS) cells highly capable of releasing HGF and TGF-β1 and iPS cells barely capable of releasing them, and administered each EV to SS model mice to see if there was a difference in therapeutic effect. EVs were collected from each iPS cell and their characteristics and shapes were examined. When they were administered to SS model mice, the EVs from iPS cells with higher concentrations of HGF and TGF-β1 showed significantly reduced inflammatory cell infiltration in salivary gland tissues, increased saliva volume, and decreased anti-SS-A and anti-SS-B antibodies. A comprehensive search of microRNA arrays for differences among those EVs revealed that EVs from iPS cells with higher concentrations of HGF and TGF-β1 contained more of the let-7 family. Thereafter, we examined the expression of toll-like receptors (TLRs), which are said to be regulated by the let-7 family, by qPCR, and found decreased TLR4 expression. Focusing on MAPK, a downstream signaling pathway, we examined cytokine concentrations in mouse macrophage culture supernatants and Western blotting of murine splenic tissues and found higher concentrations of anti-inflammatory cytokines in the EVs-treated group and decreased TLR4, NF-κB and phosphorylation (p)-p-38 MAPK expression by Western blotting. Alternatively, p-Smad2/3 was upregulated in the EVs-treated group. Our findings suggest that the let-7 family in EVs may suppress the expression of TLR4 and NF-κB, which may be involved in the suppression of MAPK-mediated pro-inflammatory cytokine production.

DOI： 10.1016/j.cellsig.2023.110980

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Language：Japanese   Publisher：Japanese Society of Oral and Maxillofacial Traumatology  

In recent years, various surgical procedures have been reported for the open reduction and internal fixation （ORIF） of mandibular condyle fracture. In our department, the Risdon approach （RA） had been used for the ORIF of mandibular condyle fracture in the past, but since 2019, the high perimandibular approach （HPA） has been adopted. In this study, to clarify the differences between RA and HPA in mandibular condyle fracture, we compared the fracture site, operative time, postoperative facial nerve palsy, postoperative fixation, and amount of opening at discharge and at the end of opening training of these two techniques. Ninety cases and 105 sides with mandibular condyle fracture were diagnosed at our department during the ten years from 2013 to 2022. Twenty-two cases and 22 sides with ORIF were divided into the following two groups: RA group （11 cases and 11 sides） and HPA group （11 cases and 11 sides）, and then examined retrospectively. The operating time of the HA group （median time: 55 min） was significantly shorter than that of the RA group （median time: 89 min） （P＜0.01）. Postoperative facial paralysis was observed in 8 of 11 patients （72.7％） in the RA group only. No postoperative occlusal dysfunction or oral opening disorder was observed in either group. The results suggest that HPA is a useful technique that causes less postoperative paralysis in the mandibular marginal branch of the facial nerve and shorter operative time than RA.

DOI： 10.24787/jsomft.23.1_15

CiNii Research

Language：Japanese   Publisher：九州矯正歯科学会  

18歳の女性.前歯で食べものを咬み切れないことを主訴に九州大学病院矯正歯科を受診した.左側Angle III級,右側Angle I級で上下顎骨右方偏位を伴う非対称の骨格性III級前歯部開咬,long face type,顎変形症の成長終了後女性症例と診断した.上顎両側小臼歯抜歯による上顎前歯の舌側傾斜および上下顎骨切り術により治療を行うこととした.5年間の動的治療により側貌の改善と正常な前歯部被蓋の獲得,Angle II級の臼歯関係となり調和のとれた歯列咬合と側貌プロファイルが得られ保定開始2年3ヵ月において安定性を示した.(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Cancer immunotherapy targeting CD8+ T cells has made remarkable progress, even for oral squamous cell carcinoma (OSCC), a heterogeneous epithelial tumor without a substantial increase in the overall survival rate over the past decade. However, the therapeutic effects remain limited due to therapy resistance. Thus, a more comprehensive understanding of the roles of CD4+ T cells and B cells is crucial for more robust development of cancer immunotherapy. METHODS: In this study, we examined immune responses and effector functions of CD4+ T cells, CD8+ T cells and B cells infiltrating in OSCC lesions using single-cell RNA sequencing analysis, T cell receptor (TCR) and B cell receptor (BCR) repertoire sequencing analysis, and multi-color immunofluorescence staining. Finally, two Kaplan-Meier curves and several Cox proportional hazards models were constructed for the survival analysis. RESULTS: We observed expansion of CD4+ cytotoxic T lymphocytes (CTLs) expressing granzymes, which are reported to induce cell apoptosis, with a unique gene expression patterns. CD4+ CTLs also expressed CXCL13, which is a B cell chemoattractant. Cell-cell communication analysis and multi-color immunofluorescence staining demonstrated potential interactions between CD4+ CTLs and B cells, particularly IgD- CD27- double negative (DN) B cells. Expansion of CD4+ CTLs, DN B cells, and their contacts has been reported in T and B cell-activated diseases, including IgG4-related disease and COVID-19. Notably, we observed upregulation of several inhibitory receptor genes including CTLA-4 in CD4+ CTLs, which possibly dampened T and B cell activity. We next demonstrated comprehensive delineation of the potential for CD8+ T cell differentiation towards dysfunctional states. Furthermore, prognostic analysis revealed unfavorable outcomes of patients with a high proportion of CD4+ CTLs in OSCC lesions. CONCLUSION: Our study provides a dynamic landscape of lymphocytes and demonstrates a systemic investigation of CD4+ CTL effects infiltrating into OSCC lesions, which may share some pathogenesis reported in severe T and B cell-activated diseases such as autoimmune and infectious diseases.

DOI： 10.3389/fimmu.2023.1305783

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ajoms.2023.11.001

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.bbamcr.2022.119404

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Mixed tumor of the skin (MTS) is a rare neoplasm derived from the sweat glands with a reported frequency of 0.01‑0.098% among all primary skin tumors. MTS often occurs in the head and neck region and is characterized by a mixture of epithelial, myoepithelial and stromal components. MTS also shows various morphological patterns, thus the presence of variants with rare components and its rarity make the clinical diagnosis even more difficult. A 47‑year‑old man was referred due to a painless, slowly growing, exophytic swelling intracutaneous mass of the upper lip. Magnetic resonance imaging revealed that the mass was a solid tumor with a fatty component in the proximal portion, while the distal portion was cystic and possibly contained highly viscous fluid. The mass was located between the skin and the orbicularis oris muscle in the upper lip. Excisional biopsy was performed and the lesion showed two intriguing features: A tumor with extensive lipomatous stroma and some large cysts. It was histopathologically diagnosed as lipomatous MTS with cystic formation in the upper lip. No evident signs of recurrence were observed during follow‑up. The present report describes this case and includes a brief literature review of reported cases in the lip, since MTS can be confused with various skin lesions in clinical settings due to this rarity. Recognition by clinicians of different variants of MTSs, including the present case, is important for preventing erroneous diagnosis and treatment.

DOI： 10.3892/etm.2022.11600

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

An alternative source of mesenchymal stem cells has recently been discovered: dental pulp stem cells (DPSCs), including deciduous teeth, which can thus comprise potential tools for regenerative medicine. DPSCs derive from the neural crest and are normally implicated in dentin homeostasis. The clinical application of mesenchymal stem cells (MSCs) involving DPSCs contains various limitations, such as high cost, low safety, and cell handling issues, as well as invasive sample collection procedures. Although MSCs implantation offers favorable outcomes on specific diseases, implanted MSCs cannot survive for a long period. It is thus considered that their mediated mechanism of action involves paracrine effects. It has been recently reported that secreted molecules in DPSCs-conditioned media (DPSC-CM) contain various trophic factors and cytokines and that DPSC-CM are effective in models of various diseases. In the current study, we focus on the characteristics of DPSC-CM and their therapeutic potential against various disorders.

DOI： 10.3390/biomedicines10051049

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Patients with plasma cell type idiopathic multicentric Castleman disease (PC-iMCD) often show elevated serum IgG4 levels and IgG4-positive cell infiltration in tissues due to overproduction of interleukin-6, and may meet the diagnostic criteria for IgG4-related disease (IgG4-RD). Although PC-iMCD has been listed as a major exclusion disease for IgG4-RD, distinguishing between these diseases is challenging due to a lack of highly specific diagnostic biomarkers. In 2020, we proposed exclusion criteria of IgG4-RD mimickers. In this paper, we validated the accuracy of the criteria in excluding one of the mimickers, PC-iMCD, from IgG4-RD. Validation was performed on 57 PC-iMCD patients (39 presenting lymph node lesions and 19 with lung lesions) and 29 IgG4-RD patients (22 presenting lymph node lesions and seven with lung lesions). According to our results, 20.5% of the PC-iMCD patients with lymph node lesions and 42.1% of those with lung lesions met the diagnostic criteria for IgG4-RD. All these patients with PC-iMCD were excluded from a diagnosis of IgG4-RD by the proposed criteria. Additionally, 6.9% of IgG4-RD patients met the exclusion criteria. Thus, if the exclusion criteria are met, diagnosis should be made based on a combination of findings including organ distribution of disease, response to steroid therapy, and other pathological findings.

DOI： 10.1111/pin.13185

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

2020年に提唱された、IgG4関連疾患(IgG4-RD)の類似疾患除外基準の有用性について検討するため、IgG4-RD類似疾患の1つである形質細胞型特発性多中心性Casthleman病(PC-iMCD)患者を対象に検証した。病理組織学的/免疫組織学的検査ならびに血清学的検査で調べた結果、PC-iMCD患者ではリンパ節病変患者が39例(男性25例、女性14例、年齢34～89歳)、肺病変患者が19例(男性8例、女性11例、年齢26～73歳)に認められた。一方、IgG4-RD患者ではリンパ節病変患者が22例(男性7例、女性15例、年齢47～81歳)、肺病変患者が7例(男性7例、年齢39～77歳)であった。また、リンパ節病変を伴うPC-iMCD患者の20.5%と、肺病変を伴うPC-iMCD患者の42.1%はIgG4-RDの診断基準を満たしていたが、提唱された除外基準により、全例がIgG4-RDの診断から除外され、IgG4-RD患者の6.9%は、除外基準を満たしていることが明らかにされた。以上より、提唱されたIgG4-RD類似疾患除外基準は100%の感度と93.1%の特異度を有し、IgG4-RDの診断に有用と結論付けられた。

Language：Others   Publishing type：Research paper (scientific journal)  

<title>Abstract</title><sec>
<title>Background</title>
Sjögren’s syndrome (SS) is a chronic autoimmune disease primarily characterized by inflammation in the salivary and lacrimal glands. Activated T cells contribute to disease pathogenesis by producing proinflammatory cytokines, which leads to a positive feedback loop establishment. The study aimed to evaluate the effects of secreted factors derived from dental pulp stem cells (DPSCs) or bone marrow mesenchymal stem cells (BMMSCs) on hyposalivation in SS and to investigate the mechanism involved.


</sec><sec>
<title>Methods</title>
Eighty percent confluent stem cells were replenished with serum-free Dulbecco’s modified Eagle’s medium and incubated for 48 h; following which, conditioned media from DPSCs (DPSC-CM) and BMMSCs (BMMSC-CM) were collected. Cytokine array analysis was performed to assess the types of cytokines present in the media. Flow cytometric analysis was performed to evaluate the number of activated T cells cultured in DPSC-CM or BMMSC-CM. Subsequently, DPSC-CM or BMMSC-CM was administered to an SS mouse model. The mice were categorized into the following groups (<italic>n</italic> = 6 each): non-treatment, Dulbecco’s modified Eagle’s medium (−), BMMSC-CM, and DPSC-CM. Histological analysis of the salivary glands was performed. The gene and protein expression levels of cytokines associated with T helper subsets in the submandibular glands (SMGs) were evaluated.


</sec><sec>
<title>Results</title>
DPSC-CM contained more secreted factors with tissue-regenerating mechanisms, such as cell proliferation, anti-inflammatory effects, and immunomodulatory effects. DPSC-CM was more effective in suppressing the activated T cells than other groups in the flow cytometric analysis. The stimulated salivary flow rate increased in SS mice with DPSC-CM compared with that in the other groups. In addition, the number of inflammation sites in SMGs of the mice administered with DPSC-CM was lower than that in the other groups. The expression levels of <italic>interleukin</italic> (<italic>Il</italic>)<italic>-10</italic> and transforming growth factor-β1 were upregulated in the DPSC-CM group, whereas those of <italic>Il-4</italic> and <italic>Il-17a</italic> were downregulated. The DPSC-CM-administered group presented with a significantly increased percentage of regulatory T (Treg) cells and a significantly decreased percentage of type 17 Th (Th17) cells compared with the other groups.


</sec><sec>
<title>Conclusions</title>
These results indicated that DPSC-CM ameliorated SS by promoting Treg cell differentiation and inhibiting Th17 cell differentiation in the mouse spleen.


</sec>

DOI： 10.1186/s13287-021-02236-6

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Arthritis and Rheumatology  

OBJECTIVE: IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition that can affect multiple organs. We previously demonstrated that human Toll-like receptor 7 (huTLR7)-transgenic C57BL/6 mice showed elevated serum IgG1 levels and inflammation with fibrosis in the salivary glands (SGs), lungs, and pancreas. Moreover, we observed extensive TLR7+ CD163+ M2 macrophage infiltration in SGs from IgG4-RD patients. Here, we examined the fibrotic mechanism via the TLR7 pathway. METHODS: Gene expression in SGs from huTLR7-transgenic mice and IgG4-RD patients was analyzed using DNA microarrays. We extracted the common upregulated TLR7-related genes in SGs from huTLR7-transgenic mice and IgG4-RD patients. Finally, we investigated the interaction between CD163+ M2 macrophages and fibroblasts before/after stimulation with the TLR7 agonist loxoribine. RESULTS: In huTLR7-transgenic mice and IgG4-RD patients, IL-1 receptor-associated kinase 3 (IRAK3) and IRAK4 were significantly overexpressed. Real-time PCR validated the upregulation of only IRAK4 in IgG4-RD patients compared with the other groups. IRAK4 was strongly detected in/around germinal centers in SGs from IgG4-DS patients alone. Double immunofluorescence staining showed that IRAK4-positive cells were mainly co-localized with CD163+ M2 macrophages in SGs. After stimulation with loxoribine, CD163+ M2 macrophages exhibited significantly enhanced expression of IRAK4 and nuclear factor kappa B (NF-κB) and increased supernatant concentrations of fibrotic cytokines. Finally, we confirmed that the number of fibroblasts was increased by culture with the supernatant of CD163+ M2 macrophages following stimulation with loxoribine. CONCLUSION: CD163+ M2 macrophages promote fibrosis in IgG4-RD by increasing the production of fibrotic cytokines via TLR7/IRAK4/NF-κB signaling. This article is protected by copyright. All rights reserved.

DOI： 10.1002/art.42043

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/ijms22179475

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.reth.2021.01.006

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s12865-020-00361-0

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

DOI： 10.1080/14397595.2019.1576271

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/odi.13255

Language：English  

DOI： 10.5125/jkaoms.2020.46.1.3

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/MD.0000000000018300

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1080/14397595.2019.1632061

Language：Japanese  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/intimm/dxy075

Language：Japanese  

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/s41598-018-28405-x

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Low-grade myofibroblastic sarcoma arising in the tip of the tongue with intravascular invasion: A case report.
Low-grade myofibroblastic sarcoma (LGMS) is a rare intermediate tumor, which rarely metastasizes and has myofibroblastic differentiation in various sites. It is particularly associated with the tongue in the head and neck region. The lack of any pathological features means it is difficult to make a conclusive diagnosis of LGMS. The immunohistochemical features and genomic rearrangements, including SS18-SSXs and MYH9-USP6s and the genetic mutations of cancer-associated genes, including APC, CTNNB1, EGFR, KRAS, PIK3CA and p53 were examined in a case of LGMS arising in the tip of the tongue. Immunohistochemically, the tumor cells were positive for alpha-smooth muscle actin and vimentin, as in previous reports. They demonstrated neither genomic rearrangements nor point mutations of cancer-associated genes. Although several tumor cells demonstrated intravascular invasion, the MIB-l labeling index of the cells was the same as the original lesion. To the best of our knowledge, this is the first case report of LGMS arising in the tip of the tongue with intravascular invasion.

DOI： 10.3892/ol.2018.9115

Language：English  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/jbm4.10013

Language：English  

DOI： 10.1016/j.ijom.2018.01.004

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.26508/lsa.201800050

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1136/annrheumdis-2016-210758

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1038/srep28110

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/MD.0000000000002853

Language：English  

DOI： 10.1007/978-4-431-55687-9_3

Language：English  

DOI： 10.1007/978-4-431-55687-9_3

Language：English   Publishing type：Research paper (scientific journal)  

DNA Microarray Analysis of Labial Salivary Glands in Patients with Sjogren's Syndrome: Comparison with IgG4-Related Disease

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13075-015-0751-x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s12957-015-0644-0

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3892/or.2015.3838

Language：Others  

IL-33 Secreted by M2 Macrophage Promotes the Pathogenesis of IgG4-Related Disease

Language：English   Publishing type：Research paper (scientific journal)  

DNA Microarray Analysis of Labial Salivary Glands in Patients with Sjogren's Syndrome: Comparison with IgG4-Related Disease

Language：Japanese  

Language：English  

DOI： 10.1097/MD.0000000000000704

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s12957-015-0459-z

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ajoms.2014.04.011

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/art.38748

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1371/journal.pone.0101156

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3109/14397595.2013.843765

Language：English  

Mikulicz’s disease (MD) was considered to be a subtype of Sjögren’s syndrome (SS), based on histopathological similarities. However, recent studies have indicated that patients with MD show high serum IgG4 concentrations and suggested that MD is an “IgG4-related disease” and distinguishable from SS. We examined the clinical and serological features of MD and SS in detail to determine the ways in which the two conditions can be differentiated. MD can be diagnosed quickly and simply using diagnostic criteria such as serum IgG4 values and the presence of IgG4+ cells in the salivary glands, in conjunction with salivary gland imaging, sonography, and CT scans. Glucocorticoid therapy of MD reduces IgG and IgG4 levels and improves salivary function. A negative correlation between disease duration and increasing rate of salivary flow was observed in MD.

DOI： 10.1007/978-4-431-54228-5_13

Language：English  

Mikulicz’s disease (MD) was considered to be a subtype of Sjögren’s syndrome (SS), based on histopathological similarities. However, recent studies have indicated that patients with MD show high serum IgG4 concentrations and suggested that MD is an “IgG4-related disease” and distinguishable from SS. We examined the clinical and serological features of MD and SS in detail to determine the ways in which the two conditions can be differentiated. MD can be diagnosed quickly and simply using diagnostic criteria such as serum IgG4 values and the presence of IgG4+ cells in the salivary glands, in conjunction with salivary gland imaging, sonography, and CT scans. Glucocorticoid therapy of MD reduces IgG and IgG4 levels and improves salivary function. A negative correlation between disease duration and increasing rate of salivary flow was observed in MD.

DOI： 10.1007/978-4-431-54228-5_13

Language：English   Publishing type：Research paper (scientific journal)  

IgG4-related disease (IgG4-RD) is a systemic disease characterized by the elevation of serum IgG4 and infiltration of IgG4-positive plasma cells in the target organs, and its molecular mechanism of pathogenesis remains to be clarified. IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease or Küttner's tumor, is included in IgG4-RD and shows clinical and histological similarities to Sjögren's syndrome (SS). In this review, we focus on the selective localization and respective functions of Th cell subsets and discuss the differences between IgG4-DS and SS to clarify the clinical and pathogenic mechanisms of these diseases.

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s00784-012-0905-z

Language：English   Publishing type：Research paper (scientific journal)  

ANALYSIS OF MOLECULAR MECHANISM IN IGG4-RELATED DISEASE: COMPARISON WITH SJOGREN'S SYNDROME

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ajoms.2012.05.018

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s10165-012-0812-9

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Others  

Molecular Mechanism of IgG4 Class Switch Recombination in IgG4-Related Disease.

Language：Others  

In vitro induction of specific CD8+ T lymphocytes by tumor-associated antigenic peptides in patients with oral squamous cell carcinoma.

DOI： 10.1016/j.canlet.2012.02.016

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.tripleo.2009.02.032

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

Language：Japanese   Book type：Scholarly book

Language：Japanese   Book type：Scholarly book

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Language：Japanese   Book type：Scholarly book

Language：Japanese   Book type：Scholarly book

Responsible for pages：43-54頁, 2017   Language：English   Book type：Scholarly book

Responsible for pages：第67巻 第4号、337-342頁、2017   Language：Japanese   Book type：Scholarly book

Responsible for pages：1-4頁   Language：Japanese   Book type：Scholarly book

Responsible for pages：52-54頁   Language：Japanese   Book type：Scholarly book

Language：Japanese   Book type：Scholarly book

Responsible for pages：1033-1043頁   Language：Japanese   Book type：General book, introductory book for general audience

Language：Japanese   Book type：Scholarly book

Responsible for pages：page 85-92   Language：English   Book type：Scholarly book

Responsible for pages：第50巻、第6号、648-654頁   Language：Japanese   Book type：Scholarly book

Responsible for pages：第50巻、第4号、482-491頁   Language：Japanese   Book type：Scholarly book

Responsible for pages：第21巻、第5号、111-118頁   Language：Japanese   Book type：Scholarly book

Responsible for pages：第67巻、第4号、979-989頁   Language：Japanese   Book type：Scholarly book

Responsible for pages：68-74頁   Language：Japanese   Book type：Scholarly book

Responsible for pages：111-116頁   Language：Japanese   Book type：Scholarly book

Total pages：7  

CiNii Research

Total pages：7  

CiNii Research

Total pages：7  

CiNii Research

Total pages：7  

CiNii Research

Total pages：4  

CiNii Research

Responsible for pages：99-105頁   Language：Japanese   Book type：Scholarly book

Event date： 2023.3

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Venue：金沢   Country：Japan  

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Venue：WEB   Country：Japan  

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Event date： 2022.9

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：金沢   Country：Japan  

Event date： 2022.9

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Venue：金沢   Country：Japan  

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Event date： 2022.9 - 2022.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンデマンド配信   Country：Japan  

Event date： 2022.9 - 2022.10

Language：Japanese  

Venue：オンデマンド配信   Country：Japan  

researchmap

Event date： 2022.7

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：WEB   Country：Japan  

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Venue：WEB   Country：Japan  

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Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：福岡   Country：Japan  

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Venue：WEB   Country：Japan  

Event date： 2021.10 - 2022.10

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Venue：WEB   Country：Japan  

Event date： 2021.10 - 2022.10

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Venue：WEB   Country：Japan  

researchmap

Event date： 2021.10

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Venue：WEB   Country：Japan  

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Venue：WEB   Country：Japan  

Event date： 2019.11 - 2020.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：幕張   Country：Japan  

Event date： 2019.9

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Country：Australia  

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Presentation type：Oral presentation (general)  

Venue：名古屋   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

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Venue：福岡   Country：Japan  

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Venue：福岡   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：福岡   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：福岡   Country：Japan  

Event date： 2017.2

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Country：Japan  

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Language：English   Presentation type：Oral presentation (general)  

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Event date： 2013.10

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Venue：福岡   Country：Japan  

Event date： 2013.10

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Venue：福岡   Country：Japan  

Event date： 2013.10

Language：English  

Venue：Kyoto   Country：Japan  

Event date： 2013.10

Language：English  

Country：Japan  

Event date： 2013.10

Language：English  

Country：Japan  

Event date： 2013.10

Language：English  

Country：Japan  

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Venue：Kyoto   Country：Japan  

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Country：Japan  

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Venue：福岡   Country：Japan  

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Venue：新潟   Country：Japan  

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Country：Japan  

Event date： 2012.11

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Country：Indonesia  

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Venue：横浜   Country：Japan  

Event date： 2012.10

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Venue：横浜   Country：Japan  

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Venue：バリ   Country：Indonesia  

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Venue：大阪   Country：Japan  

Event date： 2011.10

Language：Japanese  

Venue：大阪   Country：Japan  

Event date： 2011.10

Language：Japanese  

Venue：広島   Country：Japan  

Event date： 2011.9

Language：English  

Venue：アテネ   Country：Greece  

Event date： 2011.9

Language：English  

Venue：アテネテネ   Country：Greece  

Event date： 2011.7

Language：Japanese  

Venue：神戸   Country：Japan  

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：京都   Country：Japan  

Language：Japanese  

Venue：鹿児島   Country：Japan  

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：京都   Country：Japan  

Language：Japanese  

Venue：金沢   Country：Japan  

Language：Japanese  

Country：Japan  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

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Language：Japanese  

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Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese   Publisher：(有)科学評論社  

Language：Others  

Pathogenesis of IgG4-related disease: a critical review.

DOI： 10.1007/s10266-018-0377-y

Type：Competition, symposium, etc. 

Number of participants：98

Type：Competition, symposium, etc. 

researchmap

Type：Scientific advice/Review 

researchmap

Type：Competition, symposium, etc. 

Number of participants：60

Type：Competition, symposium, etc. 

Number of participants：65

Type：Competition, symposium, etc. 

Number of participants：65

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：10

Proceedings of domestic conference Number of peer-reviewed papers：3

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：10

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：8

Type：Competition, symposium, etc. 

Number of participants：150

Type：Scientific advice/Review 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：5

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：7

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：4

Type：Competition, symposium, etc.