Publications by authors named "Yumi Tsuchida"

31 Publications

Identifying the most influential gene expression profile in distinguishing ANCA-associated vasculitis from healthy controls.

J Autoimmun 2021 May 4;119:102617. Epub 2021 Mar 4.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address:

Objective: Previous gene expression analyses seeking genes specific to antineutrophil cytoplasmic antibody-associated vasculitis (AAV) have been limited due to crude cell separation and the use of microarrays. This study aims to identify AAV-specific gene expression profiles in a way that overcomes those limitations.

Methods: Blood samples were collected from 26 AAV patients and 28 healthy controls (HCs). Neutrophils were isolated by negative selection, whereas 19 subsets of peripheral blood mononuclear cells were sorted by fluorescence assisted cell sorting. RNA-sequencing was then conducted for each sample, and iterative weighted gene correlation network analysis (iterativeWGCNA) and random forest were consecutively applied to identify the most influential gene module in distinguishing AAV from HCs. Correlations of the identified module with clinical parameters were evaluated, and the biological role was assessed with hub gene identification and pathway analysis. Particularly, the module's association with neutrophil extracellular trap formation, NETosis, was analyzed. Finally, the module's overlap with GWAS-identified autoimmune disease genes (GADGs) was assessed for validation.

Results: A neutrophil module (Neu_M20) was ranked top in the random forest analysis among 255 modules created by iterativeWGCNA. Neu_M20 correlated with disease activity and neutrophil counts but not with the presence of antineutrophil cytoplasmic antibody. The module comprised pro-inflammatory genes, including those related to NETosis, supported by experimental evidence. The genes in the module significantly overlapped GADGs.

Conclusion: We identified the distinct group of pro-inflammatory genes in neutrophils, which characterize AAV. Further investigations are warranted to confirm our findings as they could serve as novel therapeutic targets.
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http://dx.doi.org/10.1016/j.jaut.2021.102617DOI Listing
May 2021

Effects of build orientation on adaptation of casting patterns for three-unit partial fixed dental prostheses fabricated by using digital light projection.

J Prosthet Dent 2021 Feb 26. Epub 2021 Feb 26.

Professor, Department of Oral Biomaterials Engineering, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Statement Of Problem: The lost-wax technique is commonly used for fabricating partial fixed dental prostheses. The casting patterns can be fabricated by using vat photopolymerization (a type of additive manufacturing), but the adaptation of these casting patterns has not been elucidated.

Purpose: The purpose of this in vitro study was to evaluate the effect of build orientation on the adaptation of casting patterns fabricated by digital light projection (DLP).

Material And Methods: A 3-unit partial fixed dental prosthesis with mandibular left second premolar and second molar abutment teeth was scanned and virtually designed with a computer-aided design software program. The cement space was designed to be 30 μm. Specimens were fabricated with 3 build orientations: 0 degrees (with the occlusal surface parallel to the platform), 30 degrees, and 45 degrees (by rotating the file along the long axis). The casting patterns were fabricated by using DLP (Cara Print 4.0) with a photopolymerizable monomer (dima Print Cast Q). Photopolymerization, cleaning, and postpolymerization processes were performed according to the manufacturer's instructions. The adaptation of the specimens was examined by using a silicone replica method. The vertical marginal discrepancy and axial wall, occlusal, and marginal gaps were measured by using a digital measuring microscope. The effect of build orientation at each cross-sectional area was statistically analyzed by using the Kruskal-Wallis test followed by the pairwise Wilcoxon rank sum test with Bonferroni correction (α=.05).

Results: Excess polymerized resin was observed along the intaglio buccal wall at build orientations of 30 degrees and 45 degrees. Vertical marginal discrepancies in the buccolingual section ranged from -50 to 248 μm, while those in the mesiodistal section ranged from -25 to 182 μm. The gaps in the buccolingual section ranged from 0 to 236 μm, while those in the mesiodistal section ranged from 0 to 177 μm. According to the observation of vertical marginal discrepancies and gaps, the 30-degree specimens inclined during insertion, and the 45-degree specimens were not completely seated. However, the marginal gaps of the 0- and 30-degree specimens were within the clinically acceptable limit of 120 μm.

Conclusions: The limited data indicated that the build orientation influenced the adaptation of casting patterns for 3-unit partial fixed dental prostheses fabricated by using DLP. A build orientation of 0 degrees is recommended for fabricating casting patterns for 3-unit partial fixed dental prostheses because no excess polymerization of the intaglio buccal wall was observed.
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http://dx.doi.org/10.1016/j.prosdent.2021.01.006DOI Listing
February 2021

Contribution of a European-Prevalent Variant near CD83 and an East Asian-Prevalent Variant near IL17RB to Herpes Zoster Risk in Tofacitinib Treatment: Results of Genome-Wide Association Study Meta-Analyses.

Arthritis Rheumatol 2021 Jan 17. Epub 2021 Jan 17.

Pfizer Inc, Cambridge, Massachusetts, USA.

Objective: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis, and ulcerative colitis, and has been previously investigated for psoriasis (PsO). Genome-wide association studies (GWAS) were performed to identify genetic factors associated with increased risk/faster onset of herpes zoster (HZ) upon tofacitinib treatment, and potential mechanisms of the varying HZ rate across ethnicities.

Methods: In an ethnicity-/indication-specific and trans-ethnic trans-indication meta-analysis of GWAS in subjects from RA and PsO phase II, III, and long-term extension tofacitinib studies, 8 million genetic variants on time to HZ and HZ event (case versus control) were evaluated via Cox and logistic regression, respectively.

Results: 5,246 subjects were included (RA: 3,168; PsO: 2,078). Adjusting for age, baseline absolute lymphocyte count, genetically-defined ethnicity, and concomitant methotrexate use (RA only), 4 loci were significantly associated with faster HZ onset in Europeans (P < 5×10 ), including a single-nucleotide polymorphism (SNP) near CD83 (risk allele in Europeans ~2%, East Asian ~0.1%). In the trans-ethnic trans-population meta-analysis, the CD83 SNP remained significant, and 4 additional significant loci were identified, among which a SNP near IL17RB was associated with faster HZ onset (meta-analysis hazard ratio [95% confidence interval] 3.6 [2.40, 5.44], P = 7.6×10 ; risk allele in East Asian subjects ~12%, European subjects <0.2%).

Conclusion: Genetic analysis of tofacitinib-treated RA and PsO subjects identified multiple loci associated with increased HZ risk. European or East Asian population-specific prevalent variants near immune-relevant genes of CD83 and IL17RB, respectively, may contribute to HZ risk in tofacitinib-treated subjects.
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http://dx.doi.org/10.1002/art.41655DOI Listing
January 2021

Fertility preservation in patients receiving gonadotoxic therapies for systemic autoimmune diseases in Japan.

Mod Rheumatol 2021 Jan 18:1-8. Epub 2021 Jan 18.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Objectives: Gonadotoxic therapies, mainly cyclophosphamide, are used for the treatment of various systemic autoimmune diseases. In Japan, the number of patients who undergo gonadotoxic therapy for autoimmune diseases, fertility preservation procedures performed in these patients, and problems associated with performing such procedures have not been reported. This study was performed to address these issues.

Methods: A questionnaire was sent to Certified Educational Facilities of the Japanese Society of Rheumatology, and a single rheumatologist at each center completed the questionnaire.

Results: A total of 63 facilities completed the questionnaire. Between April 2014 and March 2019, a total of 1302 men and premenopausal women had received gonadotoxic therapies for systemic autoimmune disease. Nearly half of the respondents reported that gonadotropin releasing hormone analog therapy was available in their area. However, the availability of other fertility preservation procedures was limited, and the number of patients undergoing fertility preservation procedures was limited. 85.7% of the respondents responded that measures to preserve fertility in patients receiving gonadotoxic therapies for autoimmune diseases were inadequate.

Conclusions: A substantial number of patients are receiving gonadotoxic therapies for the treatment of autoimmune diseases in Japan, and those patients may not be receiving adequate care regarding their fertility.
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http://dx.doi.org/10.1080/14397595.2020.1856020DOI Listing
January 2021

Parsing multiomics landscape of activated synovial fibroblasts highlights drug targets linked to genetic risk of rheumatoid arthritis.

Ann Rheum Dis 2020 Nov 2. Epub 2020 Nov 2.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Objectives: Synovial fibroblasts (SFs) are one of the major components of the inflamed synovium in rheumatoid arthritis (RA). We aimed to gain insight into the pathogenic mechanisms of SFs through elucidating the genetic contribution to molecular regulatory networks under inflammatory condition.

Methods: SFs from RA and osteoarthritis (OA) patients (n=30 each) were stimulated with eight different cytokines (interferon (IFN)-α, IFN-γ, tumour necrosis factor-α, interleukin (IL)-1β, IL-6/sIL-6R, IL-17, transforming growth factor-β1, IL-18) or a combination of all 8 (8-mix). Peripheral blood mononuclear cells were fractioned into five immune cell subsets (CD4 T cells, CD8 T cells, B cells, natural killer (NK) cells, monocytes). Integrative analyses including mRNA expression, histone modifications (H3K27ac, H3K4me1, H3K4me3), three-dimensional (3D) genome architecture and genetic variations of single nucleotide polymorphisms (SNPs) were performed.

Results: Unstimulated RASFs differed markedly from OASFs in the transcriptome and epigenome. Meanwhile, most of the responses to stimulations were shared between the diseases. Activated SFs expressed pathogenic genes, including whose induction by IFN-γ was significantly affected by an RA risk SNP (rs6074022). On chromatin remodelling in activated SFs, RA risk loci were enriched in clusters of enhancers (super-enhancers; SEs) induced by synergistic proinflammatory cytokines. An RA risk SNP (rs28411362), located in an SE under synergistically acting cytokines, formed 3D contact with the promoter of gene, whose binding motif showed significant enrichment in stimulation specific-SEs. Consistently, inhibition of MTF1 suppressed cytokine and chemokine production from SFs and ameliorated mice model of arthritis.

Conclusions: Our findings established the dynamic landscape of activated SFs and yielded potential therapeutic targets associated with genetic risk of RA.
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http://dx.doi.org/10.1136/annrheumdis-2020-218189DOI Listing
November 2020

A case of granulomatous myositis in a patient with rheumatoid arthritis receiving anti-TNF-α treatment.

Mod Rheumatol Case Rep 2020 01 24;4(1):1-5. Epub 2019 Jun 24.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

A 66-year old woman with a 14-year history of rheumatoid arthritis (RA) and uveitis was admitted to our department for evaluation of a mass in the left neck. Fourteen months prior to this admission the patient was started on golimumab. Serum creatine kinase (CK) level was elevated and myositis-specific and -associated antibodies were negative. Manual muscle test showed weakness in the neck flexor, sternocleidomastoid and deltoid muscles. Magnetic resonance imaging (MRI) of the neck, erector muscle of spine, breech, thigh and lower thigh demonstrated high-intensity lesions in the muscles in short-tau inversion recovery images. Electromyography in the right deltoid detected fibrillation potentials. Muscle biopsy from the left neck mass showed granulomatous myositis. Muscle weakness improved and CK levels normalized after discontinuation of golimumab. We report a case of granulomatous myositis under anti-TNF-α treatment for RA.
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http://dx.doi.org/10.1080/24725625.2019.1628427DOI Listing
January 2020

Decreased peripheral blood memory B cells are associated with the presence of interstitial lung disease in rheumatoid arthritis: a case-control study.

Mod Rheumatol 2021 Jan 5;31(1):127-132. Epub 2020 Feb 5.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Objectives: Interstitial lung disease sometimes occurs in rheumatoid arthritis patients. Although the underlying immunological mechanisms responsible for interstitial lung disease associated with rheumatoid arthritis have not yet been clarified, some reports have suggested possible roles of B cells. To examine the role of B-cell subsets in interstitial lung disease in rheumatoid arthritis patients, we analyzed peripheral blood B-cell subsets.

Methods: We analyzed the frequencies of the peripheral blood B-cell subsets by flow cytometry in rheumatoid arthritis patients with and without interstitial lung disease ( = 16 and 81, respectively) and in healthy donors ( = 110) by high-resolution computed tomography.

Results: Compared with healthy donors, rheumatoid arthritis patients showed statistically higher frequencies of naive B cells and lower frequencies of memory B cells. Moreover, the frequencies of memory B cells were lower in rheumatoid arthritis patients with interstitial lung disease than in those without. Multivariate analysis showed that the frequency of memory B cells, particularly switched memory B cells, was significantly decreased in rheumatoid arthritis patients with interstitial lung disease, even after adjusting for prednisolone dose.

Conclusions: We suspect memory B cells play important roles in interstitial lung disease associated with rheumatoid arthritis.
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http://dx.doi.org/10.1080/14397595.2020.1719596DOI Listing
January 2021

2019 Diagnostic criteria for mixed connective tissue disease (MCTD): From the Japan research committee of the ministry of health, labor, and welfare for systemic autoimmune diseases.

Mod Rheumatol 2021 Jan 7;31(1):29-33. Epub 2020 Jan 7.

Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Objective: To update and revise the diagnostic criteria for mixed connective tissue disease (MCTD) issued by the Japan Research Committee of the Ministry of Health, Labor, and Welfare (MHLW), a round table discussion by experts from rheumatology, dermatology, and pediatric medicine was conducted in multiple occasions.

Methods: The definition of MCTD, and items included in the diagnostic criteria were generated by consensus method and evaluation using clinical data of typical and borderline cases of MCTD, by applying to the diagnostic criteria for MCTD proposed in 1996 and 2004 by the Research Committee of MHLW.

Results: To the end, all committee members reached consensus. Then, the criteria were assessed in an independent validation cohort and tested against preexisting criteria. The revised criteria facilitate an understanding of the overall picture of this disease by describing the concept of MCTD, common manifestations, immunological manifestation and characteristic organ involvement. Conditions with characteristic organ involvement include pulmonary arterial hypertension, aseptic meningitis and trigeminal neuropathy. Even if the overlapping manifestations are absent, MCTD can be diagnosed based on the presence of the characteristic organ involvement. Furthermore, the criteria were validated for applicability in actual clinical cases, and public comments were solicited from the Japan College of Rheumatology and other associated societies.

Conclusion: After being reviewed through public comments, the revised diagnostic criteria have been finalized.
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http://dx.doi.org/10.1080/14397595.2019.1709944DOI Listing
January 2021

Extremely high levels of multiple cytokines in the cord blood of neonates born to mothers with systemic autoimmune diseases.

Cytokine 2020 03 19;127:154926. Epub 2019 Dec 19.

Department of Obstetrics and Gynecology, The University of Tokyo Hospital, Tokyo, Japan.

Most infants born to mothers with autoimmune diseases are thought to be entirely healthy. However, the immunological conditions have not been examined thoroughly. Fourteen neonates born to mothers with systemic autoimmune diseases, namely systemic lupus erythematosus, mixed connective tissue disease, Sjögren's syndrome, rheumatoid arthritis, and systemic sclerosis, were included. Serum concentrations of 17 cytokines from the infants' umbilical artery (UA) and vein (UV) and from the mothers' peripheral blood were investigated by a bead array system. Cytokine expression in the placenta was investigated by immunohistochemical staining. The disease was controlled in all mothers, and none had chorioamnionitis. Hypercytokinemia was found in 11 neonates irrespective of their mothers' autoimmune diseases. In six neonates, serum cytokines were at extremely high levels. Four neonates were born by cesarean section because of a non-reassuring fetal status (NRFS) of unknown cause were all included in the hypercytokinemia group. However, all the subjects were discharged without any complications. The cytokine levels were almost the same between UA and UV, but the mothers' blood samples did not show elevation of serum cytokines. There were no differences in the expression of cytokines in the placenta among three patients with different serum cytokines levels. Hypercytokinemia frequently occurred and a cytokine storm state sometimes developed in neonates born to mothers with systemic autoimmune diseases. Growth restriction and NRFS may be related to hypercytokinemia in utero. It is plausible that the high level of cytokines in cord blood originate in neither the mother nor the placenta but in fetal immune tissues. It is important to investigate the immunological mechanisms, prevalence, and long-term influence of hypercytokinemia in a large sample size of neonates and mothers with systemic autoimmune diseases.
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http://dx.doi.org/10.1016/j.cyto.2019.154926DOI Listing
March 2020

Evaluation of mechanical properties of new elastomer material applicable for dental 3D printer.

J Mech Behav Biomed Mater 2019 12 22;100:103390. Epub 2019 Aug 22.

Cariology and Operative Dentistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo, Japan.

Purpose: Digital technology has advanced and changed clinical dentistry. The utility of various thermoplastic materials for 3D dental printing has not been thoroughly explored. The aim of this study was to evaluate mechanical properties of a new thermoplastic elastomer material applicable for a dental 3D printer.

Material & Method: Three thermoplastic elastomers: ABS, PLA and an acrylic block copolymer (KUR) and a dental self-curing resin (PMMA) were used in this study. Physical properties were evaluated by measuring water sorption (WS), dimensional accuracy (DA), ultimate tensile strength (UTS) and shear bond strength (SBS) to PMMA. For WS and DA, specimens were measured by weight and length, respectively after desiccation and immersion in 37 °C distilled water for 1 day, 1 week and 1 month. For UTS, the specimens were prepared according to ISO 527-2-5A and loaded to test the UTS at a crosshead speed of 5 mm/min after storage in 37 °C distilled water for 24 h and 1 month. For SBS, MMA self-curing resin was filled in a Teflon ring which was mounted onto polished specimens to make the adhesive area. The prepared specimens were tested for SBS after storage in 37 °C distilled water for 24 h and 37 °C distilled water for 24 h followed by 10000 times thermal cycling. The data were analyzed by repeated measures ANOVA, two-way ANOVA and t-test with Bonferroni correction at 95% confidence level.

Result: The WS value of PMMA was significantly higher than those of the other materials after 1 day (p < 0.05), while the WS values of KUR were significantly higher than those of the other materials after 1 week and 1 month (p < 0.05). The DA values were influenced by water storage periods except for KUR. There were no significant differences among ABS, PLA and PMMA in SBS before thermal cycling (p > 0.05). The SBS of KUR was the lowest among the materials before thermal cycling (p < 0.05). However, there was no significant difference between PMMA and KUR after thermal cycling (p > 0.05).

Conclusion: The acrylic block copolymer demonstrated acceptable physical properties, suggesting the potential to be a material to make provisional restorations for a dental 3D printer.
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http://dx.doi.org/10.1016/j.jmbbm.2019.103390DOI Listing
December 2019

Eosinophilic cholangitis with eosinophilic granulomatosis with polyangiitis: A case report and review of the literature.

Allergol Int 2020 Jan 31;69(1):154-156. Epub 2019 Aug 31.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

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http://dx.doi.org/10.1016/j.alit.2019.08.002DOI Listing
January 2020

CD4CD25LAG3 T Cells With a Feature of Th17 Cells Associated With Systemic Lupus Erythematosus Disease Activity.

Front Immunol 2019 12;10:1619. Epub 2019 Jul 12.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple immune cell subsets. We analyzed immune cell subsets in human peripheral blood mononuclear cells (PBMC) in order to identify the cells that are significantly associated with SLE disease activity and treatment. The frequencies of various subsets of CD4 T cells, B cells, monocytes and NK cells in PBMC were assessed in 30 healthy controls (HC), 30 rheumatoid arthritis (RA) patients and 26 SLE patients using flow cytometry. The correlations between subset frequencies in SLE and clinical traits including Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were examined. Changes in subset frequencies after the treatment in SLE patients were investigated. We focused on CD25LAG3 T cells and investigated their characteristics, including cytokine secretion, mRNA expression and suppression capacity. We assessed correlations between CD25LAG3 T cells and SLEDAI by Spearman's rank correlation coefficient. CD25LAG3 T cells were significantly increased in SLE whereas there were few in RA and HC groups. CD25LAG3 T cell frequencies were significantly correlated with SLEDAI and were increased in patients with a high SLEDAI score (> 10). CD25LAG3 T cells produced both IL-17 and FOXP3, expressed mRNA of both and and lacked suppressive capacity. CD25LAG3 T cells were associated with disease activity of SLE. CD25LAG3 T cells had features of both CD25FOXP3 regulatory T cells (CD25 Treg) and Th17. CD25LAG3 T cells could be associated with the inflammatory pathophysiology of SLE.
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http://dx.doi.org/10.3389/fimmu.2019.01619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640175PMC
October 2020

Effect of fiberglass orientation on flexural properties of fiberglass-reinforced composite resin block for CAD/CAM.

Dent Mater J 2019 Oct 21;38(5):738-742. Epub 2019 Jun 21.

Oral Biomaterials Development Engineering, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University.

A fiberglass-reinforced composite resin (FRP) block using a plain woven fiberglass sheet for CAD/CAM has been introduced in dental practice. The aim of the present study was to evaluate the effects of the fiberglass sheet orientation on the flexural properties of an FRP block. The flexural properties of five types of fiberglass sheet-assigned specimens were examined using a three-point bending test. A one-way analysis of variance revealed that the orientation of fiberglass sheet significantly influenced the flexural strength, 0.2% yield strength, and flexural modulus. The values of the flexural properties of the FRP were the largest when the fiberglass sheets were perpendicular to the applied force, and the smallest when the fiberglass was parallel to the same. The flexural properties of the FRP block were anisotropic and they were significantly influenced by the orientation of fiberglass sheet.
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http://dx.doi.org/10.4012/dmj.2018-249DOI Listing
October 2019

Effects of number of metal restorations and mandibular position during computed tomography imaging on accuracy of maxillofacial models.

J Prosthodont Res 2019 Apr 15;63(2):239-244. Epub 2019 Jan 15.

Department of Oral Prosthetic Engineering, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Purpose: Computed tomography (CT) imaging for three-dimensional (3D) printed models may improve the quality of surgical preoperative plans. Although metal objects can cause artifacts in CT images, integration of CT and digital dental arch imaging may solve this problem. The present study aimed to evaluate effects of the number of metal restorations and mandibular position during CT imaging on accuracy of reproduced models.

Methods: Stereolithography datasets from three sets of dental models having different numbers of metal restorations were obtained using a laboratory digitizing device (control) and CT equipment (nonintegrated data). CT scanning was performed under two conditions: intercuspal position (closed) and separated using paraffin wax (open). Nonintegrated data after metal artifact removal were separated into maxillary and mandibular dentition groups. The occlusal part of the control dentition and nonintegrated data were superimposed and integrated (integrated data). The root mean square (RMS) between the control and stereolithography data was calculated and analyzed with three-way analysis of variance and t-test with Bonferroni correction.

Results: Increasing numbers of metal restorations resulted in increase in metal artifacts and RMS values. Moreover, the RMS of the closed dataset was significantly greater than that of the open dataset because of the creation of artificial occlusal surfaces. The RMSs of the integrated datasets were significantly smaller than those of the nonintegrated datasets, except for the open model without metal restorations.

Conclusions: Accuracies of reproduced maxillary and mandibular models decreased with increasing numbers of metal restorations and in the closed mandibular position during CT scanning.
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http://dx.doi.org/10.1016/j.jpor.2018.12.006DOI Listing
April 2019

The development of new image receptor-holding instruments with appropriate horizontal X-ray beam angulation for periapical radiographs.

Dentomaxillofac Radiol 2019 May 10;48(4):20180354. Epub 2019 Jan 10.

1 Department of Oral and Maxillofacial Radiology, Tokyo Medical and Dental University , Tokyo , Japan.

Objectives: This study aimed to develop new image receptor-holding instruments with appropriate horizontal X-ray beam angulation, based on the anatomical data of posterior region interproximal surfaces derived from archived CT images.

Methods: CT images of 92 patients with sound upper and lower dental arches were collected from our CT database and analyzed to determine the angles between the tangential interproximal contact line and the central groove line of posterior teeth. The average angle for each site was calculated and used to modify instruments using a three-dimensional printer. The utilities of the conventional and the modified instruments for viewing proximal surfaces were compared using two dry skulls.

Results: The right and left sides of each site, except for the lower second premolar and first molar sites, did not differ significantly. The difference between the sites was 2.0°; hence, we calculated mean values for the two sides at each site. In the maxilla, the angles of the first and second premolar, second premolar and first molar, and first and second molar to the groove line were 83.9° (±5.4°), 84.4° (±3.9°), 81.6° (±5.1°), while those in the mandible were 85.0° (±9.2°), 85.0° (±4.0°), and 90.6° (±4.9°), respectively. The holding instruments modified to 80° demonstrated better proximal viewing ability in the upper molar region than conventional instruments.

Conclusions: The mean angles of the interproximal surfaces were determined from CT data. The image receptor holding-instruments were modified according to these angles to allow appropriate X-ray angulation, which facilitated improved observation of the proximal surfaces of teeth in the posterior region in this pilot study.
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http://dx.doi.org/10.1259/dmfr.20180354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592581PMC
May 2019

Transcriptome analysis of peripheral blood from patients with rheumatoid arthritis: a systematic review.

Inflamm Regen 2018 5;38:21. Epub 2018 Nov 5.

4Center for Integrative Medical Sciences, the Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehirocho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045 Japan.

In the era of precision medicine, transcriptome analysis of whole gene expression is an essential technology. While DNA microarray has a limited dynamic range and a problem of background hybridization, RNA sequencing (RNA-seq) has a broader dynamic range and a lower background signal that increase the sensitivity and reproducibility. While transcriptome analyses in rheumatoid arthritis (RA) have generally focused on whole peripheral blood mononuclear cells (PBMC), analyses of detailed cell subsets have an increased need for understanding the pathophysiology of disease because the involvement of CD4 T cells in the pathogenesis of RA has been established. Transcriptome analysis of detailed CD4 T cell subsets or neutrophils shed new light on the pathophysiology of RA. There are several analyses about the effect of biological treatment. Many studies report the association between type I interferon signature gene expression and response to therapy.
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http://dx.doi.org/10.1186/s41232-018-0078-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217768PMC
November 2018

Trends in domiciliary dental care including the need for oral appliances and dental technicians in Japan.

J Oral Sci 2018 Dec 26;60(4):626-633. Epub 2018 Oct 26.

Department of Oral Prosthetic Engineering, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University.

The need for domiciliary dental care (DDC) for people requiring long-term nursing care is increasing as the super-aged society of Japan grows still older. Dysphagia diagnosis and rehabilitation are becoming more important in DDC; thus, the need for prostheses used for dysphasia rehabilitation is presumed to be increasing. To identify DDC trends in Japan, as well as the need for prostheses and dental technicians for DDC, we sent a self-administered questionnaire to dentists providing DDC and analyzed responses from 138 dentists (valid response rate, 39.8%). The results showed that 37.7% of respondents reported treating ≥50 patients per month. The most frequently performed procedures were removable prosthetic treatment and oral care, followed by dysphagia rehabilitation. Use of palatal augmentation prostheses was experienced by 54.3% of respondents, and most indicated that the prostheses were effective for improvement of oropharyngeal function. The rates of cooperation with primary care doctors and nursing care professionals were 76.8% and 85.5%, respectively. Only 6.5% of respondents reported accompanying dental technicians to DDC. The present analysis of trends in DDC indicates that oral care and dysphagia rehabilitation have become more frequent and that cooperation with healthcare professionals other than dental technicians has increased in recent DDC.
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http://dx.doi.org/10.2334/josnusd.18-0053DOI Listing
December 2018

HLA-DRB1 Shared Epitope Alleles and Disease Activity Are Correlated with Reduced T Cell Receptor Repertoire Diversity in CD4+ T Cells in Rheumatoid Arthritis.

J Rheumatol 2018 07 15;45(7):905-914. Epub 2018 Apr 15.

From the Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo; Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.

Objective: Shared epitope (SE) alleles are the most significant genetic susceptibility locus in rheumatoid arthritis (RA); however, their target populations in CD4+ T cells are not well elucidated. We analyzed the association between SE alleles and the T cell receptor (TCR) repertoire diversity of naive and memory CD4+ T cells using next-generation sequencing (NGS).

Methods: The TCR beta chains in naive and memory CD4+ T cells from the peripheral blood of 22 patients with RA and 18 age- and sex-matched healthy donors (HD) were analyzed by NGS. The Renyi entropy was used to evaluate TCR repertoire diversity and its correlations with SE alleles and other variables were examined. Serum cytokine levels were measured by multiplex ELISA.

Results: The TCR repertoire diversity in memory CD4+ T cells was reduced in SE allele-positive patients with RA compared with HD, and showed a significant negative correlation with the SE allele dosage in RA. The TCR repertoire diversity of naive and memory T cells was also negatively correlated with disease activity, and the SE allele dosage and disease activity were independently associated with reduced TCR repertoire diversity. TCR repertoire diversity showed a significant positive correlation with the serum interleukin 2 levels.

Conclusion: SE alleles and disease activity were negatively correlated with the TCR repertoire diversity of CD4+ T cells in RA. Considering the pivotal role of CD4+ T cells in RA, restoring the altered TCR repertoire diversity will provide a potential RA therapeutic target.
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http://dx.doi.org/10.3899/jrheum.170909DOI Listing
July 2018

A gene module associated with dysregulated TCR signaling pathways in CD4 T cell subsets in rheumatoid arthritis.

J Autoimmun 2018 05 13;89:21-29. Epub 2017 Nov 13.

Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), 1-7-22 Suehirocho, Tsurumi-ku, Yokohama City, Kanagawa, 230-0045, Japan.

We analyzed the transcriptome of detailed CD4 T cell subsets including them after abatacept treatment, and examined the difference among CD4 T cell subsets and identified gene sets that are closely associated disease activity and abatacept treatment. Seven CD4 T cell subsets (naive, Th1, Th17, Th1/17, nonTh1/17, Tfh and Treg) were sorted from PBMCs taken from 10 RA patients and 10 healthy controls, and three RA patients donated samples before and 6 months after abatacept treatment. Paired-end RNA sequencing was performed using HiSeq 2500. A total of 149 samples except for 12 outliers were analyzed. Overview of expression pattern of RA revealed that administration of abatacept exerts a large shift toward the expression pattern of HC. Most of differentially expressed gene (DEG) upregulated in RA (n = 1776) were downregulated with abatacept treatment (n = 1349). Inversely, most of DEG downregulated in RA (n = 1860) were upregulated with abatacept treatment (n = 1294). This DEG-based analysis revealed shared pathway changes in RA CD4 T cell subsets. Knowledge-based pathway analysis revealed the upregulation of activation-related pathways in RA that was substantially ameliorated by abatacept. Weighted gene co-expression network analysis (WGCNA) evaluated CD4 T cells collectively and identified a gene module that consisted of 227 genes and was correlated with DAS28-CRP (Spearman's rho = 0.46, p = 4 × 10) and abatacept administration (Spearman's rho = -0.91, p = 5 × 10). The most highly connected 30 genes of this module included ZAP70 and JAK3, and pathway analysis of this module revealed dysregulation of the TCR signaling pathway network, which was ameliorated by abatacept.
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http://dx.doi.org/10.1016/j.jaut.2017.11.001DOI Listing
May 2018

Increased serum concentrations of IL-1 beta, IL-21 and Th17 cells in overweight patients with rheumatoid arthritis.

Arthritis Res Ther 2017 05 31;19(1):111. Epub 2017 May 31.

Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.

Backgrounds: Obesity is associated with worse disease activity and drug responses in patients with rheumatoid arthritis (RA). However, the immunological mechanisms responsible for the relationship between RA and obesity have not yet been clarified in detail. This study aimed to elucidate the immunological mechanisms contributing to the pathogenesis of RA in overweight patients.

Methods: The frequencies of CD4 T cell, B cell and monocyte subsets were analyzed in RA (n = 81) and healthy donors (n = 99) by flow cytometry, and were compared between three groups (body mass index (BMI) <20,  ≥20 to 25, >25). Serum cytokines were measured using multiplex ELISA. Gene expression was analyzed by quantitative PCR. Clinical information was extracted from medical records.

Results: The frequencies of T helper (Th)17 (CD4CD45RA-CXCR5-CXCR3-CCR6) cells and plasmablasts (PB) were significantly increased in patients with RA with BMI >25. Significant correlation was observed between BMI and Th17 cells in patients with RA. No significant differences in cell frequencies between the three BMI groups were observed in the healthy donors. Serum interleukin (IL)-1β and IL-21 significantly correlated with BMI in RA patients. Gene expression patterns in Th17 cells from overweight patients with RA showed the characteristics of pathogenic Th17 cells.

Conclusions: Quantitative and qualitative changes in Th17 cells were characteristic in overweight patients with RA.
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http://dx.doi.org/10.1186/s13075-017-1308-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452609PMC
May 2017

Polygenic burdens on cell-specific pathways underlie the risk of rheumatoid arthritis.

Nat Genet 2017 Jul 29;49(7):1120-1125. Epub 2017 May 29.

Laboratory for Autoimmune Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.

Recent evidence suggests that a substantial portion of complex disease risk alleles modify gene expression in a cell-specific manner. To identify candidate causal genes and biological pathways of immune-related complex diseases, we conducted expression quantitative trait loci (eQTL) analysis on five subsets of immune cells (CD4 T cells, CD8 T cells, B cells, natural killer (NK) cells and monocytes) and unfractionated peripheral blood from 105 healthy Japanese volunteers. We developed a three-step analytical pipeline comprising (i) prediction of individual gene expression using our eQTL database and public epigenomic data, (ii) gene-level association analysis and (iii) prediction of cell-specific pathway activity by integrating the direction of eQTL effects. By applying this pipeline to rheumatoid arthritis data sets, we identified candidate causal genes and a cytokine pathway (upregulation of tumor necrosis factor (TNF) in CD4 T cells). Our approach is an efficient way to characterize the polygenic contributions and potential biological mechanisms of complex diseases.
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http://dx.doi.org/10.1038/ng.3885DOI Listing
July 2017

Interleukin-10-producing LAG3 regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis.

Arthritis Res Ther 2017 05 16;19(1):97. Epub 2017 May 16.

Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Background: Regulatory T cells (Tregs) play a role in the suppression of inflammation in autoimmune diseases, and lymphocyte activation gene 3 (LAG3) was reported as a marker of interleukin (IL)-10-producing Tregs. We aimed to clarify the function of human IL-10-producing CD4CD25LAG3 T cells (LAG3 Tregs) and their association with rheumatoid arthritis (RA).

Methods: LAG3 Tregs of human peripheral blood mononuclear cells (PBMCs) were cultured with B cells and follicular helper T cells to examine antibody suppression effects. The frequency of LAG3 Tregs was evaluated in peripheral blood samples from 101 healthy donors and 85 patients with RA. In patients treated with abatacept, PBMC samples were analyzed before and after treatment. Naive CD4 T cells were sorted and cultured in the presence of abatacept, followed by flow cytometric analysis and function assays.

Results: LAG3 Tregs produced high amounts of IL-10 and interferon-γ, and they suppressed B-cell antibody production more strongly than CD25 Tregs. Cell-to-cell contact was required for the suppressive function of LAG3 Tregs. The frequency of LAG3 Tregs was lower in patients with RA, especially those with higher Clinical Disease Activity Index scores. LAG3 Tregs significantly increased after 6 months of abatacept treatment, whereas CD25 Tregs generally decreased. Abatacept treatment in vitro conferred LAG3 and EGR2 expression on naive CD4 T cells, and abatacept-treated CD4 T cells exhibited suppressive activity.

Conclusions: IL-10-producing LAG3 Tregs are associated with the immunopathology and therapeutic response in RA. LAG3 Tregs may participate in a mechanism for the anti-inflammatory and immune-modulating effects of targeted therapy for costimulation.
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http://dx.doi.org/10.1186/s13075-017-1309-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434528PMC
May 2017

Enhanced gut homing receptor expression of unswitched memory B cells in rheumatoid arthritis.

Clin Exp Rheumatol 2017 Mar-Apr;35(2):354-355. Epub 2017 Jan 27.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Japan.

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June 2017

TGF-β3 Inhibits Antibody Production by Human B Cells.

PLoS One 2017 4;12(1):e0169646. Epub 2017 Jan 4.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

TGF-β is a pleotropic cytokine involved in various biological processes. Of the three isoforms of TGF-β, TGF-β1 has long been recognized as an important inhibitory cytokine in the immune system and has been reported to inhibit B cell function in both mice and humans. Recently, it has been suggested that TGF-β3 may play an important role in the regulation of immune system in mice. Murine CD4+CD25-LAG3+ regulatory T cells suppress B cell function through the production of TGF-β3, and it has been reported that TGF-β3 is therapeutic in a mouse model of systemic lupus erythematosus. The effect of TGF-β3 on human B cells has not been reported, and we herein examined the effect of TGF-β3 on human B cells. TGF-β3 suppressed B cell survival, proliferation, differentiation into plasmablasts, and antibody secretion. Although the suppression of human B cells by TGF-β1 has long been recognized, the precise mechanism for the suppression of B cell function by TGF-β1 remains elusive; therefore, we examined the effect of TGF-β1 and β3 on pathways important in B cell activation and differentiation. TGF-β1 and TGF-β3 inhibited some of the key molecules of the cell cycle, as well as transcription factors important in B cell differentiation into antibody secreting cells such as IRF4, Blimp-1, and XBP1. TGF-β1 and β3 also inhibited B cell receptor signaling. Our results suggest that TGF-β3 modifying therapy might be therapeutic in autoimmune diseases with B cell dysregulation in humans.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169646PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215424PMC
August 2017

Macrophage activation syndrome associated with tocilizumab treatment in adult-onset Still's disease.

Mod Rheumatol 2017 05 25;27(3):556-557. Epub 2016 Oct 25.

a Department of Allergy and Rheumatology, Graduate School of Medicine , The University of Tokyo , Bunkyo-ku , Tokyo , Japan.

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http://dx.doi.org/10.1080/14397595.2016.1221875DOI Listing
May 2017

Identification of tonsillar CD4CD25LAG3 T cells as naturally occurring IL-10-producing regulatory T cells in human lymphoid tissue.

J Autoimmun 2017 01 18;76:75-84. Epub 2016 Sep 18.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Electronic address:

IL-10-producing regulatory T cells (IL-10-producing Tregs) are one of the regulatory T cell subsets characterized by the production of high amounts of IL-10, the lack of FOXP3 expression and the strong immunosuppressive capabilities. IL-10-producing Tregs have been primarily reported as induced populations thus far, in part because identifying naturally occurring IL-10-producing Tregs was difficult due to the lack of definitive surface markers. Lymphocyte-activation gene 3 (LAG3) is a CD4 homologue that we have identified as being expressed on IL-10 producing Tregs. In human PBMC, LAG3 combined with CD49b efficiently identifies IL-10-producing Tregs. However, naturally occurring IL-10-producing Tregs in human secondary lymphoid tissue have not been described. In this report, we identified CD4CD25LAG3 T cells in human tonsil. This T cell subset produced high amounts of IL-10 and expressed low levels of FOXP3. Surface markers and microarray analysis revealed that this is a distinct tonsillar CD4 T cell subset. CD4CD25LAG3 T cells expressed interleukin 10 (IL10), PR/SET domain 1 (PRDM1), and CD274 at high levels and chemokine receptor 5 (CXCR5) at low levels. CD4CD25LAG3 T cells suppressed antibody production more efficiently than CD4CD25 T cells, and CD4CD25LAG3 T cells induced B cell apoptosis. Moreover, analysis of humanized mice revealed that this cell subset suppressed a graft-versus-host disease (GVHD) reaction in vivo. Our study reveals the existence of naturally occurring IL-10-producing Tregs in human secondary lymphoid tissue and their function in immune regulation.
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http://dx.doi.org/10.1016/j.jaut.2016.09.005DOI Listing
January 2017

Immunophenotyping of rheumatoid arthritis reveals a linkage between HLA-DRB1 genotype, CXCR4 expression on memory CD4(+) T cells, and disease activity.

Sci Rep 2016 07 7;6:29338. Epub 2016 Jul 7.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that leads to destructive arthritis. Although the HLA class II locus is the strongest genetic risk factor for rheumatoid arthritis, the relationship between HLA class II alleles and lymphocyte activation remains unclear. We performed immunophenotyping of peripheral blood mononuclear cells on 91 HLA-DRB1-genotyped RA patients and 110 healthy donors. The frequency of memory CXCR4(+)CD4(+) T cells, and not Th1 and Th17 cells, was significantly associated with disease severity by multiple linear regression analysis. RA patients with one or more susceptible HLA-DR haplotypes (shared epitope: SE) displayed a significantly higher frequency of memory CXCR4(+)CD4(+) T cells. Moreover, the frequency of memory CXCR4(+)CD4(+) T cells significantly correlated with the expression level of HLA-DR on B cells, which was elevated in RA patients with SE. In vitro analysis and transcriptomic pathway analysis suggested that the interaction between HLA-DR and T cell receptors is an important regulator of memory CXCR4(+)CD4(+) T cells. Clinically, a higher frequency of memory CXCR4(+)CD4(+) T cells predicted a better response to CTLA4-Ig. Memory CXCR4(+)CD4(+) T cells may serve as a powerful biomarker for unraveling the linkage between HLA-DRB1 genotype and disease activity in RA.
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http://dx.doi.org/10.1038/srep29338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935954PMC
July 2016

Massive calcinosis cutis associated with primary Sjögren's syndrome.

BMJ Case Rep 2016 Feb 4;2016. Epub 2016 Feb 4.

Department of Allergy and Rheumatology, The University of Tokyo, Tokyo, Japan.

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http://dx.doi.org/10.1136/bcr-2015-214006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746507PMC
February 2016

Characteristics of granulomatosis with polyangiitis patients in Japan.

Mod Rheumatol 2015 Mar 28;25(2):219-23. Epub 2014 Jul 28.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo , Bunkyo-ku, Tokyo , Japan.

Objectives: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a disease with significant ethnic differences. Reports on characteristics of Japanese granulomatosis with polyangiitis (GPA) patients are limited, and this study was undertaken to determine the characteristics of Japanese GPA patients.

Methods: This was a retrospective chart study of 24 Japanese GPA patients. GPA was defined according to the European Medicines Agency algorithm.

Results: The percentage of MPO-ANCA-positive patients was 33.3%, higher than the percentages reported in studies from Western countries. MPO-ANCA-positive GPA patients differed from PR3-ANCA-positive GPA patients in organs involved at diagnosis with MPO-ANCA-positive patients having nose and sinus involvement less frequently compared to PR3-ANCA-positive patients. Interstitial lung infiltrates were more common among MPO-ANCA-positive GPA patients compared to PR3-ANCA-positive GPA patients.

Conclusion: Among Japanese GPA patients, the proportion of MPO-ANCA-positive patients is higher compared to reports from Western countries, and those patients are often different from the classical picture of GPA.
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http://dx.doi.org/10.3109/14397595.2014.937475DOI Listing
March 2015