| Maehara Takashi | Last modified date：2024.04.25 |
Lecturer /
Maxill Ofacial Surgery /
Kyushu University Hospital
Papers
| 1. | Risako Koga, Takashi Maehara, Ryuichi Aoyagi, Ryusuke Munemura, Yuka Murakami, Atsushi Doi, Michihito Kono, Hidetaka Yamamoto, Hiroaki Niiro, Tamotsu Kiyoshima, Mika Tanabe, Toshiaki Nakano, Yuta Matsukuma, Mitsuhiro Kawano, John H Stone, Shiv Pillai, Seiji Nakamura, Shintaro Kawano , Granzyme K- and amphiregulin-expressing cytotoxic T cells and activated extrafollicular B cells are potential drivers of IgG4-related disease , J Allergy Clin Immunol, 10.1016/j.jaci.2023.11.916, 2023.12. |
| 2. | Ryuichi Aoyagi, Takashi Maehara, Risako Koga, Ryusuke Munemura, Tadashi Tomonaga, Yuka Murakami, Atsushi Doi, Hidetaka Yamamoto , Tamotsu Kiyoshima, Shintaro Kawano, Seiji Nakamura , Single-cell transcriptomics reveals granzyme K-expressing cytotoxic Tfh cells in tertiary lymphoid structures in IgG4-RD, J Allergy Clin Immunol, 10.1016/j.jaci.2023.08.019, 2023.08. |
| 3. | Maehara T, Koga R, Nakamura S., Immune dysregulation in immunoglobulin G4-related disease., Jpn Dent Sci Rev., 2023.06. |
| 4. | Ryusuke Munemura, TAKASHI MAEHARA, Yuka Murakami, Risako Koga, Ryuichi Aoyagi, Naoki Kaneko, Atsushi Doi, Cory A. Perugino, Emanuel Della-Torre, Takako Saeki, Yasuharu Sato, Hidetaka Yamamoto, Tamotsu Kiyoshima, John H. Stone, Shiv Pillai, Seiji Nakamura., Distinct disease-specific Tfh cell populations in two different fibrotic diseases: IgG4- related disease and Kimura’s disease, The Journal of Allergy and Clinical Immunology, doi: 10.1016/j.jaci.2022.03.034., 2022.04, Background: How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T-cell–dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs in patients with elevated tissue expression levels of IgE (Kimura disease, KD) and those of IgG4 (IgG4-related disease, IgG4-RD) can provide important insights regarding cytokine expression by Tfh cells. Objective: We sought to identify disease-specific Tfh cell subsets in secondary and tertiary lymphoid organs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in 2 distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes). Methods: Single-cell RNA sequencing, in situ sequencing, and multicolor immunofluorescence analysis were used to investigate B cells, Tfh cells, and infiltrating type 2 cells in lesion tissues from patients with KD or IgG4-RD. Results: Infiltrating Tfh cells in tertiary lymphoid organs from IgG4-RD were divided into 6 main clusters. We encountered abundant infiltrating IL-10–expressing LAG31 Tfh cells in patients with IgG4-RD. Furthermore, we found that infiltrating AICDA1CD191 B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG4 expression. In contrast, we found that infiltrating IL-13–expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13–expressing Tfh cells in tissues from patients with IgG4-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG4-RD; in contrast, type 2 immune cells were abundant in KD. Conclusions: Our analysis revealed a novel subset of IL-101LAG31 Tfh cells infiltrating the affected organs of IgG4-RD patients. In contrast, IL-131 Tfh cells and type 2 immune cells infiltrated those of KD patients. (J Allergy Clin Immunol 2022;150:440-55.). |
| 5. | Chinju A, Moriyama M, Kakizoe-Ishiguro N, Chen H, Miyahara Y, Rafiul Haque ASM, Furusho K, Sakamoto M, Kai K, Kibe K, Hatakeyama-Furukawa S, Ito-Ohta M, Maehara T, Nakamura S., CD163+ M2 macrophages promote fibrosis in IgG4-related disease via TLR7/IRAK4/NF-κB signaling., Arthritis & Rheumatology, 10.1002/art.42043. , 2021.12. |
| 6. | Kazuhiko Higashioka, Yuri Ota, Takashi Maehara, Masafumi Moriyama, Masahiro Ayano, Hiroki Mitoma, Mitsuteru Akahoshi, Yojiro Arinobu, Takahiko Horiuchi, Seiji Nakamura, Koichi Akashi, Hiroaki Niiro, Association of circulating SLAMF7+Tfh1 cells with IgG4 levels in patients with IgG4-related disease, BMC Immunology, 10.1186/s12865-020-00361-0, 21, 1, 2020.06, Background: Follicular helper CD4+ T (Tfh) cells have a critical role in IgG4 production by B cells in IgG4-related disease (IgG4-RD). Recent studies including ours showed that SLAMF7+CD4+ T cells are an important pathological driver of IgG4-RD. In this study, we have sought to elucidate a relationship between helper CD4+ T (Th), particularly Tfh, cells and SLAMF7+ CD4+ T cells in IgG4-RD. Results: The patients with IgG4-RD enrolled in this study were aged 66 ± 12 years and their titers of serum IgG4 were 372 ± 336 mg/dl. Th1 cells, activated circulating Tfh1 (cTfh1), and activated cTfh2 cells increased in IgG4-RD. SLAMF7 was mainly expressed on Th1 and cTfh1, but not cTfh2, cells in the patients. SLAMF7+ cTfh1 cells were PD-1/CD28 double-positive, whereas SLAMF7+ Th1 cells were CD28 negative. Positive correlations were noted between serum IgG4 levels and the number of activated cTfh2 cells and SLAMF7+ cTfh1 cells, but not SLAMF7+ Th1 cells. Intriguingly, among cTfh1 cells, activated SLAMF7+ cTfh1 cells were high producers of IL-10 along with IL-21. Blimp-1, but not Bcl-6, mRNA was expressed at high levels in activated SLAMF7+ cTfh1 cells. In addition to CD4+ T cells, the frequency of SLAMF7+ fraction was higher in memory B cells than naïve B cells in patients with IgG4RD. Finally, upon stimulation via B-cell receptor and CD40, Tfh1-associated cytokines, IL-21 and IFN-γ, most significantly induced SLAMF7 expression in memory B cells. Conclusions: Together, these results suggest that circulating SLAMF7+ Tfh1 cells, along with Tfh2 cells, play a pathologic role in IgG4 production in IgG4-RD.. |
| 7. | Cory A. Perugino, Naoki Kaneko, Takashi Maehara, Hamid Mattoo, Jesper Kers, Hugues Allard-Chamard, Vinay S. Mahajan, Hang Liu, Emanuel Della-Torre, Samuel JH. Murphy, Musie Ghebremichael, Zachary S. Wallace, Geetha Mylvaganam, Yesim Tuncay, Lloyd Liang, Sydney B. Montesi, Akira Tinju, Keita Mochizuki, Ryusuke Munemura, Mizuki Sakamoto, Masafumi Moriyama, Seiji Nakamura, Nir Yosef,John H. Stone, Shiv Pillai, CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease, J Allergy Clin Immunol, 2020.05. |
| 8. | Takashi Maehara, Naoki Kaneko, Cory A. Perugino, Hamid Mattoo, Jesper Kers, Hugues Allard-Chamard, Vinay S. Mahajan, Hang Liu, Samuel J.H. Murphy, Musie Ghebremichael, David Fox, Aimee S. Payne, Robert Lafyatis, John H. Stone, Dinesh Khanna, Shiv Pillai, Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis, Journal of Clinical Investigation, 10.1172/JCI131700, 130, 5, 2451-2464, 2020.05, Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that CD4<sup>+</sup> cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR-expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction.. |
| 9. | Mizuki Sakamoto, Masafumi Moriyama, Mayumi Shimizu, Akira Chinju, Keita Mochizuki, Ryusuke Munemura, Keiko Oyama, Takashi Maehara, Kenichi Ogata, Miho Ohta, Masaki Yamauchi, Noriko Ishiguro, Mayu Matsumura, Yukiko Ohyama, Tamotsu Kiyoshima, Seiji Nakamura, The diagnostic utility of submandibular gland sonography and labial salivary gland biopsy in IgG4-related dacryoadenitis and sialadenitis Its potential application to the diagnostic criteria, Modern Rheumatology, 10.1080/14397595.2019.1576271, 30, 2, 379-384, 2020.03, Objectives: In this study, we investigated the diagnostic utility of submandibular gland (SMG) sonography and labial salivary gland (LSG) biopsy as a less invasive procedure for diagnosing IgG4-related dacryoadenitis and sialadenitis (IgG4-DS) Methods: Sixty-eight patients with suspected IgG4-DS by presenting swelling of elevated serum IgG (>1747 mg/dl) and/or swelling glands underwent SMG sonography, LSG biopsy and measurement for serum IgG4. SMG sonographic diagnosis was determined by the following characteristic changes; ‘hypoechoic areas of a nodal pattern with high vascularity’ and/or ‘hypoechoic areas of a reticular pattern in the superficial part’. Results: Thirty-one patients were diagnosed with IgG4-DS, 5 with IgG4-RD unaccompanied by lacrimal and salivary gland lesions, 28 with Sjögren’s syndrome, and 4 with malignant lymphoma. The sensitivity, specificity, and accuracy of SMG sonography and LSG biopsy were 100%, 83.8%, 91.2% and 64.5%, 73.8%, 75.0%, respectively. Moreover, those of SMG sonography and LSG biopsy combined with serum IgG4 concentration (>135 mg/dl) were 100%, 94.6%, 97.1% and 64.5%, 91.9%, 79.4%, respectively. Conclusion: LSG biopsy needs to be extremely careful to diagnose IgG4-DS because of its low sensitivity. SMG sonography is sufficient for the diagnosis of IgG4-DS, especially when combined with serologic analysis. Thus, SMG sonography could adapt to the diagnostic criteria of IgG4-DS as a non-invasive method.. |
| 10. | Takashi Maehara, Masafumi Moriyama, Seiji Nakamura, Review of a novel disease entity, immunoglobulin G4-related disease, Journal of the Korean Association of Oral and Maxillofacial Surgeons, 10.5125/jkaoms.2020.46.1.3, 46, 1, 3-11, 2020.02, Immunoglobulin G4 (IgG4)-related dacryoadenitis and sialoadenitis (IgG4-DS) are part of a multiorgan fibroinflammatory condition of unknown etiology termed IgG4-related disease (IgG4-RD), which has been recognized as a single diagnostic entity for less than 15 years. Histopathologic examination is critical for diagnosis of IgG4-RD. CD4+ T and B cells, including IgG4-expressing plasma cells, constitute the major inflammatory cell populations in IgG4-RD and are thought to cause organ damage and tissue fibrosis. Patients with IgG4-RD who have active, untreated disease exhibit significant increase of IgG4-secreting plasmablasts in the blood. Considerable insight into the immunologic mechanisms of IgG4-RD has been achieved in the last decade using novel molecular biology approaches, including next-generation and single-cell RNA sequencing. Exploring the interactions between CD4+ T cells and B lineage cells is critical for understanding the pathophysiology of IgG4-RD. Establishment of pathogenic T cell clones and identification of antigens specific to these clones constitutes the first steps in determining the pathogenesis of the disease. Herein, the clinical features and mechanistic insights regarding pathogenesis of IgG4-RD were reviewed.. |
| 11. | Takashi Maehara, Masafumi Moriyama, Seiji Nakamura, A novel disease entity IgG4-related disease, including so-called Mikulicz's disease and Kuttner's tumor, KAOMS, 2020.01. |
| 12. | Ishiguro N, Moriyama M, Furusho K, Furukawa S, Shibata T, Murakami Y, Chinju A, Rafiul Haque ASM, Gion Y, Ohta M, Maehara T, Tanaka A, Yamauchi M, Sakamoto M, Mochizuki K, Ono Y, Hayashida JN, Sato Y, Kiyoshima T, Yamamoto H, Miyake K, Nakamura S, Activated M2 macrophage contributes to the pathogenesis of IgG4-related disease via TLR7/IL-33 signaling, Arthritis & Rheumatology, 2020.01. |
| 13. | Kazuhiko Higashiosa, Yuri Ota, Takashi Maehara, Masafumi Moriyama, Masahiro Ayano, Hiroki Mitoma, Mitsuteru Akahoshi, Yojiro Arinobu, Takahiko Horiuchi, Seiji Nakamura, Koichi Akashi, Hiroaki Niiro., Association of circulating SLAMF7+Tfh1 cells with IgG4 levels in patients with IgG4-related disease., BMC Immunology, 2020.01. |
| 14. | Noriko Ishiguro, Masafumi Moriyama, Katsuhiro Furusho, Sachiko Furukawa, Takuma Shibata, Yusuke Murakami, Akira Chinju, A. S.M.Rafiul Haque, Yuka Gion, Miho Ohta, Takashi Maehara, Akihiko Tanaka, Masaki Yamauchi, Mizuki Sakamoto, Keita Mochizuki, Yuko Ono, Jun Nosuke Hayashida, Yasuharu Sato, Tamotsu Kiyoshima, Hidetaka Yamamoto, Kensuke Miyake, Seiji Nakamura, Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-like Receptor 7/Interleukin-33 Signaling, Arthritis and Rheumatology, 10.1002/art.41052, 72, 1, 166-178, 2020.01, Objective: IgG4-related disease (IgG4-RD) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll-like receptor (TLR) pathway. This study was undertaken to examine the expression of TLRs in salivary glands (SGs) from patients with IgG4-RD. Methods: SGs from 15 patients with IgG4-RD, 15 patients with Sjögren's syndrome (SS), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically. TLR family gene expression (TLR-1 through TLR-10) was analyzed by DNA microarray in the submandibular glands (SMGs). Up-regulation of TLRs was confirmed in SGs from patients with IgG4-RD. Finally, the phenotype of human TLR-7 (huTLR-7)–transgenic C57BL/6 mice was assessed before and after stimulation with TLR agonist. Results: In patients with IgG4-RD, TLR-4, TLR-7, TLR-8, and TLR-9 were overexpressed. Polymerase chain reaction validated the up-regulation of TLR-7 in IgG4-RD compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of TLR-7–positive cells in the SGs of patients with IgG4-RD. Double immunohistochemical staining showed that TLR-7 expression colocalized with CD163+ M2 macrophages. After in vitro stimulation with a TLR-7 agonist, CD163+ M2 macrophages produced higher levels of interleukin-33 (IL-33), which is a Th2-activating cytokine. In huTLR-7–transgenic mice, the focus and fibrosis scores in SMGs, pancreas, and lungs were significantly higher than those in wild-type mice (P |
| 15. | Claudia Minici, Elena Rigamonti, Marco Lanzillotta, Antonella Monno, Lucrezia Rovati, Takashi Maehara, Naoki Kaneko, Vikram Deshpande, Maria Pia Protti, Lucia De Monte, Cristina Scielzo, Stefano Crippa, Paolo Giorgio Arcidiacono, Erica Dugnani, Lorenzo Piemonti, Massimo Falconi, Shiv Pillai, Angelo A. Manfredi, Emanuel Della-Torre, B lymphocytes contribute to stromal reaction in pancreatic ductal adenocarcinoma, OncoImmunology, 10.1080/2162402X.2020.1794359, 9, 1, 2020.01, Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent stromal reaction that has been variably implicated in both tumor growth and tumor suppression. B-lymphocytes have been recently implicated in PDAC progression but their contribution to the characteristic stromal desmoplasia has never been assessed before. In the present work, we aimed to verify whether B-lymphocytes contribute to stromal cell activation in PDAC. CD19+ B-lymphocytes purified from peripheral blood of patients with PDAC were cultivated in the presence of human pancreatic fibroblasts and cancer-associated fibroblasts. Released pro-fibrotic soluble factors and collagen production were assessed by ELISA and Luminex assays. Quantitative RT-PCR was used to assess fibroblast activation in the presence of B cells. The expression of selected pro-fibrotic and inflammatory molecules was confirmed on PDAC tissue sections by multi-color immunofluorescence studies. We herein demonstrate that B-cells from PDAC patients (i) produce the pro-fibrotic molecule PDGF-B and stimulate collagen production by fibroblasts; (ii) express enzymes implicated in extracellular matrix remodeling including LOXL2; and (iii) produce the chemotactic factors CCL-4, CCL-5, and CCL-11. In addition we demonstrate that circulating plasmablasts are expanded in the peripheral blood of patients with PDAC, stimulate collagen production by fibroblasts, and infiltrate pancreatic lesions. Our results indicate that PDAC is characterized by perturbations of the B-cell compartment with expansion of B-lymphocyte subsets that directly contribute to the stromal reaction observed at disease site. These findings provide an additional rationale for modulating B-cell activity in patients with pancreatic cancer.. |
| 16. | Cory A. Perugino, Naoki Kaneko, Takashi Maehara, Hamid Mattoo, Jesper Kers, Hugues Allard-Chamard, Vinay S. Mahajan, Hang Liu, Emanuel Della-Torre, Samuel J.H. Murphy, Musie Ghebremichael, Zachary S. Wallace, Marcy B. Bolster, Liam M. Harvey, Geetha Mylvaganam, Yesim Tuncay, Lloyd Liang, Sydney B. Montesi, Xiuwei Zhang, Akira Tinju, Keita Mochizuki, Ryusuke Munemura, Mizuki Sakamoto, Masafumi Moriyama, Seiji Nakamura, Nir Yosef, John H. Stone, Shiv Pillai, CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease, Journal of Allergy and Clinical Immunology, 10.1016/j.jaci.2020.05.022, 2020, Background: IgG4-related disease (IgG4-RD) is an immune-mediated fibrotic disorder that has been linked to CD4+ cytotoxic T lymphocytes (CD4+CTLs). The effector phenotype of CD4+CTLs and the relevance of both CD8+ cytotoxic T lymphocytes (CD8+CTLs) and apoptotic cell death remain undefined in IgG4-RD. Objective: We sought to define CD4+CTL heterogeneity, characterize the CD8+CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG4-RD. Methods: Blood analyses were undertaken using flow cytometry, cell sorting, transcriptomic analyses at the population and single-cell levels, and next-generation sequencing for the TCR repertoire. Tissues were interrogated using multicolor immunofluorescence. Results were correlated with clinical data. Results: We establish that among circulating CD4+CTLs in IgG4-RD, CD27loCD28loCD57hi cells are the dominant effector subset, exhibit marked clonal expansion, and differentially express genes relevant to cytotoxicity, activation, and enhanced metabolism. We also observed prominent infiltration of granzyme A–expressing CD8+CTLs in disease tissues and clonal expansion in the blood of effector/memory CD8+ T cells with an activated and cytotoxic phenotype. Tissue studies revealed an abundance of cells undergoing apoptotic cell death disproportionately involving nonimmune, nonendothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR. Conclusions: CD4+CTLs and CD8+CTLs may induce apoptotic cell death in tissues of patients with IgG4-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin.. |
| 17. | Takashi Maehara, Naoki Kaneko, Cory A Perugino, Hamid Matteo, Jesper Kers, Hugues Allard-Chamard, Vinay S Mahajan, Hang Liu, Samuel JH Murphy, Musie Ghebremichael, David Fox, Rovert Lafyatis, John H. Stone, Dinesh Khanna, Shiv Pillai., Cytotoxic CD4+T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis, Journal of Clinical Investigation, 2019.12. |
| 18. | A. S.M.Rafiul Haque, Masafumi Moriyama, Keigo Kubota, Noriko Ishiguro, Mizuki Sakamoto, Akira Chinju, Keita Mochizuki, Taiki Sakamoto, Naoki Kaneko, Ryusuke Munemura, Takashi Maehara, Akihiko Tanaka, Jun Nosuke Hayashida, Shintaro Kawano, Tamotsu Kiyoshima, Seiji Nakamura, CD206+ tumor-associated macrophages promote proliferation and invasion in oral squamous cell carcinoma via EGF production, Scientific reports, 2019.12. |
| 19. | A. S.M.Rafiul Haque, Masafumi Moriyama, Keigo Kubota, Noriko Ishiguro, Mizuki Sakamoto, Akira Chinju, Keita Mochizuki, Taiki Sakamoto, Naoki Kaneko, Ryusuke Munemura, Takashi Maehara, Akihiko Tanaka, Jun Nosuke Hayashida, Shintaro Kawano, Tamotsu Kiyoshima, Seiji Nakamura, CD206+ tumor-associated macrophages promote proliferation and invasion in oral squamous cell carcinoma via EGF production, Scientific reports, 10.1038/s41598-019-51149-1, 9, 1, 2019.12, Tumor-associated macrophages (TAMs) promote tumor progression and inhibit anti-tumor immune response by producing various mediators and preferentially express CD163, CD204, and CD206. However, the role of these TAM subsets in oral squamous cell carcinoma (OSCC) remains unclear. Here we investigated the expression and function of TAM subsets in OSCC, especially in cancer cell proliferation. Biopsy sample from 44 patients with OSCC were examined for the expression of TAM markers and EGF by immunohistochemistry. EGF production of TAM subsets isolated from OSCC patients was assessed by flow cytometry. We also examined the effect of conditioned medium from TAM subsets on the proliferation of OSCC cells. CD163+ cells were detected diffusely all over the tumor and connective tissue area, while CD204+ and CD206+ cells were mainly detected in/around the tumors. Flow cytometric analysis found that CD206+ TAMs strongly produced EGF compared with CD163+ and CD204+ TAMs. Cell proliferation and invasion of OSCC cells cultured with conditioned medium of CD206+ TAMs were strongly enhanced and inhibited by anti-EGFR. The number of CD206+ TAMs positively correlated with worse clinical prognosis. Our results revealed differences in localization and EGF production among these TAM subsets. CD206+ TAMs might play a critical role in the proliferation of OSCC via EGF production.. |
| 20. | Takashi Maehara, Ryusuke Minemura, Mayumi Shimizu, Noriko Kakizoe, Naoki Kaneko, Moriyama Masafumi, Yuka Murakami, Tamotsu Kiyoshima, Shintaro Kawano, Seiji Nakamura., Tissue-infiltrating immune cells contribute to understanding the pathogenesis of Kimura's Disease: a case report, Medicine, 2019.11. |
| 21. | Takashi Maehara, Yuka Murakami, Shintaro Kawano, Yurie Mikami, Tamotsu Kiyoshima, Toru Chikui, Noriko Kakizoe, Ryusuke Munemura, Seiji Nakamura, Osteoid osteoma of mandibular bone Case report and review of the literature, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, 10.1016/j.ajoms.2019.04.002, 31, 5, 322-326, 2019.09, Osteoid osteoma is a benign bone-forming tumor and characterized by its limited growth potential, not exceeding 2 cm. The radiological hallmark of this tumor is a nidus, which is a small round area of relative radiolucency. Osteoid osteoma can involve any bone but is most commonly found in long bones and is extremely rare in the head and neck region. This disease characteristically presents with dull pain, worse at night, and sometimes relieved with NSAIDs. A 24-year-old Japanese woman presented with spontaneous pain and tenderness on the lingual side of her mandibular second molar on the right side. The patient reported that her pain had gradually increased, becoming more continuous and severe and no longer responding to NSAIDs. An initial panoramic radiograph revealed an oval, internally non-uniform, somewhat obscure boundaries in the right mandible. Computed tomography (CT) scan revealed a sclerotic lesion with a delineated central calcified nidus surrounded by a radiolucent band. The interior of the nidus was a non-uniform, irregularly shaped area of high absorption. The nidus was removed with intralesional curettage under general anesthesia. The histopathology of the specimen consisted of actively proliferating osteoblasts mixed with an interlacing network of immature bone and osteoid trabeculae. Immunohistochemistry revealed that hardly detected osteoblasts or fibrous stromal cells with intense nuclear immunoreactivity for p16 and/or murine double minute 2 (mdm2). We thus distinguished the tumor from Low-grade central osteosarcoma (LGCO) with immunohistochemical findings. The histopathological diagnosis was thus osteoid osteoma.. |
| 22. | Della-Torre E, Rigamonti E, Perugino C, Sain SB, Sun N, Kaneko N, Maehara T, Rovati L, Ponzoni M, Milani R, Lanzillotta M, Mahajan V, Mattoo H, Molineris I, Deshpande V, Stone JH, Falconi M, Manfredi AA, Pillai S., B lymphocytes directly contribute to tissue fibrosis in IgG4-Related Disease., J Allergy Clin Immunol, 10.1016/j.jaci.2019.07.004, 2019.07. |
| 23. | T. Maehara, S. Pillai, J. H. Stone, S. Nakamura, Clinical features and mechanistic insights regarding IgG4-related dacryoadenitis and sialoadenitis a review, International Journal of Oral and Maxillofacial Surgery, 10.1016/j.ijom.2019.01.006, 48, 7, 908-916, 2019.07, Immunoglobulin G4-related disease (IgG4-RD), recognized only recently as a single diagnostic entity, is a chronic inflammatory condition of unknown etiology. The diagnosis of IgG4-RD relies heavily on histopathological analysis and the correlation of histology findings with clinical, serological, and radiological data. CD4+ T and B cells, including IgG4-expressing plasmablasts, constitute the major inflammatory cell populations in IgG4-RD and are believed to cause organ damage and tissue fibrosis. Patients with IgG4-RD, who have active, untreated disease, exhibit marked expansion of IgG4-secreting plasmablasts in the blood. Important mechanistic insights correlated with the pathogenesis of IgG4-RD have been disclosed in recent years through the application of novel molecular biology approaches, including next-generation and single-cell RNA sequencing. Exploration of the interactions between these CD4+ T cells and cells of the B lymphocyte lineage is critical to understanding the pathophysiology of IgG4-RD. The establishment of pathogenic T cell clones and the identification of antigens specific to these clones constitute the first steps in determining the pathogenesis of this disease. This review focuses on clinical features and mechanistic insights regarding IgG4-related dacryoadenitis and sialoadenitis, from a perspective suitable for oral and maxillofacial surgeons.. |
| 24. | Takashi Maehara, Yuka Murakami, Shintaro Kawano, Yurie Mikami, Tamotsu Kiyoshima, Toru Chikui, Noriko Kakizoe, Ryusuke Munemura, Seiji Nakamura, Osteoid osteoma of mandibular bone: Case report and review of the literature, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, 2019.04. |
| 25. | Takashi Maehara, Masafumi Moriyama, Seiji Nakamura, Pathogenesis of IgG4-related disease a critical review, Odontology, 10.1007/s10266-018-0377-y, 107, 2, 127-132, 2019.04, Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic, systemic, inflammatory condition of unknown etiology. Histopathologic examination is the key to diagnosis of IgG4-RD. The histopathologic features of IgG4-RD are lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. As for fewer than 15 years, IgG4-RD has been recognized as a unified diagnostic entity. CD4 + T and B cells, which likely cause organ damage and disabling tissue fibrosis, constitute the major inflammatory cell population in patients with IgG4-RD. Affected patients with active, untreated disease have a marked expansion of IgG4-secreting plasmablasts in the blood. Important mechanistic insights regarding the pathogenesis of IgG4-RD have been gradually disclosed in recent years. Exploring the role of interactions between these CD4 + T and B cells in patients with IgG4-RD is a highly promising field of investigation. In this review, we focus on CD4 + T cell subsets and the T-cell clones that are involved in the pathogenesis of IgG4-RD.. |
| 26. | Takashi Maehara, Ryusuke Munemura, Mayumi Shimizu, Noriko Kakizoe, Naoki Kaneko, Yuka Murakami, Moriyama Masafumi, Tamotsu Kiyoshima, Shintaro Kawano, Seiji Nakamura, Tissue-infiltrating immune cells contribute to understanding the pathogenesis of Kimura disease A case report, Medicine (United States), 10.1097/MD.0000000000018300, 98, 50, 2019, Rationale:Kimura disease (KD) is a rare, chronic inflammatory disorder characterized by subcutaneous granuloma in the head and neck region, as well as increased eosinophil counts and high serum immunoglobulin E (IgE) levels. Kimura disease is suspected to be an IgE-mediated disease, associated with an allergic response, in which antigen-specific B cells are stimulated to undergo specific IgE class switching with disease-specific CD4+ T (Th) cells help. Thus, exploration of the Th cells in affected tissues with KD is a highly promising field of the investigation. However, there have been no reports with direct evidence to implicate Th cells in affected lesions with KD. Here we quantitatively demonstrate that CD4+ GATA3+ T cells and interleukin (IL)-4+ IgE+ c-kit+ mast cells prominently infiltrate in affected lesion with KD.Patient concerns:A 56-year-old Japanese man who exhibited painless swelling in the left parotid region.Diagnoses:Diagnosis of KD was made based on characteristic histopathologic findings, in conjunction with peripheral eosinophilia and elevated serum IgE levels.Interventions:The patient underwent corticosteroid therapy and had been followed for 2 years.Outcomes:We report a rare case of KD of the parotid region in a 56-year-old man, followed by corticosteroid therapy for 2 years. The mass decreased in size and skin itchiness decreased after therapy. He was discharged without any complications. Furthermore, we quantitatively demonstrate the dominance of CD4+ GATA3+ T cells in affected tissues of KD and detect IL-4+ IgE+ c-kit+ mast cells in lesions by multicolor staining approaches.Lessons:The findings from this case suggest that peripheral blood eosinophilia might serve as a marker of recurrent disease, long-term follow-up is necessary due to the possibility of recurrent. Interactions among expanded IgE+ B cells, CD4+ GATA3+ T cells, eosinophils, and activated mast cells might play a critical role in the pathogenesis of KD.. |
| 27. | Takashi Maehara, Shiv Pillai, John H Stone, and Seiji Nakamura, Clinical Features and Mechanistic Insights Regarding IgG4-Related Dacryoadenitis and Sialoadenitis: a review, International Journal of Oral & Maxillofacial Surgery , 2018.11. |
| 28. | Julia Roider, Takashi Maehara, Abigail Ngoepe, Duran Ramsuran, Maximilian Muenchhoff, Emily Adland, Toby Aicher, Samuel W. Kazer, Pieter Jooste, Farina Karim, Warren Kuhn, Alex K. Shalek, Thumbi Ndung'u, Lynn Morris, Penny L. Moore, Shiv Pillai, Henrik Kløverpris, Philip Goulder, Alasdair Leslie, High-frequency, functional HIV-specific T-follicular helper and regulatory cells are present within germinal centers in children but not adults, Frontiers in Immunology, 10.3389/fimmu.2018.01975, 9, SEP, 2018.09, Broadly neutralizing antibodies (bnAbs) against HIV-1 are an effective means of preventing transmission. To better understand the mechanisms by which HIV-specific bnAbs naturally develop, we investigated blood and lymphoid tissue in pediatric infection, since potent bnAbs develop with greater frequency in children than adults. As in adults, the frequency of circulating effector T-follicular helper cells (TFH) in HIV infected, treatment naïve children correlates with neutralization breadth. However, major differences between children and adults were also observed both in circulation, and in a small number of tonsil samples. In children, TFH cells are significantly more abundant, both in blood and in lymphoid tissue germinal centers, than in adults. Second, HIV-specific TFH cells are more frequent in pediatric than in adult lymphoid tissue and secrete the signature cytokine IL-21, which HIV-infected adults do not. Third, the enrichment of IL-21-secreting HIV-specific TFH in pediatric lymphoid tissue is accompanied by increased TFH regulation via more abundant regulatory follicular T-cells and HIV-specific CXCR5+ CD8 T-cells compared to adults. The relationship between regulation and neutralization breadth is also observed in the pediatric PBMC samples and correlates with neutralization breadth. Matching neutralization data from lymphoid tissue samples is not available. However, the distinction between infected children and adults in the magnitude, quality and regulation of HIV-specific TFH responses is consistent with the superior ability of children to develop high-frequency, potent bnAbs. These findings suggest the possibility that the optimal timing for next generation vaccine strategies designed to induce high-frequency, potent bnAbs to prevent HIV infection in adults would be in childhood.. |
| 29. | Julia Roider1, TAKASHI MAEHARA2, Abgail Ngoepe3, Duran Ramsuran3, Maximilian Münchhoff4, Emily Adland5, Toby Aicher6, Samuel Kazer6, Pieter Jooste7, Farina Karim3, Warren Kuhn8, Alex Shalek6, Thumbi Ndung'u3, Lynn Morris9, Penny Moore9, Shiv Pillai2, Henrik Kloverpris3, Philip Goulder5* and Alasdair Leslie, High-frequency, functional HIV-specific T-follicular helper and regulatory cells are present within germinal centers in children but not adults., Frontiers in Immunology, 2018.08. |
| 30. | Maehara T, Moriyama M, Nakamura S., Pathogenesis of IgG4-related disease: a critical review., Odontology, doi: 10.1007/s10266-018-0377-y., 2018.07. |
| 31. | Maehara T, Mattoo H, Mahajan V, Murphy S, Yuen G, Ishiguro N, Ohta M, Moriyama M, Saeki T, Yamamoto H, Yamauchi M, Daccache J, Kiyoshima T, Nakamura S, Stone JH, Pillai S., The expansion in lymphoid organs of IL-4+BATF+T follicular helper cells is linked to IgG4 class switching in vivo., Life Science Alliance., 10.26508/lsa.201800050, 2018.04, [URL]. |
| 32. | Keigo Kubota, Masafumi Moriyama, Sachiko Furukawa, Haque A.S.M. Rafiul, Yasuyuki Maruse, Teppei Jinno, Akihiko Tanaka, Miho Ohta, Noriko Ishiguro, Masaaki Yamauchi, Mizuki Sakamoto, Takashi Maehara, Hayashida Jun-Nosuke, Shintarou Kawano, Tamotsu Kiyoshima, Seiji Nakamura, CD163+CD204+ tumor-associated macrophages contribute to T cell regulation via interleukin-10 and PD-L1 production in oral squamous cell carcinoma, Scientific Reports, 2017.12. |
| 33. | Keigo Kubota, Masafumi Moriyama, Sachiko Furukawa, Haque A.S.M. Rafiul, Yasuyuki Maruse, Teppei Jinno, Akihiko Tanaka, Miho Ohta, Noriko Ishiguro, Masaaki Yamauchi, Mizuki Sakamoto, Takashi Maehara, Jun Nosuke Hayashida, Shintaro Kawano, Tamotsu Kiyoshima, Seiji Nakamura, CD163+CD204+ tumor-associated macrophages contribute to T cell regulation via interleukin-10 and PD-L1 production in oral squamous cell carcinoma, Scientific reports, 10.1038/s41598-017-01661-z, 7, 1, 2017.12, Tumor-associated macrophages (TAMs) promote cancer cell proliferation, invasion, and metastasis by producing various mediators.Although preclinical studies demonstrated that TAMs preferentially express CD163 and CD204, the TAM subsets in oral squamous cell carcinoma (OSCC) remain unknown.In this study, we examined the expression and role of TAM subsets in OSCC.Forty-six patients with OSCC were analyzed for expression of TAMs in biopsy samples by immunohistochemistry.We examined TAM subsets and their production of immune suppressive molecules (IL-10 and PD-L1) in peripheral blood mononuclear cells from three OSCC patients by flow cytometry.CD163 was detected around the tumor or connective tissue, while CD204 was detected in/around the tumors.Flow cytometric analysis revealed that CD163+CD204+ TAMs strongly produced IL-10 and PD-L1 in comparison with CD163+CD204- and CD163-CD204+ TAMs.Furthermore, the number of activated CD3+ T cells after co-culture with CD163+CD204+ TAMs was significantly lower than that after co-culture with other TAM subsets.In clinical findings, the number of CD163+CD204+ TAMs was negatively correlated with that of CD25+ cells and 5-year progression-free survival.These results suggest that CD163+CD204+ TAMs possibly play a key role in the invasion and metastasis of OSCC by T-cell regulation via IL-10 and PD-L1 production.. |
| 34. | Perugino CA, Matto H, Mahajan VS, Maehara T, Wallace ZS, Pillai S, Stone JH., IgG4-related disease: Insights into human immunology and targeted therapies., Arthritis Rheumatol. 2017 Sep;69(9):1722-1732., 2017.09. |
| 35. | Cory A. Perugino, Hamid Mattoo, Vinay S. Mahajan, Takashi Maehara, Zachary S. Wallace, Shiv Pillai, John H. Stone, Emerging Treatment Models in Rheumatology IgG4-Related Disease: Insights Into Human Immunology and Targeted Therapies, Arthritis and Rheumatology, 10.1002/art.40168, 69, 9, 1722-1732, 2017.09. |
| 36. | Maehara Takashi., IgG4-related disease –Mechanistic insights from both clinical and immunologic understanding of this condition., The Japan Society for Clinical Immunology. 2017;40(3):206-212., 2017.05. |
| 37. | Masaki Yamauchi, Masafumi Moriyama, Hayashida Jun-Nosuke, Takashi Maehara, Noriko Ishiguro, Keigo Kubota, Sachiko Furukawa, Miho Ohta, Mizuki Sakamoto, Akihiko Tanaka, Seiji Nakamura, Myeloid dendritic cells stimulated by thymic stromal lymphopoietin promote Th2 immune responses and the pathogenesis of oral lichen planus, PLoS One, 0173017, 12, 3, 2017.03, 2017.03. |
| 38. | Masaki Yamauchi, Masafumi Moriyama, Jun Nosuke Hayashida, Takashi Maehara, Noriko Ishiguro, Keigo Kubota, Sachiko Furukawa, Miho Ohta, Mizuki Sakamoto, Akihiko Tanaka, Seiji Nakamura, Myeloid dendritic cells stimulated by thymic stromal lymphopoietin promote Th2 immune responses and the pathogenesis of oral lichen planus, PloS one, 10.1371/journal.pone.0173017, 12, 3, 2017.03, Oral lichen planus (OLP) is a chronic inflammatory disease characterized by subepithelial Tcell infiltration. Recent studies reported that specific T helper (Th) subsets, especially Th2 cells, are involved in the pathogenesis of OLP. Thymic stromal lymphopoietin (TSLP) is mainly secreted by epithelial cells and potently activates myeloid dendritic cells (mDCs) to induce Th2-mediated inflammation. Here, we investigated the expression of TSLP and related molecules in OLP. Buccal mucosa specimens from patients with OLP, hyperkeratosis, and ulcer were analyzed by immunohistochemistry for expression of TSLP, its receptor (TSLPR), and inflammatory cells. TSLP was detected in/around the epithelium of patients with OLP and hyperkeratosis, whereas TSLPR, CD11c (mDC), and GATA3 (Th2) were strongly expressed in the subepithelial layer only in OLP patients. Double immunofluorescence staining showed that TSLPR expression mainly co-localized with CD11c. Moreover, the number of CD11c- and GATA-3 positive cells was correlated in OLP patients. In lesions selectively extracted by laser microdissection, the mRNA expression of Th2 (IL-4, MDC, TARC, GATA3)- and Th17 (IL-17, RORγt)-related molecules in OLP patients was significantly higher than in other groups. These results suggest that CD11c+ mDCs expressing TSLPR contribute to aberrant Th2 immune responses and the pathogenesis of OLP via TSLP stimulation.. |
| 39. | Maehara T, Mattoo H, Ohta M, Mahajan V, Moriyama M, Yamauchi M, Drijvers S, Nakamura S, Stone JH, Pillai S., Lesional CD4+IFN-gamma+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis., Ann. Rheum. Dis. 2017 Feb;76(2):377-385., 2017.02. |
| 40. | Sachiko Furukawa, Masafumi Moriyama, Kensuke Miyake, Hitoshi Nakashima, Akihiko Tanaka, Takashi Maehara, Mana Iizuka-Koga, Hiroto Tsuboi, Hayashida Jun-Nosuke, Noriko Ishiguro, Masaki Yamauchi, Takayuki Sumida, Seiji Nakamura, Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease, Scientific Reports, 2017.02. |
| 41. | Sachiko Furukawa, Masafumi Moriyama, Kensuke Miyake, Hitoshi Nakashima, Akihiko Tanaka, Takashi Maehara, Mana Iizuka-Koga, Hiroto Tsuboi, Jun Nosuke Hayashida, Noriko Ishiguro, Masaki Yamauchi, Takayuki Sumida, Seiji Nakamura, Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease, Scientific reports, 10.1038/srep42413, 7, 2017.02, IgG4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and marked infiltration of IgG4-positive cells in multiple organs. Interleukin-33 (IL-33) is a recently described cytokine that is secreted by damaged epithelial cells, macrophages, and dendritic cells, and potently activates helper T type 2 (Th2) immune responses, which have been suggested to play a major role in IgG4 production of IgG4-RD. Here, we assessed the expression of IL-33 and related molecules in the salivary glands (SGs) of patients with IgG4-RD versus that in patients with Sjögren's syndrome (SS) and controls. Expression of IL-33 and its receptor (ST2) was strongly detected around ectopic germinal centers (GCs) in the SGs from patients with IgG4-RD, whereas IL-33 was expressed only in epithelial cells in patients with SS and controls. Moreover, IL-33 and CD68+/CD163+macrophages were mainly distributed around ectopic GCs in patients with IgG4-RD. Double immunofluorescence staining showed that IL-33 expression co-localized with CD68+/CD163+macrophages. Finally, mRNA expression levels of IL-33 showed a positive correlation to those of Th2 cytokines (IL-4 and IL-13) in patients with IgG4-RD. Our data suggest that IL-33 produced by M2 macrophages might contribute to the pathogenesis of IgG4-RD via aberrant activation of Th2 immune responses.. |
| 42. | Takashi Maehara, Hamid Mattoo, Miho Ohta, Vinay S. Mahajan, Masafumi Moriyama, Masaki Yamauchi, Jefte Drijvers, Seiji Nakamura, John H. Stone, Shiv S. Pillai, Lesional CD4+ IFN-γ+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis, Annals of the Rheumatic Diseases, 10.1136/annrheumdis-2016-209139, 76, 2, 377-385, 2017.02, Objectives IgG4-related disease (IgG4-RD) is a chronic, systemic, inflammatory condition of unknown aetiology. We have recently described clonally expanded circulating CD4+ cytotoxic T lymphocytes (CTLs) in IgG4-RD that infiltrate affected tissues where they secrete interleukin (IL)-1β and transforming growth factor -β1 (TGF-β1). In this study, we sought to examine the role of CD4+ CTLs in the pathogenesis of IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) and to determine whether these cells secrete interferon-gamma (IFN-γ) at lesional sites. Methods Salivary glands of 25 patients with IgG4-DS, 22 patients with Sjögren's syndrome (SS), 12 patients with chronic sialoadenitis (CS) and 12 healthy controls were analysed in this study. Gene expression analysis was performed on submandibular glands (SMGs) from five patients with IgG4-DS, three with CS and three healthy controls. Infiltrating CD4+ CTLs were examined by quantitative multicolour imaging in tissue samples from 20 patients with IgG4-DS, 22 patients with SS, 9 patients with CS and 9 healthy controls. Results In IgG4-DS tissues, nine genes associated with CD4+ CTLs were overexpressed. The expression of granzyme A (GZMA) mRNA was significantly higher in samples from patients with IgG4-RD compared with corresponding tissues from SS and healthy controls. Quantitative imaging showed that infiltrating CD4+ GZMA+ CTLs were more abundant in patients with IgG4-DS than in the other groups. The ratio of CD4+ GZMA+ CTLs in SMGs from patients with IgG4-DS correlated with serum IgG4 concentrations and the number of affected organs. A large fraction of CD4+ GZMA+ CTLs in SMGs from patients with IgG4-DS secreted IFN-γ. Conclusions The pathogenesis of IgG4-DS is associated with tissue infiltration by CD4+ GZMA+ CTLs that secrete IFN-γ.. |
| 43. | Takashi Maehara, IgG4-related disease – mechanistic insights from both clinical and immunologic understanding of this condition–, Japanese Journal of Clinical Immunology, 10.2177/jsci.40.206, 40, 3, 206-212, 2017.01, IgG4-related disease (IgG4-RD) is a chronic inflammatory disease characterized by tumescent lesions with characteristic storiform fibrosis, obliterative phlebitis and a marked lymphoplasmacytic infiltrate that includes a large number of IgG4 positive plasma cells. It’s widely accepted that rituximab-mediated B cell depletion therapy is effective for this disease. Important mechanistic insights correlated with the pathogenesis of IgG4-RD have been gradually disclosed from studies of patients treated by B cell depletion. 1) IgG4-RD patients have the large clonal expansion of activated plasmablasts and CD4+CTLs, so this disease might be antigen-driven. 2) CD4+CTLs are the dominant population in affected tissues, on the other hands direct examination of TH1 and TH2 cells in tissues reveal that these subsets are sparse. 3) CD4+CTLs into affected lesions secret cytotoxic, inflammatory, and pro-fibrotic cytokines, indicating reactivation by antigen in tissue sites. 4) The decline in CD4+CTLs number by B cell depletion is associated with clinical remission of IgG4-RD patients. 5) CD4+CXCR5+TFH cells that express IL-4 are located outside germinal centers and specialized TFH cells that expanded dramatically in conditions with polarized class switching to IgG4. These results suggested that the disease pathogenesis might be based on orchestrating of activated plasmablasts, CD4+CTLs, and TFH cells.. |
| 44. | Matoo H, Mahajan V, Maehara T, Deshpande V, Della-Torre E, Wallace ZS, Kulikova M, Drijvers S, Daccache J, Carruthers MN, Castelino FV, Stone JR, Stone JH, Pillai S., Clonal expansion of CD4+ cytotoxic T lymphocytes in patients with IgG4-related disease., J Allergy Clin Immunol. 2016 Sep;138(3):825-38., 2016.09. |
| 45. | Masafumi Moriyama, Miho Ohta, Sachiko Furukawa, Yurie Mikami, Akihiko Tanaka, Takashi Maehara, Masaki Yamauchi, Noriko Ishiguro, Hayashida Jun-Nosuke, Shintarou Kawano, Yukiko Ohyama, Tamotsu Kiyoshima, Seiji Nakamura, The diagnostic utility of labial salivary gland biopsy in IgG4-related disease, Modern Rheumatology, 2016.09. |
| 46. | Hamid Mattoo, Vinay S. Mahajan, Takashi Maehara, Vikram Deshpande, Emanuel Della-Torre, Zachary S. Wallace, Maria Kulikova, Jefte M. Drijvers, Joe Daccache, Mollie N. Carruthers, Flavia V. Castelino, James R. Stone, John H. Stone, Shiv Pillai, Clonal expansion of CD4+ cytotoxic T lymphocytes in patients with IgG4-related disease, Journal of Allergy and Clinical Immunology, 10.1016/j.jaci.2015.12.1330, 138, 3, 825-838, 2016.09, Background IgG4-related disease (IgG4-RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4+ T cells constitute the major inflammatory cell population in IgG4-RD lesions. Objective We used an unbiased approach to characterize CD4+ T-cell subsets in patients with IgG4-RD based on their clonal expansion and ability to infiltrate affected tissue sites. Methods We used flow cytometry to identify CD4+ effector/memory T cells in a cohort of 101 patients with IgG4-RD. These expanded cells were characterized by means of gene expression analysis and flow cytometry. Next-generation sequencing of the T-cell receptor β chain gene was performed on CD4+SLAMF7+ cytotoxic T lymphocytes (CTLs) and CD4+GATA3+ TH2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined by using quantitative multicolor imaging. Results CD4+ effector/memory T cells with a cytolytic phenotype were expanded in patients with IgG4-RD. Next-generation sequencing revealed prominent clonal expansions of these CD4+ CTLs but not CD4+GATA3+ memory TH2 cells in patients with IgG4-RD. The dominant T cells infiltrating a range of inflamed IgG4-RD tissue sites were clonally expanded CD4+ CTLs that expressed SLAMF7, granzyme A, IL-1β, and TGF-β1. Clinical remission induced by rituximab-mediated B-cell depletion was associated with a reduction in numbers of disease-associated CD4+ CTLs. Conclusions IgG4-RD is prominently linked to clonally expanded IL-1β– and TGF-β1–secreting CD4+ CTLs in both peripheral blood and inflammatory tissue lesions. These active, terminally differentiated, cytokine-secreting effector CD4+ T cells are now linked to a human disease characterized by chronic inflammation and fibrosis.. |
| 47. | Masafumi Moriyama, Miho Ohta, Sachiko Furukawa, Yurie Mikami, Akihiko Tanaka, Takashi Maehara, Masaki Yamauchi, Noriko Ishiguro, Jun Nosuke Hayashida, Shintaro Kawano, Yukiko Ohyama, Tamotsu Kiyoshima, Seiji Nakamura, The diagnostic utility of labial salivary gland biopsy in IgG4-related disease, Modern Rheumatology, 10.3109/14397595.2016.1148225, 26, 5, 725-729, 2016.09, Objective: For the definitive diagnosis of IgG4-related disease (IgG4-RD), biopsies of local lesions are recommended so as to exclude other diseases, including lymphoma and cancer. However, performing biopsies of underlying organs is technically difficult. In this study, we examined the diagnostic utility of labial salivary gland (LSG) biopsy as a less invasive procedure. Methods: Sixty-six patients with suspected IgG4-RD by clinical findings or high serum IgG4 underwent LSG biopsy. We examined the relationship between the number of IgG4-positive plasma cells in LSG and clinical findings. Results: The final diagnosis was 45 patients with IgG4-RD, 12 with Sjögren’s syndrome, four with suspected Sjögren’s syndrome, three with malignant lymphoma, one with systemic lupus erythematosus, and one with Warthin’s tumor. The sensitivity, specificity, and accuracy of LSG biopsy were 55.6%, 100.0%, and 70.0%, respectively. Forty-five IgG4-RD patients were divided into two groups: 1) 25 with lesions of salivary glands (IgG4-RD S+) and 2) 20 without these lesions (IgG4-RD S−). Seventeen of 25 (68.0%) IgG4-RD S + and 8 of 20 (40.0%) IgG4-RD S − patients were positive for LSG biopsy. In the IgG4-RD S − patients, the mean number of affected organs and serum IgG4 in the positive cases for LSG biopsy were significantly higher than in the negative cases. Conclusion: A solo LSG biopsy is insufficient for the diagnosis of IgG4-RD because of its low sensitivity. However, LSG biopsy combined with clinical findings, including serum IgG4 and number of affected organs, may contribute towards a diagnosis of IgG4-RD patients with affected underlying organs.. |
| 48. | Yumi Imabayashi, Masafumi Moriyama, Toru Takeshita, Shinsuke Ieda, Hayashida Jun-Nosuke, Akihiko Tanaka, Takashi Maehara, Sachiko Furukawa, Miho Ohta, Keigo Kubota, Masaki Yamauchi, Noriko Ishiguro, Yoshihisa Yamashita, Seiji Nakamura, Molecular analysis of fungal populations in patients with oral candidiasis using next-generation sequencing, Scientific Reports, 2016.06. |
| 49. | Yumi Imabayashi, Masafumi Moriyama, Toru Takeshita, Shinsuke Ieda, Jun Nosuke Hayashida, Akihiko Tanaka, Takashi Maehara, Sachiko Furukawa, Miho Ohta, Keigo Kubota, Masaki Yamauchi, Noriko Ishiguro, Yoshihisa Yamashita, Seiji Nakamura, Molecular analysis of fungal populations in patients with oral candidiasis using next-generation sequencing, Scientific reports, 10.1038/srep28110, 6, 2016.06, Oral candidiasis is closely associated with changes in oral fungal biodiversity and is caused primarily by Candida albicans. However, the widespread use of empiric and prophylactic antifungal drugs has caused a shift in fungal biodiversity towards other Candida or yeast species. Recently, next-generation sequencing (NGS) has provided an improvement over conventional culture techniques, allowing rapid comprehensive analysis of oral fungal biodiversity. In this study, we used NGS to examine the oral fungal biodiversity of 27 patients with pseudomembranous oral candidiasis (POC) and 66 healthy controls. The total number of fungal species in patients with POC and healthy controls was 67 and 86, respectively. The copy number of total PCR products and the proportion of non-C. albicans, especially C. dubliniensis, in patients with POC, were higher than those in healthy controls. The detection patterns in patients with POC were similar to those in controls after antifungal treatment. Interestingly, the number of fungal species and the copy number of total PCR products in healthy controls increased with aging. These results suggest that high fungal biodiversity and aging might be involved in the pathogenesis of oral candidiasis. We therefore conclude that NGS is a useful technique for investigating oral candida infections.. |
| 50. | Miho Ohta, Masafumi Moriyama, Takashi Maehara, Yuka Gion, Sachiko Furukawa, Akihiko Tanaka, Hayashida Jun-Nosuke, Masaki Yamauchi, Noriko Ishiguro, Yurie Mikami, Hiroto Tsuboi, Mana Iizuka-Koga, Shintarou Kawano, Yasuharu Sato, Tamotsu Kiyoshima, Takayuki Sumida, Seiji Nakamura, DNA microarray analysis of submandibular glands in IgG4-related disease indicates a role for MARCO and other innate immune-related proteins, Medicine, 2016.01. |
| 51. | Miho Ohta, Masafumi Moriyama, Takashi Maehara, Yuka Gion, Sachiko Furukawa, Akihiko Tanaka, Jun Nosuke Hayashida, Masaki Yamauchi, Noriko Ishiguro, Yurie Mikami, Hiroto Tsuboi, Mana Iizuka-Koga, Shintaro Kawano, Yasuharu Sato, Tamotsu Kiyoshima, Takayuki Sumida, Seiji Nakamura, DNA microarray analysis of submandibular glands in IgG4-related disease indicates a role for MARCO and other innate immune-related proteins, Medicine (United States), 10.1097/MD.0000000000002853, 95, 7, e2853, 2016, IgG4-related disease (IgG4-RD) is a novel systemic disease entity characterized by elevated serum IgG4 and tissue infiltration of IgG4-positive plasma cells accompanied by severe fibrosis. Although recent studies demonstrated that innate immune cells including monocytes and macrophages might promote local fibrosis and IgG4 production, the pathological mechanism remains unclear. In this study, we sought to identify the disease-associated genes, especially innate immune molecules. Gene expression was analyzed by DNA microarray in submandibular glands (SMGs) from patients with IgG4-RD (n=5), chronic sialoadenitis (CS) (n=3), and controls (n=3). Differentially expressed genes (DEGs) were validated by real-time polymerase chain reaction (PCR) and immunohistochemical staining in IgG4-RD (n=18), CS (n=4), Sjogren syndrome (n=11), and controls (n=10). Gene expression patterns in the 3 groups were quite different from each other by the pvclust method and principal components analysis. In IgG4-RD, 1028 upregulated genes and 692 downregulated genes were identified as DEGs (P |
| 52. | Yoshikazu Hayashi, Masafumi Moriyama, Takashi Maehara, Yuichi Goto, Shintarou Kawano, Miho Ohta, Akihiko Tanaka, Sachiko Furukawa, Hayashida Jun-Nosuke, Tamotsu Kiyoshima, Mayumi Shimizu, Toru Chikui, Seiji Nakamura, A case of mantle cell lymphoma presenting as IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease, World Journal of Surgical Oncology, 2015.07. |
| 53. | Yoshikazu Hayashi, Masafumi Moriyama, Takashi Maehara, Yuichi Goto, Shintaro Kawano, Miho Ohta, Akihiko Tanaka, Sachiko Furukawa, Jun Nosuke Hayashida, Tamotsu Kiyoshima, Mayumi Shimizu, Toru Chikui, Seiji Nakamura, A case of mantle cell lymphoma presenting as IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease, World Journal of Surgical Oncology, 10.1186/s12957-015-0644-0, 13, 1, 2015.07, Background: Mantle cell lymphoma (MCL) is a relatively uncommon type of non-Hodgkin lymphoma. It develops in the outer edge of a lymph node called the mantle zone. In contrast, IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) is characterized by elevated serum IgG4 and persistent bilateral enlargement of lacrimal glands (LGs) and salivary glands (SGs), with infiltration of IgG4-positive plasma cells. Recent studies indicated the importance of differentiation between IgG4-DS and malignant lymphoma. Case presentation: An 82-year-old man was suspected of IgG4-DS because of a high serum IgG level (2174 mg/dL) and bilateral swelling of LGs and SGs. Lip biopsy and fine needle biopsy of submandibular gland were performed, and subsequently, MCL was diagnosed through the histopathological findings. Conclusions: MCL most commonly occurs in the Waldeyer ring, but rarely in the stomach, spleen, skin, LG, and SG. We report an unusual case of MCL involving LGs and SGs mimicking IgG4-DS, which suggests that IgG4 testing may be useful in the differentiation of IgG4-DS in the presence of bilateral swelling of LGs or SGs.. |
| 54. | Takashi Maehara, Masafumi Moriyama, Shintarou Kawano, Hayashida Jun-Nosuke, Sachiko Furukawa, Miho Ohta, Akihiko Tanaka, Masaki Yamauchi, Yukiko Ohyama, Tamotsu Kiyoshima, Seiji Nakamura., Cytokine profiles contribute to understanding the pathogenic difference between Good syndrome and oral lichen planus two case reports and literature review, Medicine (Baltimore). 2015 Apr;94(14):e704. doi: 10.1097/MD.0000000000000704., 2015.04. |
| 55. | Takashi Maehara, Masafumi Moriyama, Shintaro Kawano, Jun Nosuke Hayashida, Sachiko Furukawa, Miho Ohta, Akihiko Tanaka, Masaki Yamauchi, Yukiko Ohyama, Tamotsu Kiyoshima, Seiji Nakamura, Cytokine profiles contribute to understanding the pathogenic difference between good syndrome and oral lichen planus, Medicine (United States), 10.1097/MD.0000000000000704, 94, 14, 2015.04, We described and analyzed the pathogenic difference between Good syndrome (GS) and oral lichen planus (OLP) in oral mucosa. Good syndrome (GS) is a rare disease characterized by B and T cell immunodeficiency associated with hypogammaglobulinemia and thymoma. GS patients frequently develop oral lichenoid lesions with lymphocytic infiltration beneath the basal layer. Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa characterized by destruction of basal cells by Langerhans cells, macrophages, and T lymphocytes. Although the histological features of the lesions of both diseases are very similar, the pathogenesis of GS in the oral mucosa remains unknown. In this study, we thus investigated the expression of infiltrating lymphocyte subsets (CD3, CD20, CD4, and CD8) and T helper (Th) cytokines including interferon (IFN)-γ (Th1 type), interleukin (IL)-4 (Th2 type), IL-17 (Th17 type), and IL-10 (regulatory T cell type) by immunohistochemistry in buccal mucosa specimens from 2 GS patients compared with 15 OLP patients. All patients showed a predominance of CD3 + T cells over CD20 + B cells, and CD4 + Th cells over CD8 + cytotoxic T cells. This polarization was especially prominent in GS. IFN-γ and IL-10 were strongly detected in the infiltrating lymphocytes of all patients. However, IL-4 and IL-17 were detected in OLP patients only. These results suggest that the pathogenesis of GS is different from that of OLP. GS is a unique inflammatory disorder characterized by dysfunction of Th2 and Th17 immune reactions via abnormal T-B cell interaction.. |
| 56. | Keiko Oyama, Masafumi Moriyama, Hayashida Jun-Nosuke, A. Tanaka, T. Maehara, S. Ieda, S. Furukawa, M. Ohta, Y. Imabayashi, Seiji Nakamura, Saliva as a potential tool for diagnosis of dry mouth including Sjögren's syndrome, Oral Diseases, 2015.03. |
| 57. | S. Furukawa, Masafumi Moriyama, Shintarou Kawano, A. Tanaka, T. Maehara, Hayashida Jun-Nosuke, Y. Goto, Tamotsu Kiyoshima, H. Shiratsuchi, Yukiko Ohyama, M. Ohta, Y. Imabayashi, Seiji Nakamura, Clinical relevance of Küttner tumour and IgG4-related dacryoadenitis and sialoadenitis, Oral Diseases, 2015.03. |
| 58. | S. Furukawa, M. Moriyama, S. Kawano, A. Tanaka, T. Maehara, J. N. Hayashida, Y. Goto, T. Kiyoshima, H. Shiratsuchi, Y. Ohyama, M. Ohta, Y. Imabayashi, S. Nakamura, Clinical relevance of Küttner tumour and IgG4-related dacryoadenitis and sialoadenitis, Oral Diseases, 10.1111/odi.12259, 21, 2, 257-262, 2015.03, 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 (+).. |
| 59. | K. Ohyama, M. Moriyama, J. N. Hayashida, A. Tanaka, T. Maehara, S. Ieda, S. Furukawa, M. Ohta, Y. Imabayashi, S. Nakamura, Saliva as a potential tool for diagnosis of dry mouth including Sjögren's syndrome, Oral Diseases, 10.1111/odi.12252, 21, 2, 224-231, 2015.03, 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.. |
| 60. | Miho Ohta, Masafumi Moriyama, Yuichi Goto, Shintarou Kawano, Akihiko Tanaka, Takashi Maehara, Sachiko Furukawa, Hayashida Jun-Nosuke, Tamotsu Kiyoshima, Mayumi Shimizu, Yojiro Arinobu, Seiji Nakamura, A case of marginal zone B cell lymphoma mimicking IgG4-related dacryoadenitis and sialoadenitis, World Journal of Surgical Oncology, 2015.02. |
| 61. | Miho Ohta, Masafumi Moriyama, Yuichi Goto, Shintaro Kawano, Akihiko Tanaka, Takashi Maehara, Sachiko Furukawa, Jun Nosuke Hayashida, Tamotsu Kiyoshima, Mayumi Shimizu, Yojiro Arinobu, Seiji Nakamura, A case of marginal zone B cell lymphoma mimicking IgG4-related dacryoadenitis and sialoadenitis, World Journal of Surgical Oncology, 10.1186/s12957-015-0459-z, 13, 1, 2015.02, Background: IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease, is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma cells in glandular tissues. Recently, several studies reported both malignant lymphoma developed on the background of IgG4-associated conditions and IgG4-producing malignant lymphoma (non-IgG4-related disease). Case presentation: We report on the case of a 70-year-old man who was strongly suspected IgG4-DS because of high serum IgG4 concentration (215 mg/dl) and bilateral swelling of parotid and submandibular glands. Biopsies of cervical lymph node and a portion of submandibular gland were performed. These histopathological findings subsequently confirmed a diagnosis of marginal zone B cell lymphoma. Conclusion: Differential diagnosis of IgG4-DS is necessary from other disorders, including Sjögren's syndrome, sarcoidosis, Castleman's disease, Wegener's granulomatosis, lymphoma, and cancer. We suggest that biopsy of swollen lesions is important for a definitive diagnosis of IgG4-DS and discuss the mechanism of development in this case.. |
| 62. | Sachiko Furukawa, Masafumi Moriyama, Akihiko Tanaka, Takashi Maehara, Hiroto Tsuboi, Mana Iizuka, Hayashida Jun-Nosuke, Miho Ohta, Takako Saeki, Kenji Notohara, Takayuki Sumida, Seiji Nakamura, Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease, 2015.01. |
| 63. | Hayashida Jun-Nosuke, Sakae Minami, Masafumi Moriyama, Takeshi Toyoshima, Shouichi Shinozaki, Akihiko Tanaka, Takashi Maehara, Seiji Nakamura, Differences of stimulated and unstimulated salivary flow rates in patients with dry mouth, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, 2015.01. |
| 64. | Hayashida Jun-Nosuke, Sakae Minami, Masafumi Moriyama, Takeshi Toyoshima, Shouichi Shinozaki, Akihiko Tanaka, takashi maehara, Seiji Nakamura, Differences of stimulated and unstimulated salivary flow rates in patients with dry mouth, Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology, 10.1016/j.ajoms.2014.04.011, 27, 1, 96-101, 2015.01, Purpose: The purpose of this study was to clarify the usefulness of noninvasive examination items such as sialometry and Visual Analog Scale (VAS) in distinguishing Sjögren's syndrome (SS) in dry mouth patients from neurogenic/neuropsychiatric disorders and drugs (DND). Patients and methods: The study cohort comprised 50 patients with SS and 28 patients with DND. The gum test and Saxon test for stimulated salivary flow rate (SSFR), the spitting test for unstimulated salivary flow rate (USFR) and VAS were performed in all the patients with dry mouth. Results: In SS patients, the SSFR (mean: gum test, 6.34 mL/10. min; Saxon test, 1.19 g/2. min) and USFR (0.61 mL/15. min) were decreased. In DND patients, the SSFR (gum test, 16.35. mL/10 min; Saxon test, 3.58 g/2 min) was within the normal range, but the USFR (0.90 mL/15 min) was decreased. In VAS, SS patients scored significantly higher in the items of "water-drinking at meals", "difficulty in swallowing", and "taste abnormality", while significantly lower in the item of "oral pain". Conclusion: These results suggest that the SSFR, USFR and VAS could be useful in distinguishing DND from SS.. |
| 65. | Sachiko Furukawa, Masafumi Moriyama, Akihiko Tanaka, Takashi Maehara, Hiroto Tsuboi, Mana Iizuka, Jun Nosuke Hayashida, Miho Ohta, Takako Saeki, Kenji Notohara, Takayuki Sumida, Seiji Nakamura, Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease, Clinical Immunology, 10.1016/j.clim.2014.10.008, 156, 1, 9-18, 2015.01, IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) is characterized by bilateral swelling of glandular tissues with extensive fibrosis, and is immunologically considered a Th2-predominant disease. Recent studies reported that alternatively activated (M2) macrophages enhanced Th2 immune responses and fibrosis by production of pro-fibrotic factors (IL-10, IL-13 and CCL18). Therefore, we examined the association between M2 macrophages and fibrosis in submandibular glands from 7 patients with IgG4-DS, 10 patients with chronic sialoadenitis, 10 patients with Sjögren's syndrome, and 10 healthy subjects. The number of M2 macrophages in SMGs from patients with IgG4-DS was also significantly higher than in the other groups. Double immunofluorescence staining showed that IL-10 and CCL18 expression co-localized with M2 macrophage-marker (CD163). Furthermore, the SMG fibrosis score was positively correlated with the frequency of M2 macrophages in only IgG4-DS. These results indicate that IL-10 and CCL18 secreted by preferential M2 macrophages possibly play a key role in the development of severe fibrosis in IgG4-DS.. |
| 66. | Moriyama M, Tanaka A, Maehara T, Furukawa S, Nakashima H, Nakamura S., T helper subsets in Sjogren’s syndrome and IgG4-related dacryoadenitis and sialoadenitis: a critical review., J Autoimmune. 2014 Jun;51:81-8., 2014.06. |
| 67. | Shinsuke Ieda, Masafumi Moriyama, Toru Takashita, Takashi Maehara, Yumi Imabayashi, Shoichi Shinozaki, Akihiko Tanaka, Jun Nosuke Hayashida, Sachiko Furukawa, Miho Ohta, Yoshihisa Yamashita, Seiji Nakamura, Molecular analysis of fungal populations in patients with oral candidiasis using internal transcribed spacer region, PloS one, 10.1371/journal.pone.0101156, 9, 6, 2014.06, Oral candidiasis is closely associated with changes in the oral fungal flora and is caused primarily by Candida albicans. Conventional methods of fungal culture are time-consuming and not always conclusive. However, molecular genetic analysis of internal transcribed spacer (ITS) regions of fungal rRNA is rapid, reproducible and simple to perform. In this study we examined the fungal flora in patients with oral candidiasis and investigated changes in the flora after antifungal treatment using length heterogeneity-polymerization chain reaction (LH-PCR) analysis of ITS regions. Fifty-two patients with pseudomembranous oral candidiasis (POC) and 30 healthy controls were included in the study. Fungal DNA from oral rinse was examined for fungal species diversity by LH-PCR. Fungal populations were quantified by real-time PCR and previouslyunidentified signals were confirmed by nucleotide sequencing. Relationships between the oral fungal flora and treatmentresistant factors were also examined. POC patients showed significantly more fungal species and a greater density of fungi than control individuals. Sixteen fungi were newly identified. The fungal populations from both groups were composed predominantly of C. albicans, though the ratio of C. dubliniensis was significantly higher in POC patients than in controls. The diversity and density of fungi were significantly reduced after treatment. Furthermore, fungal diversity and the proportion of C. dubliniensis were positively correlated with treatment duration. These results suggest that C. dubliniensis and high fungal flora diversity might be involved in the pathogenesis of oral candidiasis. We therefore conclude that LH-PCR is a useful technique for diagnosing and assessing the severity of oral candidal infection.. |
| 68. | Masafumi Moriyama, Akihiko Tanaka, Takashi Maehara, Sachiko Furukawa, Hitoshi Nakashima, Seiji Nakamura, T helper subsets in Sjögren's syndrome and IgG4-related dacryoadenitis and sialoadenitis A critical review, Journal of Autoimmunity, 10.1016/j.jaut.2013.07.007, 51, 81-88, 2014.06, IgG4-related disease (IgG4-RD) is a systemic disease characterized by the elevation of serum IgG4 and infiltration of IgG4-positive plasma cells in multiple target organs, including the pancreas, kidney, biliary tract and salivary glands. In contrast, Mikulicz's disease (MD) has been considered a subtype of Sjögren's syndrome (SS) based on histopathological similarities. However, it is now recognized that MD is an IgG4-RD distinguishable from SS and called as IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS). Regarding immunological aspects, it is generally accepted that CD4+ T helper (Th) cells play a crucial role in the pathogenesis of SS. Since it is well known that IgG4 is induced by Th2 cytokines such as interleukin (IL)-4 and IL-13, IgG4-DS is speculated to be a unique inflammatory disorder characterized by Th2 immune reactions. However, the involvement of Th cells in the pathogenesis of IgG4-DS remains to be clarified. Exploring the role of Th cell subsets in IgG4-DS is a highly promising field of investigation. In this review, we focus on the selective localization and respective functions of Th cell subsets and discuss the differences between SS and IgG4-DS to clarify the pathogenic mechanisms of these diseases.. |
| 69. | Shinsuke Ieda, Masafumi Moriyama, Toru Takeshita, Takashi Maehara, Yumi Imabayashi, Shoichi Shinozaki, Akihiko Tanaka, Jun-Nosuke Hayashida, Sachiko Furukawa, Miho Ohta, Seiji Nakamura, Molecular analysis of fungal populations in patients with oral candidiasis using internal transcribed spacer region, PLoS One, 2014.05. |
| 70. | Masafumi Moriyama, S. Furukawa, Shintarou Kawano, Y. Goto, Tamotsu Kiyoshima, A. Tanaka, T. Maehara, Hayashida Jun-Nosuke, M. Ohta, Seiji Nakamura, The diagnostic utility of biopsies from the submandibular and labial salivary glands in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease, International Journal of Oral and Maxillofacial Surgery, 2014.01. |
| 71. | Masafumi Moriyama, S. Furukawa, Shintarou Kawano, Y. Goto, Tamotsu Kiyoshima, A. Tanaka, takashi maehara, Hayashida Jun-Nosuke, M. Ohta, Seiji Nakamura, The diagnostic utility of biopsies from the submandibular and labial salivary glands in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease, International Journal of Oral and Maxillofacial Surgery, 10.1016/j.ijom.2014.06.014, 43, 10, 1276-1281, 2014.01, IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) is characterized by serum IgG4 elevation and the infiltration of IgG4-positive plasma cells in glandular tissues. For definitive diagnosis of IgG4-DS, biopsies of local lesions are recommended to exclude Sjögren's syndrome (SS), malignant tumours, and similar disorders. In this study, we examined the diagnostic utility of submandibular gland (SMG) and labial salivary gland (LSG) biopsies in IgG4-DS. Fourteen patients presenting with swelling of the SMG (eight females and six males) underwent both SMG and LSG biopsies. The sensitivity, specificity, and accuracy of SMG biopsies were all 100.0%. In contrast, those of LSG biopsies were 69.2%, 100.0%, and 71.4%, respectively. Thirty-three out of 61 LSG biopsies (54.1%) from all 14 patients were positive for the diagnostic criteria of IgG4-DS (IgG4-positive/IgG-positive plasma cells >0.4). None of the patients experienced complications such as facial nerve palsy, sialocele, or hyposalivation. The IgG4/IgG ratio showed no significant correlation between the LSG and SMG. The final diagnosis was IgG4-DS in 13 patients and marginal zone B-cell lymphoma (MZL) in one. These results suggest that incisional biopsy of the SMG is useful and appropriate for the definitive diagnosis of IgG4-DS, while diagnosis by LSG biopsy alone requires more caution.. |
| 72. | Masafumi Moriyama, Akihiko Tanaka, Takashi Maehara, Yukiko Ohyama, Mayumi Shimizu, Hitoshi Nakashima, Hayashida Jun-Nosuke, Shoichi Shinozaki, Yoshiaki Kubo, Sachiko Furukawa, Toshihiro Kikuta, Seiji Nakamura, Clinical characteristics of Mikulicz's disease as an IgG4-related disease, Clinical Oral Investigations, 2013.12. |
| 73. | Masafumi Moriyama, Akihiko Tanaka, Takashi Maehara, Yukiko Ohyama, Mayumi Shimizu, Hitoshi Nakashima, Jun Nosuke Hayashida, Shoichi Shinozaki, Yoshiaki Kubo, Sachiko Furukawa, Toshihiro Kikuta, Seiji Nakamura, Clinical characteristics of Mikulicz's disease as an IgG4-related disease, Clinical Oral Investigations, 10.1007/s00784-012-0905-z, 17, 9, 1995-2002, 2013.12, Objectives: 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 concentration, and suggested that MD is one of "IgG4-related disease" and distinguishable from SS. Therefore, we clinically and histopathologically examined the disease states of MD and SS in detail. Materials and methods: Twenty patients with Mikulicz's disease and 18 with SS were comparatively studied to determine clinical characteristics in MD patients. Results: Sialography in MD patients did not show the "apple-tree sign" typically seen in SS. Serologically, high serum IgG4 levels but not anti-SS-A or anti-SS-B antibodies were observed in MD. SS showed lymphocytic infiltration of various subsets with atrophy or severe destruction of the acini, while MD showed selective infiltration of IgG4+ plasma cells with hyperplastic germinal centers and mild acini destruction. Corticosteroid treatment of MD reduced IgG and IgG4 levels and improved salivary function. A negative correlation between disease duration and increasing rate of salivary flow was observed in MD. Conclusions: These results suggested that the pathogenesis of MD might be different from those of SS. Clinical Relevance: early diagnosis and treatment of MD is important for the improvement of salivary function.. |
| 74. | Maehara T, Moriyama M, Nakashima H, Miyake K, Hayashida JN, Tanaka A, Shinozaki S, Kubo Y, Nakamura S., Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz’s disease., Ann. Rheum. Dis. 2012 Dec;71(12):2011-19., 2012.12. |
| 75. | S. Shinozaki, Masafumi Moriyama, Hayashida Jun-Nosuke, A. Tanaka, T. Maehara, S. Ieda, Seiji Nakamura, Close association between oral Candida species and oral mucosal disorders in patients with xerostomia, Oral Diseases, 2012.12. |
| 76. | Takashi Maehara, Masafumi Moriyama, Hitoshi Nakashima, Katsuhisa Miyake, Jun Nosuke Hayashida, Akihiko Tanaka, Shouichi Shinozaki, Yoshiaki Kubo, Seiji Nakamura, Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease, Annals of the Rheumatic Diseases, 10.1136/annrheumdis-2012-201477, 71, 12, 2011-2019, 2012.12, Objectives: Interleukin (IL)-21 is mainly produced by CD4 T helper (Th) cells including Th2, Th17 and follicular helper T (Tfh) cells. Recent studies have reported that IL-21 is involved in the formation of germinal centres (GCs) and class switching of IgG4. It has been suggested that IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS), so-called Mikulicz's disease (MD), is distinct from Sjögren's syndrome (SS) and shows a high frequency of GC formation in salivary glands. In this study the expression of IL-21 in IgG4-DS and SS patients was examined. Methods: Twelve patients with IgG4-DS, 15 with SS and 15 healthy subjects were screened for (1) ectopic GC formation in formalin-fixed labial salivary gland (LSG) biopsy samples; (2) expression of IL-21, Th2-, Th17- and Tfh-related molecules (cytokines, chemokine receptors and transcription factors) in LSGs; (3) relationship between IgG4/IgG ratio and mRNA expression of IL-21 in LSGs. Results: mRNA expression of IL-21 and Bcl-6 in LSGs from patients with IgG4-DS was significantly higher than in patients with SS and controls. IL-21 and CXCR5 were detected by immunohistochemistry in or around GC in patients with SS and those with IgG4-DS. IL-21 was detected in infiltrating lymphocytes outside GC only in patients with IgG4-DS. Expression of IL-21 was consistent with that of Th2-related molecules while IL-17 was rarely seen in IgG4-DS. Furthermore, the expression of IL-21 in LSGs was correlated with the number of GC formations and the IgG4/IgG ratio in patients with IgG4-DS. Conclusions: These results suggest that overexpression of IL-21 by Th2 cells might play a key role in GC formation and IgG4 production in IgG4-DS.. |
| 77. | S. Shinozaki, M. Moriyama, J. N. Hayashida, A. Tanaka, T. Maehara, S. Ieda, S. Nakamura, Close association between oral Candida species and oral mucosal disorders in patients with xerostomia, Oral Diseases, 10.1111/j.1601-0825.2012.01923.x, 18, 7, 667-672, 2012.10, Objective: Heightened interest in oral health has lead to an increase in patients complaining of xerostomia, which is associated with various oral mucosal disorders. In this study, we investigated the relationship between Candida species and oral mucosal disorders in patients with xerostomia. Subjects and Methods: We evaluated whole salivary flow rate and presence of oral mucosal disorders in 48 patients with xerostomia and 15 healthy controls. The number of Candida species was measured as colony-forming units after propagation on selective medium. Identification of Candida at the species level was carried out by polymerase chain reaction and restriction fragment length polymorphism analysis. We then examined the relationship between Candida species and oral mucosal symptoms. Results: Compared with controls, patients with xerostomia exhibited significantly decreased whole salivary flow rate, increased rate of oral mucosal symptoms, and higher numbers of Candida. Salivary flow rate negatively correlated with the number Candida. Among patients with oral candidiasis, Candida albicanswas isolated from the tongue mucosa and Candida glabratawas isolated from the angle of the mouth. Conclusion: These results suggest that particular Candida species are involved in the pathogenesis of oral mucosal disorders in patients with xerostomia.. |
| 78. | Maehara T, Moriyama M, Hayashida JN, Tanaka A, Shinozaki S, Kubo Y, Matsumura K, Nakamura S., Selective localization of T helper subsets in labial salivary glands from primary Sjogren’s syndrome patietns., Clin Exp Immunol. 2012 Aug;169(2):89-99., 2012.08. |
| 79. | T. Maehara, M. Moriyama, J. N. Hayashida, A. Tanaka, S. Shinozaki, Y. Kubo, K. Matsumura, S. Nakamura, Selective localization of T helper subsets in labial salivary glands from primary Sjögren's syndrome patients, Clinical and Experimental Immunology, 10.1111/j.1365-2249.2012.04606.x, 169, 2, 89-99, 2012.08, 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.. |
| 80. | Masafumi Moriyama, Hayashida Jun-Nosuke, T. Toyoshima, Yukiko Ohyama, S. Shinozaki, A. Tanaka, T. Maehara, Seiji Nakamura, Cytokine/chemokine profiles contribute to understanding the pathogenesis and diagnosis of primary Sjögren's syndrome, Clinical and Experimental Immunology, 2012.07. |
| 81. | M. Moriyama, J. N. Hayashida, T. Toyoshima, Y. Ohyama, S. Shinozaki, A. Tanaka, T. Maehara, S. Nakamura, Cytokine/chemokine profiles contribute to understanding the pathogenesis and diagnosis of primary Sjögren's syndrome, Clinical and Experimental Immunology, 10.1111/j.1365-2249.2012.04587.x, 169, 1, 17-26, 2012.07, 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.. |
| 82. | Akihiko Tanaka, Masafumi Moriyama, Hitoshi Nakashima, Katsuhisa Miyake, Hayashida Jun-Nosuke, Takashi Maehara, Shouichi Shinozaki, Yoshiaki Kubo, Seiji Nakamura, Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease, Arthritis and Rheumatology, 2012.01. |
| 83. | Akihiko Tanaka, Masafumi Moriyama, Hitoshi Nakashima, Katsuhisa Miyake, Jun Nosuke Hayashida, Takashi Maehara, Shouichi Shinozaki, Yoshiaki Kubo, Seiji Nakamura, Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease, Arthritis and rheumatism, 10.1002/art.33320, 64, 1, 254-263, 2012.01, Objective Mikulicz disease has been considered to be a subtype of Sjögren's syndrome (SS). However, recent studies have suggested that Mikulicz disease is an IgG4-related disease and is distinguishable from SS. In addition, it has been reported that both interleukin-4 (IL-4) and IL-10 induce IgG4 production and inhibit IgE. This study was undertaken to examine the expression of these cytokines in patients with Mikulicz disease and patients with SS. Methods Labial salivary gland (LSG) sections from 15 patients with Mikulicz disease and 18 patients with SS were examined for subsets of the infiltrating lymphocytes, expression patterns of messenger RNA (mRNA) for cytokines/chemokines, and relationships between the IgG4:IgG ratio and the expression of mRNA for IL-4 or IL-10. Results Immunohistochemical analysis showed lymphocyte infiltration of various subsets in the LSGs of SS patients, and the selective infiltration of IgG4-positive plasma cells and Treg cells in the LSGs of Mikulicz disease patients. The levels of mRNA for both Th1 and Th2 cytokines and chemokines in LSGs from patients with SS were significantly higher than in controls, while the expression of both Th2 and Treg cells was significantly higher in the patients with Mikulicz disease than in controls. Furthermore, the expression of IL-4 or IL-10 in the LSGs was correlated with the IgG4:IgG ratio. Conclusion These results suggest that the pathogenesis of Mikulicz disease is different from that of SS. Mikulicz disease is a unique inflammatory disorder characterized by Th2 and regulatory immune reactions that might play key roles in IgG4 production.. |
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