日米共同研究によるIgG4関連疾患の国際的疾患概念の構築と新規診断法への展開
キーワード：IgG4関連疾患、日米共同研究、国際的疾患概念、新規診断法
2017.04～2020.03.
| 森山 雅文（もりやままさふみ） | データ更新日：2024.02.08 |
主な研究テーマ
歯髄幹細胞の上清を用いた自己免疫疾患の新たな治療戦略
キーワード：歯髄幹細胞、自己免疫疾患
2017.04～2020.03.
キーワード：歯髄幹細胞、自己免疫疾患
2017.04～2020.03.
IgG4関連疾患の病態解明に向けた自然免疫からの新戦略
キーワード：マクロファージ、樹状細胞、サイトカイン
2014.04～2019.03.
キーワード：マクロファージ、樹状細胞、サイトカイン
2014.04～2019.03.
口腔扁平上皮癌の増殖・転移における腫瘍随伴性マクロファージの検討
キーワード：腫瘍随伴性マクロファージ、口腔扁平上皮癌、サイトカイン
2013.04～2017.03.
キーワード：腫瘍随伴性マクロファージ、口腔扁平上皮癌、サイトカイン
2013.04～2017.03.
口腔カンジダ症患者における真菌叢の網羅的解析 − Internal transcribed spacer (ITS) 領域を用いた口腔カンジダ症の新たな診断法の試み−
キーワード：口腔カンジダ症、Candida albicans、Candida dubliniensis、ITS領域、LH-PCR法
2010.04～2015.03.
キーワード：口腔カンジダ症、Candida albicans、Candida dubliniensis、ITS領域、LH-PCR法
2010.04～2015.03.
シェーグレン症候群およびミクリッツ病の病態形成におけるサイトカインの関与に関する研究
キーワード：シェーグレン症候群、IgG4関連疾患、ミクリッツ病
2012.05～2012.05.
キーワード：シェーグレン症候群、IgG4関連疾患、ミクリッツ病
2012.05～2012.05.
口腔扁平苔癬の発症における樹状細胞の関与
キーワード：樹状細胞、サイトカイン、ヘルパーT細胞
2015.04～2017.03.
キーワード：樹状細胞、サイトカイン、ヘルパーT細胞
2015.04～2017.03.
従事しているプロジェクト研究
厚生労働科学研究費補助金（難治性疾患政策研究事業）「自己免疫疾患に関する調査研究」
2023.04～2026.03, 代表者：渥美 達也.
2023.04～2026.03, 代表者：渥美 達也.
厚生労働科学研究費補助金（難治性疾患政策研究事業） 「IgG4関連疾患の診断基準並びに診療指針の確立を目指す研究」
2023.04～2026.03, 代表者：川野 充弘.
2023.04～2026.03, 代表者：川野 充弘.
厚生労働科学研究費補助金（難治性疾患政策研究事業） 「IgG4関連疾患の診断基準並びに診療指針の確立を目指す研究」
2020.04～2023.03, 代表者：中村 誠司.
2020.04～2023.03, 代表者：中村 誠司.
厚生労働科学研究費補助金（難治性疾患政策研究事業）「自己免疫疾患に関する調査研究」
2020.04～2023.03, 代表者：森 雅亮.
2020.04～2023.03, 代表者：森 雅亮.
厚生労働科学研究費補助金（難治性疾患等政策研究事業（難治性疾患政策研究事業）） 「自己免疫疾患に関する調査研究」
2017.04～2020.03, 代表者：上阪 等, 東京医科歯科大学 膠原病・リウマチ内科.
2017.04～2020.03, 代表者：上阪 等, 東京医科歯科大学 膠原病・リウマチ内科.
日本医療研究開発機構 難治性疾患実用化研究事業 ステップ０ 「IgG4関連疾患の新規バイオマーカーと治療ターゲット開発に関する研究」
2017.04～2020.03, 代表者：三森 経世, 京都大学 大学院医学研究科 臨床免疫学.
2017.04～2020.03, 代表者：三森 経世, 京都大学 大学院医学研究科 臨床免疫学.
私立大学戦略的研究基盤形成支援事業 「口腔の加齢制御を目指した集学的研究拠点の形成」
2015.04～2020.03, 代表者：斎藤 一郎, 鶴見大学.
2015.04～2020.03, 代表者：斎藤 一郎, 鶴見大学.
厚生労働科学研究費補助金 難治性疾患等政策研究事業 「IgG4関連疾患の診断基準並びに治療指針の確立を目指した研究」
2014.04～2017.03, 代表者：千葉 勉, 京都大学医学研究科 消化器内科学講座.
2014.04～2017.03, 代表者：千葉 勉, 京都大学医学研究科 消化器内科学講座.
日本医療研究開発機構研究費（難治性疾患実用化研究事業） 「自己免疫疾患のイノベーション研究」
2014.04～2017.03, 代表者：住田 孝之, 筑波大学医学医療系 内科（膠原病・リウマチ・アレルギー）.
2014.04～2017.03, 代表者：住田 孝之, 筑波大学医学医療系 内科（膠原病・リウマチ・アレルギー）.
厚生労働科学研究費補助金 難治性疾患等政策研究事業(難治性疾患政策研究事業) 「自己免疫疾患に関する調査研究班」
2014.04～2017.03, 代表者：住田 孝之, 筑波大学医学医療系 内科（膠原病・リウマチ・アレルギー）.
2014.04～2017.03, 代表者：住田 孝之, 筑波大学医学医療系 内科（膠原病・リウマチ・アレルギー）.
日本医療研究開発機構研究費（難治性疾患実用化研究事業） 「IgG4関連疾患の病因病態解明と新規治療法確立に関する研究」
2014.04～2017.03, 代表者：三森 経世, 京都大学大学院医学研究科内科学講座（臨床免疫学） 京都大学医学部附属病院免疫・膠原病内科.
2014.04～2017.03, 代表者：三森 経世, 京都大学大学院医学研究科内科学講座（臨床免疫学） 京都大学医学部附属病院免疫・膠原病内科.
厚生労働省科学研究費難治性疾患等克服研究事業「自己免疫疾患に関する調査研究」
2011.04～2014.03, 代表者：住田 孝之, 筑波大学医学医療系 内科（膠原病・リウマチ・アレルギー）, 日本.
2011.04～2014.03, 代表者：住田 孝之, 筑波大学医学医療系 内科（膠原病・リウマチ・アレルギー）, 日本.
厚生労働省科学研究費難治性疾患等克服研究事業 「IgG4関連疾患に関する調査研究」
2012.04～2014.03, 代表者：千葉 勉, 京都大学医学研究科消化器内科学.
2012.04～2014.03, 代表者：千葉 勉, 京都大学医学研究科消化器内科学.
厚生労働科学研究費補助金難治性疾患克服研究事業 「IgG4関連全身硬化性疾患の診断法の確立と治療方法の開発に関する研究 」
2009.04～2012.03, 代表者：岡崎 和一, 関西医科大学内科学第三講座 （消化器肝臓内科）.
2009.04～2012.03, 代表者：岡崎 和一, 関西医科大学内科学第三講座 （消化器肝臓内科）.
研究業績
主要著書
主要原著論文
| 1. | Hugues Allard-Chamard, Naoki Kaneko, Alice Bertocchi, Na Sun, Julie Boucau, Hsiao-Hsuan Kuo, Jocelyn R. Farmer, Cory Perugino, Vinay S. Mahajan, Samuel J.H. Murphy, Katherine Premo, Thomas Diefenbach, Musie Ghebremichael, Grace Yuen, Alekhya Kotta, Zafer Akman, Mathias Lichterfeld, Bruce D. Walker, Xu G. Yu, Masafumi Moriyama, Takashi Maehara, Seiji Nakamura, John H. Stone, Robert F. Padera, Shiv Pillai, Extrafollicular IgD−CD27−CXCR5−CD11c− DN3 B cells infiltrate inflamed tissues in autoimmune fibrosis and in severe COVID-19, Cell Reports, 10.1016/j.celrep.2023.112630, 42, 6, 112630-112630, 2023.06. |
| 2. | Kaneko N, Hu C, Perugino CA, Maehara T, Munemura R, Yokomizo S, Sameshima J, Diefenbach TJ, Premo KR, Chinju A, Miyahara Y, Sakamoto M, Moriyama M, Stone JH, Nakamura S., Cytotoxic CD8(+) T cells may be drivers of tissue destruction in Sjogren's syndrome, SCIENTIFIC REPORTS, 10.1038/s41598-022-19397-w, 12, 1, 2022.09. |
| 3. | Kaneko N, Moriyama M, Maehara T, Chen H, Miyahara Y, Nakamura S., Orchestration of Immune Cells Contributes to Fibrosis in IgG4-Related Disease., Immuno, 10.3390/immuno2010013, 2, 1, 170-184, 2022.02. |
| 4. | 坂本 瑞樹、森山 雅文、清水 真弓、緒方 謙一、石黒 乃理子、鎮守 晃、太田 美穂、中村 誠司, シェーグレン症候群患者におけるM3 型ムスカリン受容体アゴニスト長期投与による治療効果の検討, 日口内誌, https://iss.ndl.go.jp/books/R100000002-I000011303316-00, 6, 2, 77-83, 2020.12. |
| 5. | 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, 2020.05, [URL]. |
| 6. | 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 & rheumatology (Hoboken, N.J.), 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 |
| 7. | 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, 14611-14611, 2019.10, [URL], 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.. |
| 8. | Sumida T, Azuma N, Moriyama M, Takahashi H, Asashima H, Honda F, Abe S, Ono Y, Hirota T, Hirata S, Tanaka Y, Shimizu T, Nakamura H, Kawakami A, Sano H, Ogawa Y, Tsubota K, Ryo K, Saito I, Tanaka A, Nakamura S, Takamura E, Tanaka M, Suzuki K, Takeuchi T, Yamakawa N, Mimori T, Ohta A, Nishiyama S, Yoshihara T, Suzuki Y, Kawano M, Tomiita M, Tsuboi H, Clinical practice guideline for Sjögren's syndrome 2017., Modern rheumatology, 10.1080/14397595.2018.1438093, 28, 3, 383-408, 2018.05. |
| 9. | Sachiko Furukawa, Kazunari Oobu, Masafumi Moriyama, Shintarou Kawano, Saori Sako, Hayashida Jun-Nosuke, Ryota Matsubara, Ken Ichi Ogata, Tamotsu Kiyoshima, Seiji Nakamura, Oral methotrexate-related lymphoproliferative disease presenting with severe osteonecrosis of the Jaw A case report and literature review, Internal Medicine, 10.2169/internalmedicine.8946-17, 57, 4, 575-581, 2018.01, Long-term methotrexate (MTX) treatment can cause MTX-related lymphoproliferative disorder (MTX-LPD). We experienced a case of MTX-LPD that was associated with severe osteonecrosis of the jaw mimicking medication-related osteonecrosis of the jaw. The patient was an 81-year-old woman with rheumatoid arthritis (RA) who was treated with MTX and bisphosphonate. After 7 years, she was referred to our department for the assessment of giant ulcer and exposure of the alveolar bone of the left maxilla. Histopathological and immunological analyses confirmed a diagnosis of MTX-LPD. At seven months after the cessation of MTX treatment, the ulcerative and necrotic lesions had markedly decreased in size. A 1-year follow-up examination showed no evidence of recurrence and good RA control.. |
| 10. | H Takahashi, H Tsuboi, H Asashima, T Hirota, Y Kondo, M Moriyama, I Matsumoto, S Nakamura, T Sumida, cDNA microarray analysis identifies NR4A2 as a novel molecule involved in the pathogenesis of Sjögren's syndrome, Clinical and Experimental Immunology, 10.1111/cei.13000, 190, 1, 96-109, 2017.07, [URL], To examine genes expressed specifically in labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS) in comparison with those of patients with immunoglobulin (Ig)G4-related disease (IgG4-RD), and to identify the genes involved in the pathogenesis of SS. Gene expression in LSGs of SS patients, IgG4-RD patients and healthy controls (HC) was analysed by cDNA microarray. Quantitative polymerase chain reaction (qPCR) was used to validate the up-regulation of differentially expressed genes (DEGs) in SS. Protein production of the validated gene in LSGs was examined by immunofluorescence (IF) assay. The association of molecular functions of the gene with the pathological conditions in SS was examined using peripheral blood lymphocytes. Among 1320 DEGs up-regulated in SS, qPCR confirmed the up-regulation of NR4A2 in LSGs of SS compared with IgG4-RD. IF staining showed higher production of NR4A2 in nuclei of CD4+ T cells and interleukin (IL)-17-producing cells in LSGs of SS, compared with IgG4-RD. Over-expression of NR4A2 mRNA was observed in peripheral CD4+ T cells of SS patients, compared with HC. Nuclear NR4A2 expression in T helper type 17 (Th17)-polarized CD4+ T cells determined by cellular IF was significantly higher in SS than in HC. Importazole, an inhibitor of importin-β, inhibited nuclear transport of NR4A2 and Th17 polarization along with IL-21 expression in naive CD4+ T cells under Th17-polarizing conditions, but did not alter retinoic acid receptor-related orphan receptor C (RORC) expression. NR4A2 seems to promote Th17 polarization via increased expression and intranuclear localization in CD4+ T cells of SS patients, which could play a critical role in the pathogenesis of SS.. |
| 11. | 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, 1755, 2017.05, [URL], 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.. |
| 12. | 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, 10.1371/journal.pone.0173017, 12, 3, 2017.03, [URL], 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.. |
| 13. | 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, 42413, 2017.02, [URL], 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 Sjogren'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 colocalized 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.. |
| 14. | Maehara T, Mattoo H, Ohta M, Mahajan VS, Moriyama M, Yamauchi M, Drijvers J, Nakamura S, Stone JH, Pillai SS, 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, [URL]. |
| 15. | Masafumi Moriyama, Seiji Nakamura, Th1/Th2 immune balance and other T helper subsets in IgG4-related disease, Current Topics in Microbiology and Immunology, 10.1007/82_2016_40, 401, 75-83, 2017.01, [URL], IgG4-related disease (IgG4-RD) is a systemic disease characterized by elevated serum IgG4 levels and a strong infiltration of IgG4-positive plasma cells in various organs. IgG4-RD patients also frequently suffer from allergic diseases, including asthma and atopic dermatitis. It is well known that T helper type 2 (Th2) cells have an important role in the initiation of allergic diseases, and Th2 cytokines such as interleukin (IL)-4 and IL-13 promote class switching to IgG4. Therefore, IgG4-RD is considered to be a Th2-predominant disease. However, other Th subsets, including regulatory T cells and T follicular helper cells, have recently received increasing attention with regard to the pathogenesis of IgG4-RD. Exploring the interconnected network of Th subsets in IgG4-RD is a highly promising field of investigation. In this review, we focus on the localization and functions of individual Th subsets to clarify the involvement of these cells in the pathogenesis of IgG4-RD.. |
| 16. | 森山 雅文, IgG4関連疾患の病態形成おける自然免疫の関与 −特にM2マクロファージに注目して−, アレルギーの臨床, 36, 13, 1273-1277, 2016.10. |
| 17. | 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, 10.3109/14397595.2016.1148225, 26, 5, 725-729, 2016.09, [URL], 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.. |
| 18. | 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, 10.1111/odi.12259, 21, 2, 257-262, 2015.03, [URL], 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 (+).. |
| 19. | 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, 10.1111/odi.12252, 21, 2, 224-231, 2015.03, [URL], 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.. |
| 20. | 森山 雅文、中村 誠司, IgG4関連疾患の唾液腺病変における病態生理 −免疫学的異常を中心に−, 日サ会誌, 35, 55-60, 2015.03. |
| 21. | 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, [URL], 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 Sjogren'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. (C) 2014 The Authors. Published by Elsevier Inc.. |
| 22. | Moriyama M, Tanaka A, Maehara T, Furukawa S, Nakashima H, Nakamura S, 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, [URL]. |
| 23. | 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, 10.1016/j.ijom.2014.06.014, 43, 10, 1276-1281, 2014.01, [URL], 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.. |
| 24. | Hayashida Jun-Nosuke, Seiji Nakamura, T. Toyoshima, Masafumi Moriyama, M. Sasaki, E. Kawamura, Yukiko Ohyama, Kumamaru Wataru, K. Shirasuna, Possible involvement of cytokines, chemokines and chemokine receptors in the initiation and progression of chronic GVHD, Bone Marrow Transplantation, 10.1038/bmt.2012.100, 48, 1, 115-123, 2013.01, [URL], Chronic GVHD (cGVHD) after allogeneic hematopoietic SCT (HSCT) is characterized by an infiltration of T cells into target organs including the oral mucosa and salivary glands. This study was designed to clarify the molecular mechanism of the local accumulation of pathogenic T cells in cGVHD. The expression of cytokines, chemokines and chemokine receptors in the buccal mucosa (BM), labial salivary glands (LSG) and PBMC from 16 patients with cGVHD after allogeneic HSCT was examined. The mRNA expression of T helper 1 (Th1) and Th2 cytokines, and several chemokines and chemokine receptors was significantly increased in the BM and LSG from cGVHD patients, in comparison with both those in the BM and LSG from controls, respectively, and also with those in the PBMC from cGVHD patients. Furthermore, the mRNA expression of Th2 cytokines, macrophage-derived chemokine and CC chemokine receptor 4 was closely associated with a strong T-cell infiltration in the BM and LSG from cGVHD patients. These results suggest that cGVHD might be initiated and/or maintained by Th1/Th0 cells and thereafter progresses in association with Th2 cell accumulation via the interaction of particular chemokine and chemokine receptors.. |
| 25. | 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, [URL], 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 Sjogren'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.. |
| 26. | 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, 10.1111/j.1601-0825.2012.01923.x, 18, 7, 667-672, 2012.10, [URL], 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.. |
| 27. | T. Maehara, Masafumi Moriyama, Hayashida Jun-Nosuke, A. Tanaka, S. Shinozaki, Y. Kubo, Kaori Matsumura, Seiji 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, [URL], 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.. |
| 28. | Hiroto Tsuboi, Naomi Matsuo, Mana Iizuka, Sayaka Tsuzuki, Yuya Kondo, Akihiko Tanaka, Masafumi Moriyama, Isao Matsumoto, Seiji Nakamura, Takayuki Sumida, Analysis of IgG4 class switch-related molecules in IgG4-related disease, Arthritis Research and Therapy, 10.1186/ar3924, 14, 4, 2012.07, [URL], Introduction: Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a new disease entity characterized by high serum IgG4 levels, IgG4-positive plasmacytic infiltration, and fibrosis in various organs. The purpose of this study was to determine the mechanism of upregulation of IgG4 class switch recombination in IgG4-RD.Methods: We extracted RNA from peripheral blood mononuclear cells (PBMCs) of patients with IgG4-RD (n = 6), Sjögren syndrome (SS) (n = 6), and healthy controls (n = 8), from CD3-positive T cells and CD20-positive B cells sorted from PBMCs of patients with IgG4-RD (n = 3), SS (n = 4), and healthy controls (n = 4), as well as from labial salivary glands (LSGs) of patients with IgG4-RD (n = 11), SS (n = 13), and healthy controls (n = 3). The mRNA expression levels of IgG4-specific class switch-related molecules, such as Th2 cytokines (IL-4 and IL-13), Treg cytokines (IL-10 and TGF-β), and transcriptional factors (GATA3 and Foxp3) were examined with quantitative polymerase chain reaction (PCR). IgG4-nonspecific class switch-related molecules, such as CD40, CD154, BAFF, APRIL, IRF4, and AID, were also examined.Results: The expression levels of Treg cytokines (IL-10 and TGF-β) and AID were significantly higher in LSGs of IgG4-RD than in SS and the controls (P |
| 29. | 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, 10.1111/j.1365-2249.2012.04587.x, 169, 1, 17-26, 2012.07, [URL], 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.. |
| 30. | 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, [URL], Objective Mikulicz disease has been considered to be a subtype of Sjogren'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.. |
| 31. | H. Nakashima, K. Miyake, Masafumi Moriyama, A. Tanaka, M. Watanabe, Y. Abe, H. Sato, Seiji Nakamura, T. Saito, An amplification of IL-10 and TGF-β in patients with IgG4-related tubulointerstitial nephritis, Clinical Nephrology, 73, 5, 385-391, 2010.05, Background: IgG4-related tubulointerstitial nephritis (TIN) shows characteristic serum IgG4 elevation and increased IgG4-positive plasma cells in the renal interstitium, and inclusion of TIN as an IgG4-related systemic disease has been suggested. IgG4 is the rarest IgG subclass and is a Th2-dependent isotype with low affinity for target antigen. Although the pathogenesis of this disease has not been elucidated, positive serum immune complex and hypocomplementemia in some patients with this disease suggest that immune complex mechanisms are involved in the causation of this disease. Method:We selected 20 cases of histological diagnosed TIN. These cases were etiologically different and included 4 cases of IgG4-related TIN.We extracted RNAfrom paraffin embedded biopsied kidney and evaluated expression levels of various cytokines for each case by real time PCR. Results: Comparison of cytokine production patterns among different disease-associated TINs revealed that IgG4-related TIN exhibited a quite distinct pattern. On the one hand, there was no expression of IL-2, IFN-γ, IL-17 and IL-6, whereas production of IL-4, IL-10 and TGF-β was, on the other hand, remarkably increased in IgG4-related TIN. Conclusion: Based on these cytokine production results, Th2 and Treg appear to play a central role in IgG4-related TIN.. |
| 32. | Katsuhisa Miyake, Masafumi Moriyama, Kumiko Aizawa, Shuji Nagano, Yasushi Inoue, Atsushi Sadanaga, Hitoshi Nakashima, Seiji Nakamura, Peripheral CD4+T cells showing a Th2 phenotype in a patient with Mikulicz's disease associated with lymphadenopathy and pleural effusion, MODERN RHEUMATOLOGY, 10.1007/s10165-007-0010-3, 18, 1, 86-90, 2008.02, [URL], Mikulicz's disease (MD) is a unique IgG4-related systemic disease indicated by enlargement of the lachrymal and salivary glands and which differs substantially from Sjogren's syndrome. A male patient with pleural effusion, swelling of the submandibular glands, and swelling of the paraaortic, mediastinal, and pararenal lymph nodes was diagnosed with MD. Analysis of peripheral CD4+ T cells from the patient revealed deviation of the Th1/Th2 balance to Th2. Prednisolone therapy ameliorated the disease and corrected the Th1/Th2 imbalance.. |
| 33. | T. Toyoshima, Seiji Nakamura, Kumamaru Wataru, E. Kawamura, H. Ishibashi, Hayashida Jun-Nosuke, Masafumi Moriyama, Yukiko Ohyama, M. Sasaki, K. Shirasuna, Expression of tumor-associated antigen RCAS1 and its possible involvement in immune evasion in oral squamous cell carcinoma, Journal of Oral Pathology and Medicine, 10.1111/j.1600-0714.2006.00442.x, 35, 6, 361-368, 2006.07, [URL], BACKGROUND: RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) is known to induce apoptosis in its receptor-positive cells. The authors investigated RCAS1 expression in oral squamous cell carcinoma (SCC) and its association with the apoptosis of tumor-infiltrating lymphocytes (TILs). METHODS: In 130 patients with oral SCC, the expression of RCAS1 in tumor cells was immunohistochemically examined and the apoptosis of TILs was examined by Terminal Deoxynucleotidyltransferase-mediated dUTP Nick End Labeling (TUNEL) staining. RESULTS: RCAS1 was detected both on the cytoplasm and the membrane of tumor cells in 41 of 130 cases (31.5%). Focusing on the expression at the invasive front interacting with host immune cells, RCAS1 was detected in 22 of 130 cases (16.9%). The percentage of TUNEL-positive TILs in cases with RCAS1-positive SCCs was significantly higher than in cases with RCAS1-negative SCCs (P |
主要学会発表等
その他の優れた研究業績
2017.06, ハーバード大学および Ragon 研究所（ボストン）との国際共同研究により、IgG4 関連疾患の病変局所に新たなヘルパー T 細胞サブセット（CD4陽性細胞傷害性T細胞）が多数浸潤し、病態（IgG4産生および線維化）に関与していることを明らかにした。この研究成果は、リウマチ学のトップジャーナルである Annals of Rheumatic Diseases に掲載され、さらにNature レビュー誌でも Reseach Highlight ととして紹介された。.
学会活動
所属学会名
日本IgG4関連疾患学会
日本顎関節学会
日本免疫学会
日本口腔内科学会
日本顎変形症学会
日本口腔腫瘍学会
日本口腔外科学会
日本口腔科学会
日本シェーグレン症候群学会
日本リウマチ学会
日本口腔インプラント学会
General Session & Exhibition of the International Association of Dental Research
学会大会・会議・シンポジウム等における役割
2023.06.03～2023.06.03, 第2回 九州顎変形症手術手技検討会・交流会, 主催者・座長.
2022.10.16～2022.10.16, 第1回 九州顎変形症手術手技検討会・交流会, 主催者・座長.
2022.09.11～2022.09.11, 九州顎変形症手術手技若手検討会（vol.4）, 主催者・座長.
2021.12.19～2021.12.19, 九州顎変形症手術手技若手検討会（vol.3）, 主催者・座長.
2021.11.21～2021.11.21, 九州顎変形症手術手技若手検討会（vol.2）, 主催者・座長.
2021.10.17～2021.10.17, 九州顎変形症手術手技若手検討会, 主催者・座長.
2019.09.13～2019.09.14, 第28回 日本シェーグレン症候群学会, 座長.
2019.06.29～2019.06.29, 第87回 日本口腔外科学会九州支部学術集会, 座長.
2019.03.09～2019.03.10, 第12回 IgG4研究会, 座長.
2018.03.10～2018.03.10, 第11回 IgG4研究会, 座長.
2012.03.03～2012.03.03, 第6回 IgG4研究会, 座長（Chairmanship）.
学会誌・雑誌・著書の編集への参加状況
2014.04～2017.03, シェーグレン症候群診療ガイドライン, 国内, SR（システマティック レビュー）委員.
2015.05～2015.10, IgG4-Related Kidney Disease, 国際, 共著.
学術論文等の審査
| 年度 | 外国語雑誌査読論文数 | 日本語雑誌査読論文数 | 国際会議録査読論文数 | 国内会議録査読論文数 | 合計 |
|---|---|---|---|---|---|
| 2021年度 | 10 | 3 | 13 | ||
| 2020年度 | 10 | 10 | |||
| 2019年度 | 8 | 8 | |||
| 2018年度 | 5 | 5 | |||
| 2017年度 | 7 | 7 | |||
| 2016年度 | 4 | 4 | |||
| 2015年度 | 5 | 1 | 6 |
その他の研究活動
海外渡航状況, 海外での教育研究歴
Third International symposium of IgG4-RD & Fibrosis, UnitedStatesofAmerica, 2017.02～2017.02.
受賞
九大歯学優秀研究者賞（Impact Factor 賞）, 2023.03.
九大歯学優秀研究者賞（Field Weighted Citation Impact 賞）, 2021.03.
九大歯学優秀研究者賞（Impact Factor 賞）, 2021.03.
第64回日本口腔外科学会総会・学術集会 優秀ポスター賞, 日本口腔外科学会, 2019.11.
福岡県すこやか健康事業団 がん研究助成金 奨励賞, 福岡県すこやか健康事業団, 2013.10.
日本シェーグレン症候群学会 学術奨励賞, 日本シェーグレン症候群学会, 2013.09.
日本口腔外科学会 学術奨励賞, 日本口腔外科学会, 2013.09.
ポスター優秀賞, 第62回 日本口腔科学会総会, 2008.04.
九州大学学生後援会学術研究賞, 九州大学学生後援会, 2007.04.
メダルティス賞（口演部門）, 第51回 日本口腔外科学会総会, 2006.10.
Award for the oral presentation, 8th Biennial Congress of the European Association of Oral Medicine, 2006.09.
研究資金
科学研究費補助金の採択状況(文部科学省、日本学術振興会)
2023年度～2027年度, 海外連携研究, 代表, IgG4関連疾患の疾患特異的自己抗原の同定 -新たな診断方法と治療薬の開発-.
2022年度～2024年度, 挑戦的研究（萌芽）, 代表, Toll様受容体8に着目したシェーグレン症候群の新たな診断・治療戦略.
2021年度～2023年度, 基盤研究(B), 代表, Toll様受容体7シグナルに着目したIgG4関連疾患の新規治療法の開発.
2021年度～2024年度, 基盤研究(C), 分担, インプラントガイドシステムを応用した上顎骨の高精度位置決め法の確立.
2020年度～2022年度, 基盤研究(A), 分担, IgG4関連疾患の免疫学的特異性を基盤とした病因解明と疾患モデルマウスによる検証.
2020年度～2022年度, 基盤研究(C), 分担, 唾液中の可溶性分子を用いたシェーグレン症候群の病因解析と新たな診断方法の開発.
2019年度～2022年度, 基盤研究(B), 分担, IgG4関連疾患とその世界初モデルマウスにおける臓器線維化メカニズム解明.
2019年度～2021年度, 挑戦的研究（萌芽）, 分担, 唾液中の可溶性マーカーに着目したIgG4関連疾患の新たな診断方法の開発.
2019年度～2021年度, 基盤研究(C), 分担, シェーグレン症候群、IgG4関連涙腺唾液腺炎における腸内細菌叢と病態の関係の解明.
2018年度～2020年度, 基盤研究(B), 代表, Toll様受容体を標的としたシェーグレン症候群の新規治療戦略.
2018年度～2021年度, 国際共同研究強化(B), 分担, IgG4関連疾患の病因解明と新規治療戦略 -特異なT・B細胞を標的として-.
2017年度～2019年度, 基盤研究(A), 分担, IgG4関連疾患の病因解明とマウス疾患モデルの作製による検証.
2017年度～2020年度, 基盤研究(B), 代表, 日米共同研究によるIgG4関連疾患の国際的疾患概念の構築と新規診断法への展開.
2016年度～2018年度, 基盤研究(C), 分担, シェーグレン症候群と腸内細菌叢の構成異常・腸管免疫の関係の解明.
2016年度～2018年度, 基盤研究(C), 分担, HTLV-1関連シェーグレン症候群の病態解明に向けた免疫学的検討.
2015年度～2017年度, 基盤研究(C), 分担, 唾液を用いたシェーグレン症候群の診断および重症度分類法の確立.
2015年度～2017年度, 基盤研究(C), 分担, シェーグレン症候群国際診断基準への超音波診断導入のための基礎的研究.
2014年度～2016年度, 挑戦的萌芽研究, 分担, IgG4 関連疾患の診断における唾液腺検査の有用性の検討.
2014年度～2016年度, 挑戦的萌芽研究, 代表, LH-PCR法と次世代シーケンサーを用いた口腔カンジダ症の新たな診断方法の確立.
2014年度～2017年度, 基盤研究(B), 代表, 新疾患概念「IgG4関連疾患」の病態解明に向けた自然免疫からの新戦略.
2012年度～2014年度, 基盤研究(C), 分担, 近赤外線、ＭＲＩ、超音波を用いたシェーグレン症候群の非侵襲的画像診断法の確立.
2011年度～2013年度, 挑戦的萌芽研究, 分担, ドライマウスの診断方法の確立 ～唾液を用いた新しい鑑別診断方法～.
2010年度～2013年度, 若手研究(B), 代表, 新疾患概念「ミクリッツ病／IgG4関連疾患」の病因解明に向けての分子生物学的検討.
2008年度～2009年度, 若手研究(B), 代表, シェーグレン症候群とミクリッツ病／IgG4関連疾患の新概念.
科学研究費補助金の採択状況(文部科学省、日本学術振興会以外)
2018年度～2018年度, 臨床医学振興財団, 代表, 歯髄幹細胞の上清を用いたシェーグレン症候群の新たな治療戦略
.
.
2022年度～2022年度, 徳島大学先端酵素学研究所「(B) 共同研究」, 代表, 自然免疫を基盤とした慢性難治性唾液腺疾患の新規治療戦略.
2016年度～2016年度, QRプロジェクト わかば研究 研究助成, 代表, 腫瘍随伴性マクロファージを標的とした口腔扁平上皮癌の新規治療戦略.
2015年度～2016年度, 上原記念生命科学財団 研究奨励（臨床研究）, 代表, M2 マクロファージを標的としたIgG4 関連疾患の新規治療.
2015年度～2016年度, 臨床医学振興財団 研究助成, 代表, IgG4関連疾患の病態形成における自然免疫担当細胞の関与.
2013年度～2014年度, 武田科学振興財団 医学系奨励, 代表, ミクリッツ病／IgG4関連疾患の病態解明および新規分子治療の開発.
2013年度～2014年度, 福岡県すこやか健康事業団 がん研究助成金, 代表, 口腔扁平上皮癌の増殖・転移における腫瘍随伴性マクロファージの関与.
2013年度～2014年度, 公益財団法人 臨床奨励基金, 代表, IgG4関連疾患の新規標的分子の同定 −DNAマイクロアレイによる発現変動遺伝子の網羅的解析−.
共同研究、受託研究(競争的資金を除く)の受入状況
2017.04～2018.03, 分担, 国内初の汎用自動分析装置用IgG4測定試薬の多施設での評価.
2018.08～2020.03, 分担, GPR56を標的とした加齢に伴う自己免疫疾患の診断及び治療薬の開発研究.
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