Updated on 2024/08/17

Information

 

写真a

 
MAEHARA TAKASHI
 
Organization
Kyushu University Hospital Oral Surgery Lecturer
School of Dentistry Department of Dentistry(Concurrent)
Graduate School of Dental Science (Concurrent)
Graduate School of Dental Science Department of Dental Science(Concurrent)
Title
Lecturer
Contact information
メールアドレス
Tel
0926426447
Profile
【臨床について】口腔外科全般、特に口腔癌に関わる診療や手術を専門とする。  2023年より口腔癌部会の部会長として、口腔癌を専門として手術および治療を行なっている。 【研究について】 2015年から2018年の3年間は、ハーバード大学のRagon Instituteに留学し、『自己免疫疾患および慢性炎症性疾患の病態解明に向けた研究』に従事してきた。 具体的には、日米国際共同研究によるIgG4関連疾患の病態形成メカニズムの解明と新規治療法開発。IgG4関連疾患におけるCD4+細胞障害性T 細胞(CD4+CTLs)に関する研究。シェーグレン症候群の病態形成におけるT細胞の働きに関する研究。強皮症の病態形成におけるT細胞の働きに関する研究。口腔扁平苔癬の病態形成におけるT細胞に関する研究。 (口腔扁平上皮癌や前癌病変に対する治療標的分子の解明に向けた研究) 口腔扁平上皮癌や前癌病変におけるT細胞に関する研究。口腔癌の臨床統計学的な研究。などの研究に従事している。 【教育について】 手術手技の指導、大学院生の研究指導、歯学部学生の臨床実習指導、研修医の臨床指導を行っている。
External link

Degree

  • Doctor of Dental Science

  • Doctor of Philosophy

Research History

  • 九州大学病院 顎口腔外科 講師

    2024.4 - Present

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  • Kyushu University Faculty of Dental Science Assistant Professor

    2018.4 - 2023.3

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  • Kyushu University School of Dentistry

    - 2007.3

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Research Interests・Research Keywords

  • Research theme:IgG4関連疾患

    Keyword:IgG4関連疾患

    Research period: 2024

  • Research theme:シェーグレン症候群

    Keyword:シェーグレン症候群

    Research period: 2024

  • Research theme:全身性強皮症

    Keyword:全身性強皮症

    Research period: 2024

  • Research theme:OSCC

    Keyword:OSCC

    Research period: 2024

  • Research theme:口腔扁平苔癬

    Keyword:口腔扁平苔癬

    Research period: 2024

  • Research theme:International joint research、IgG4-related disease

    Keyword:IgG4-related disease

    Research period: 2018.7 - 2022.7

  • Research theme:IgG4-related disease

    Keyword:International joint research、IgG4-related disease

    Research period: 2018.4 - 2018.12

  • Research theme:International joint research for Systemic sclerosis

    Keyword:systemic sclerosis, SSc

    Research period: 2017.1 - 2020.12

  • Research theme:Oral lichen planus

    Keyword:Oral Lichen Planus、Th subsets

    Research period: 2016.4 - 2018.12

  • Research theme:New analysis of pathogenesis of IgG4-related disease - Th cells and Type 2 Innate lymphoid cells -

    Keyword:CD4+T cells, B cells, Th2, CD4+CTL, Tfh

    Research period: 2016.4 - 2018.3

  • Research theme:Perform further Tossue FAXS studies on T cell subsets and repertoire in IgG4-RD and other diseases including SS also examining mechanism of fibrosis, before and after Rituximab Therapy

    Keyword:Tissue FAXS、T cell subsets、IgG4-related disease、SS、Rituximab

    Research period: 2015.3 - 2016.3

  • Research theme:IgG4-related disease

    Keyword:IgG4-related disease、ectopic germinal center、Th cell

    Research period: 2014.4 - 2016.3

Awards

  • 優秀ポスター賞

    2024.2   日本口腔腫瘍学会  

  • 九大歯学優秀研究者賞

    2021.10   九州大学歯学研究院   Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis. The Journal of Clinical Investigation に論文がアクセプトされた。

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    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+ 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.

  • Web学会賞 令和2年度口腔科学会

    2020.8   日本口腔科学会   ノミネート演題として発表し優秀ポスター賞を拝受した。

  • 九大歯学優秀研究者賞(FWCI部門)

    2019.10   九州大学   過去5年のSciValのField Weighted Citation Impact (FWCI)の値が最も高く、5年間の論文数が20を超える上位2名の研究者

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    過去5年のSciValのField Weighted Citation Impact (FWCI)の値が最も高く、5年間の論文数が20を超える上位2名の研究者が受賞

  • 第64回 日本口腔外科学会 優秀ポスター賞

    2019.10   第64回 日本口腔外科学会総会   ノミネート演題として発表し優秀ポスター賞を拝受した。

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    【緒言】全身性強皮症(SSc)は、全身性の免疫異常に伴う皮膚、肺、心臓、腎臓などの多臓器に不可逆性の線維化とそれに伴う血管病変を呈する自己免疫疾患である。未だ免疫異常の原因となる疾患特異的なCD4+T (Th) 細胞は不明で、有効な治療法が無い難病である。そこで本研究では、次世代シークエンス解析により疾患特異的なTh細胞を同定し、分子標的薬治療の有効性を明らかとした。
    【対象・方法】 SSc患者35例と比較対象疾患の末梢血と罹患臓器を用いた。1) SScで特異的に増加するTh細胞の検索 2) CD4+細胞障害性T細胞(CD4+SLAMF7+CTL)を分離採取し遺伝子発現を解析3)T cell receptorレパトア解析にてCD4+CTLのクローナリティを検索4) 多重蛍光免疫染色にて発現サイトカインを同定 5) 罹患臓器のアポトーシス細胞の検索 6) CD4+CTLを標的とした分子標的薬治療の検証を行った。
    【結果】SScの末梢血と罹患臓器でCD4+CTLが増加していた。シングルセルソーティングしたCD4+CTLは、遺伝子機能分類によりHLA-class IIシグナルにて活性化し、細胞障害性を強く発現した表現系であった。レパトア解析によりCD4+CTLはオリゴクローナルに増加し、罹患臓器で細胞障害性タンパク質を発現していた。アポトーシス細胞の多くは血管内細胞であった。治療後の患者末梢血中のCD4+CTLは減少した。
    【結論】SScの病態形成にはCD4+CTLが深く関与し、この細胞に対する分子標的薬治療が有効であることが示唆された。

  • 第73回 優秀ポスター賞

    2019.4   日本口腔科学会 (第73回学術集会)  

  • 医学系研究助成

    2018.11   公益財団法人 武田科学振興財団  

  • 第63回 日本口腔外科学会 優秀講演発表賞

    2018.11   日本口腔外科学会   Clonalに増殖したCD4+CTLとTfh細胞はIgG4関連疾患の病態形成に関与する

  • 第63回 日本口腔外科学会  李 春根賞 (最優秀講演発表賞)

    2018.11   日本口腔外科学会   Clonalに増殖したCD4+CTLとTfh細胞はIgG4関連疾患の病態形成に関与する

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    IgG4関連疾患の病態解明と新規治療薬開発に向けた、国際共同研究内容について発表した。

  • 学術奨励賞

    2018.11   第46回 日本臨床免疫学会総会  

  • 研究奨励金

    2018.4   上原記念生命化学財団   日米共同研究 IgG4 関連疾患の病因解明への新戦略

  • 日本シェーグレン症候群学会 学術奨励賞

    2017.10   日本シェーグレン症候群学会   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.

  • 平成28年度 留学補助金

    2016.10   持田記念医学薬学振興財団   IgG4関連疾患の病因解明とその制御による新規治療法の開発

  • 第44回 かなえ医薬振興財団 海外留学助成金

    2015.10   かなえ医薬振興財団   「Clonally expanede CD4+ cytotoxic T lymphocytes in IgG4-related disease」

  • 日本口腔科学会 学会賞優秀発表賞

    2010.6   日本口腔科学会   「シェーグレン症候群の病変局所におけるThサブセットの局在」

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Papers

  • Granzyme K- and amphiregulin-expressing cytotoxic T cells and activated extrafollicular B cells are potential drivers of IgG4-related disease Reviewed International journal

    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

    J Allergy Clin Immunol   153 ( 4 )   1095 - 1112   2023.12   ISSN:0091-6749 eISSN:1097-6825

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

    BACKGROUND: IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound healing. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified. OBJECTIVE: We performed single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) and B-cell receptor (BCR) sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T- and B-cells. METHODS: We performed unbiased scRNA-seq analysis for the transcriptome and TCR-seq and BCR-seq on sorted CD3+ T- or CD19+ B-cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3+ T and CD19+ B subsets in 68 IgG4-RD and 30 Sjögren's syndrome (SjS) patients. RESULTS: Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4+ cytotoxic T cells (CTLs) or GZMK+CD8+ T cells. These GZMK-expressing CTLs also expressed amphiregulin and TGFβ but did not express immune-checkpoints, and the tissue-infiltrating CD8+ T cells were phenotypically heterogeneous. MKI67+ B cells and IgD-CD27-CD11c-CXCR5- double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK+CD4+ CTLs co-localized with MKI67+ B cells in the extrafollicular area from affected tissue sites. CONCLUSION: The abovementioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4+ and CD8+ T cells expressing GZMK, amphiregulin, and TGFβ in the pathogenesis of inflammatory fibrotic disorders.

    DOI: 10.1016/j.jaci.2023.11.916

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  • Single-cell transcriptomics reveals granzyme K-expressing cytotoxic Tfh cells in tertiary lymphoid structures in IgG4-RD Invited Reviewed International journal

    Ryuichi Aoyagi, Takashi Maehara, Risako Koga, Ryusuke Munemura, Tadashi Tomonaga, Yuka Murakami, Atsushi Doi, Hidetaka Yamamoto , Tamotsu Kiyoshima, Shintaro Kawano, Seiji Nakamura

    J Allergy Clin Immunol   153 ( 2 )   513 - 520.e10   2023.8   ISSN:0091-6749 eISSN:1097-6825

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    BACKGROUND: Germinal center (GC) responses controlled by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells are crucial for the generation of high-affinity antibodies. Acquired immune responses to tissue-released antigens might be mainly induced in tertiary lymphoid organs (TLOs) with GCs in affected tissues. IgG4-related disease (IgG4-RD) demonstrates polarized isotype switching and TLOs in affected tissues. We performed single-cell transcriptomics of tissue-infiltrating T cells from these TLOs to obtain a comprehensive, unbiased view of tissue-infiltrating GC-Tfh cells. OBJECTIVE: To identify GC-Tfh-cell subsets in TLOs in patients with IgG4-RD using single-cell transcriptomics. METHODS: Single-cell RNA sequencing of sorted CD3+ T cells and multicolor immunofluorescence analysis were used to investigate CD4+CXCR5+Bcl6+ GC-Tfh cells in affected lesions from patients with IgG4-RD. RESULTS: Infiltrating CD4+CXCR5+Bcl6+ Tfh cells were divided into 5 main clusters. We detected HLA+ granzyme K+ (GZMK+) Tfh cells with cytotoxicity-associated features in patients with IgG4-RD. We also observed abundant infiltrating Tfr cells with suppressor-associated features in patients with IgG4-RD. These GZMK+ Tfh cells and Tfr cells clustered together in affected tissues from patients with IgG4-RD. CONCLUSIONS: This single-cell data set revealed a novel subset of HLA+GZMK+ cytotoxic Tfh cells infiltrating affected organs in patients with IgG4-RD, suggesting that infiltrating Tfr cells might suppress cytotoxic Tfh cells.

    DOI: 10.1016/j.jaci.2023.08.019

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  • Immune dysregulation in immunoglobulin G4-related disease. Invited Reviewed International journal

    Maehara T, Koga R, Nakamura S.

    Jpn Dent Sci Rev.   2023.6

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  • Distinct disease-specific Tfh cell populations in two different fibrotic diseases: IgG4- related disease and Kimura’s disease Reviewed International journal

    2022.4

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

    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.)

    DOI: doi: 10.1016/j.jaci.2022.03.034.

  • CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease Reviewed International journal

    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

    J Allergy Clin Immunol   2020.5

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  • Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis Reviewed

    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

    Journal of Clinical Investigation   130 ( 5 )   2451 - 2464   2020.5

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    DOI: 10.1172/JCI131700

  • A novel disease entity IgG4-related disease, including so-called Mikulicz's disease and Kuttner's tumor Invited Reviewed International journal

    Takashi Maehara, Masafumi Moriyama, Seiji Nakamura

    KAOMS   2020.1

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  • B lymphocytes contribute to stromal reaction in pancreatic ductal adenocarcinoma Reviewed

    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

    OncoImmunology   9 ( 1 )   2020.1

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

    DOI: 10.1080/2162402X.2020.1794359

  • Cytotoxic CD4+T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis Reviewed International journal

    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.

    Journal of Clinical Investigation   2019.12

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  • Tissue-infiltrating immune cells contribute to understanding the pathogenesis of Kimura's Disease: a case report Reviewed International journal

    Takashi Maehara, Ryusuke Minemura, Mayumi Shimizu, Noriko Kakizoe, Naoki Kaneko, Moriyama Masafumi, Yuka Murakami, Tamotsu Kiyoshima, Shintaro Kawano, Seiji Nakamura.

    Medicine   2019.11

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  • B lymphocytes directly contribute to tissue fibrosis in IgG4-Related Disease. Reviewed International journal

    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.

    J Allergy Clin Immunol   2019.7

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    DOI: 10.1016/j.jaci.2019.07.004

  • Osteoid osteoma of mandibular bone: Case report and review of the literature Reviewed International journal

    Takashi Maehara, Yuka Murakami, Shintaro Kawano, Yurie Mikami, Tamotsu Kiyoshima, Toru Chikui, Noriko Kakizoe, Ryusuke Munemura, Seiji Nakamura

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   2019.4

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  • Clinical Features and Mechanistic Insights Regarding IgG4-Related Dacryoadenitis and Sialoadenitis: a review Reviewed International journal

    Takashi Maehara, Shiv Pillai, John H Stone, and Seiji Nakamura

    International Journal of Oral & Maxillofacial Surgery   2018.11

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  • High-frequency, functional HIV-specific T-follicular helper and regulatory cells are present within germinal centers in children but not adults. Invited Reviewed International journal

    Frontiers in Immunology   2018.8

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  • Pathogenesis of IgG4-related disease: a critical review. Invited Reviewed International journal

    Maehara T, Moriyama M, Nakamura S.

    Odontology   2018.7

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

    DOI: doi: 10.1007/s10266-018-0377-y.

  • The expansion in lymphoid organs of IL-4+BATF+T follicular helper cells is linked to IgG4 class switching in vivo. Reviewed International journal

    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.

    Life Science Alliance.   2018.4

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

    DOI: 10.26508/lsa.201800050

    Other Link: http://www.life-science-alliance.org/content/1/1/e201800050

  • IgG4-related disease: Insights into human immunology and targeted therapies. Reviewed International journal

    Perugino CA, Matto H, Mahajan VS, Maehara T, Wallace ZS, Pillai S, Stone JH.

    Arthritis Rheumatol. 2017 Sep;69(9):1722-1732.   2017.9

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  • IgG4-related disease –Mechanistic insights from both clinical and immunologic understanding of this condition. Invited Reviewed International journal

    2017.5

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  • Lesional CD4+IFN-gamma+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis. Reviewed International journal

    Maehara T, Mattoo H, Ohta M, Mahajan V, Moriyama M, Yamauchi M, Drijvers S, Nakamura S, Stone JH, Pillai S.

    Ann. Rheum. Dis. 2017 Feb;76(2):377-385.   2017.2

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  • Clonal expansion of CD4+ cytotoxic T lymphocytes in patients with IgG4-related disease. Invited Reviewed International journal

    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.

    J Allergy Clin Immunol. 2016 Sep;138(3):825-38.   2016.9

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  • Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz’s disease. Invited Reviewed International journal

    2012.12

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  • Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease Reviewed

    Takashi Maehara, Masafumi Moriyama, Hitoshi Nakashima, Katsuhisa Miyake, Jun Nosuke Hayashida, Akihiko Tanaka, Shouichi Shinozaki, Yoshiaki Kubo, Seiji Nakamura

    Annals of the Rheumatic Diseases   71 ( 12 )   2011 - 2019   2012.12

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    DOI: 10.1136/annrheumdis-2012-201477

  • Selective localization of T helper subsets in labial salivary glands from primary Sjogren’s syndrome patietns. Invited Reviewed International journal

    2012.8

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  • Wnt/β-catenin-C-kit axis may play a role in adenoid cystic carcinoma prognostication

    Shinsuke Fujii, Kana Hasegawa, Takashi Maehara, Kari J Kurppa, Kristiina Heikinheimo, Kristy A. Warner, Satoshi Maruyama, Yudai Tajiri, Jacques E. Nör, Jun-ichi Tanuma, Shintaro Kawano, Tamotsu Kiyoshima

    Pathology - Research and Practice   254   155148 - 155148   2024.2   ISSN:0344-0338 eISSN:1618-0631

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  • Immune dysregulation in immunoglobulin G4-related disease

    Maehara, T; Koga, R; Nakamura, S

    JAPANESE DENTAL SCIENCE REVIEW   59   1 - 7   2023.12   ISSN:1882-7616 eISSN:2213-6851

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    (IgG4-RD) is an immune-mediated fibrotic disorder characterized by severe resolution of inflammation and dysregulation of wound healing. IgG4-RD has been considered a unique disease since 2003, and significant progress has been achieved in the understanding of its essential features. The central role of B cells in IgG4-RD has been demonstrated by the robust clinical responsiveness of IgG4-RD to B cell depletion and the identification of multiple self-antigens that promote B cell expansion. Studies have increasingly revealed critical roles of these B cells and T cells in the pathogenesis of IgG4-RD, and we and other authors further identified CD4+ cytotoxic T lymphocytes as the main tissue-infiltrating CD4+ T cell subset in IgG4-RD tissues. Additionally, T follicular helper cell subsets that play a role in IgG4 isotype switching have been identified. In this review, we discuss research on IgG4-RD and the roles of B cell and T cell subsets, as well as the functions of CD4+ cytotoxic T cells in IgG4-RD pathogenesis. We highlight our findings from ongoing research using single-cell analysis of infiltrating CD4+ cytotoxic T cells, CD4+ follicular helper T cells, and infiltrating B cells in IgG4-RD and propose a model for the pathogenesis of IgG4-RD.

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  • Extrafollicular IgD−CD27−CXCR5−CD11c− DN3 B cells infiltrate inflamed tissues in autoimmune fibrosis and in severe COVID-19

    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

    Cell Reports   42 ( 6 )   112630 - 112630   2023.6   ISSN:2211-1247

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  • Cytotoxic CD8+ T cells may be drivers of tissue destruction in Sjögren's syndrome. International journal

    Naoki Kaneko, Hu Chen, Cory A Perugino, Takashi Maehara, Ryusuke Munemura, Shiho Yokomizo, Junsei Sameshima, Thomas J Diefenbach, Katherine R Premo, Akira Chinju, Yuka Miyahara, Mizuki Sakamoto, Masafumi Moriyama, John H Stone, Seiji Nakamura, Shiv Pillai

    Scientific reports   12 ( 1 )   15427 - 15427   2022.9   ISSN:2045-2322

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    Sjögren's syndrome is a chronic autoimmune disorder whose pathogenesis is poorly understood and that lacks effective therapies. Detailed quantitative and spatial analyses of tissues affected by Sjögren's syndrome were undertaken, including the quantitation of the frequency of selected cell-cell interactions in the disease milieu. Quantitative analyses of CD4+ T cell subsets and of CD8+ T cells in the labial salivary glands from untreated patients with primary Sjögren's syndrome revealed that activated CD8+ cytotoxic T cells (CD8+CTLs) were the most prominent T cells in these infiltrates. An accumulation of apoptotic glandular epithelial cells, mainly ductal and acinar cells, was observed, consistent with the impaired salivary secretion often observed in patients with this disease. FasL expressing activated CD8+ T cells were seen to accumulate around Fas expressing apoptotic epithelial cells. Quantitative analyses of apoptotic cell types and of conjugates between cytotoxic T cells and epithelial cells undergoing apoptosis suggest that Sjögren's syndrome is primarily driven by CD8+CTL mediated execution of epithelial cells mainly represented by ductal and acinar cells.

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  • Distinct disease-specific Tfh cell populations in two different fibrotic diseases: IgG4-related disease and Kimura's disease. International journal

    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

    The Journal of allergy and clinical immunology   150 ( 2 )   440 - +   2022.8   ISSN:0091-6749 eISSN:1097-6825

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    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 (SLOs and TLOs) in patients with elevated tissue expression levels of IgE (Kimura's disease, KD) and those of IgG4 (IgG4-related disease, IgG4-RD) can provide important insights regarding cytokine expression by Tfh cells. OBJECTIVE: To identify disease-specific Tfh cell subsets in SLOs and TLOs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in two 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 multi-color immunofluorescence analysis was 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 TLOs from IgG4-RD were divided into six main clusters. We encountered abundant infiltrating IL-10-expressing LAG3+ Tfh cells in patients with IgG4-RD. Furthermore, we found that infiltrating AID+CD19+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, and in contrast Type 2 immune cells were abundant in KD. CONCLUSIONS: This single-cell dataset revealed a novel subset of IL10+LAG3+Tfh cells infiltrating the affected organs of IgG4-RD patients. In contrast, IL13+Tfh cells and type 2 immune cells infiltrated those of KD patients.

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  • Clear cell squamous cell carcinoma of the tongue exhibits characteristics as an undifferentiated squamous cell carcinoma. International journal

    Kana Hasegawa, Shinsuke Fujii, Kari J Kurppa, Takashi Maehara, Kazunari Oobu, Seiji Nakamura, Tamotsu Kiyoshima

    Pathology, research and practice   235   153909 - 153909   2022.7   ISSN:03440338

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    Clear cell squamous cell carcinoma (CCSCC), where cells show abundant clear cytoplasm, -is a variant of squamous cell carcinoma (SCC) and a rare entity in the oral cavity. The characteristics of CCSCC, especially in immunohistochemical features, remain unclear. We characterized a case of CCSCC arising from the oral mucosal epithelium of tongue, where the clear cell lesion accounted for a predominant portion of the tumor. This CCSCC, which was partially surrounded by conventional SCC, exhibited cellular atypia immunohistopathologically and histopathologically with a high Ki-67 index, increased number of mitotic figures and enlarged nuclei. Intravascular invasion of the carcinoma cells was also observed. Furthermore, the CCSCC recurred and metastasized to the cervical lymph nodes and both lungs three months after resection. Immunohistochemical analyses demonstrated decreased expression of p40 (an isoform of SCC marker p63), ADP-ribosylation factor (ARF)-like 4c (ARL4C), yes-associated protein (YAP) and 5-methylcytosine (5mC) in the CCSCC lesion compared with the surrounding SCC lesion, where the expression of ARL4C was upregulated compared with non-tumor region and YAP showed nuclear translocation. In addition, siRNA loss-of-function experiments revealed that p63 expression was required for ARL4C expression and DNA methylation was induced by p63 and YAP/transcriptional co-activator with PDZ-binding motif (TAZ) signaling in oral SCC cell lines. These results suggest that CCSCC, in which several markers of SCC-associated intracellular signaling pathways are downregulated, together with evidence of altered epigenetic regulation, is characterized as an undifferentiated SCC variant.

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  • CD163+M2 Macrophages Promote Fibrosis in IgG4-Related Disease Via Toll-Like Receptor 7/Interleukin-1 Receptor-Associated Kinase 4/NF-kappa B Signaling

    Chinju, A; Moriyama, M; Kakizoe-Ishiguro, N; Chen, H; Miyahara, Y; Haque, ASMR; Furusho, K; Sakamoto, M; Kai, K; Kibe, K; Hatakeyama-Furukawa, S; Ito-Ohta, M; Maehara, T; Nakamura, S

    ARTHRITIS & RHEUMATOLOGY   74 ( 5 )   892 - 901   2022.5   ISSN:2326-5191 eISSN:2326-5205

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    Objective: IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition that can affect multiple organs. We previously demonstrated that TLR7-transgenic C57BL/6 mice showed elevated serum IgG1 levels and inflammation with fibrosis in the salivary glands (SGs), lungs, and pancreas. Moreover, we observed extensive Toll-like receptor 7 (TLR-7)–positive CD163+ M2 macrophage infiltration in SGs from IgG4-RD patients. We undertook this study to examine the fibrotic mechanism via the TLR-7 pathway. Methods: Gene expression in SGs from human TLR7-transgenic mice and IgG4-RD patients was analyzed using DNA microarrays. We extracted the common up-regulated TLR-7–related genes in SGs from TLR7-transgenic mice and IgG4-RD patients. Finally, we investigated the interaction between CD163+ M2 macrophages and fibroblasts before and after stimulation with the TLR-7 agonist loxoribine. Results: In TLR7-transgenic mice and IgG4-RD patients, IRAK3 and IRAK4 were significantly overexpressed. Real-time polymerase chain reaction validated the up-regulation of only IRAK4 in IgG4-RD patients compared with the other groups (P < 0.05). Interleukin-1 receptor–associated kinase 4 (IRAK4) was strongly detected in and around germinal centers in SGs from patients with IgG4-related dacryoadenitis and sialadenitis alone. Double immunofluorescence staining showed that IRAK4-positive cells were mainly colocalized with CD163+ M2 macrophages in SGs (P < 0.05). After stimulation with loxoribine, CD163+ M2 macrophages exhibited significantly enhanced expression of IRAK4 and NF-κB and increased supernatant concentrations of fibrotic cytokines. Finally, we confirmed that the number of fibroblasts was increased by culture with the supernatant of CD163+ M2 macrophages following stimulation with loxoribine (P < 0.05). Conclusion: CD163+ M2 macrophages promote fibrosis in IgG4-RD by increasing the production of fibrotic cytokines via TLR-7/IRAK4/NF-κB signaling.

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  • Orchestration of Immune Cells Contributes to Fibrosis in IgG4-Related Disease

    Kaneko, N; Moriyama, M; Maehara, T; Chen, H; Miyahara, Y; Nakamura, S

    IMMUNO   2 ( 1 )   170 - 184   2022.3   eISSN:2673-5601

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    <jats:p>This review summarizes recent progress in understanding the pathogenesis of IgG4-related disease (IgG4-RD), with a focus on fibrosis. Several studies reported that CD4+ T cells with cytotoxic activity promoted by the secretion of granzyme and perforin, cytotoxic CD4+ T cells (CD4+CTLs), and disease-specific activated B cells, infiltrated inflamed tissues and cooperated to induce tissue fibrosis in autoimmune fibrotic diseases such as IgG4-RD, systemic sclerosis, and fibrosing mediastinitis. An accumulation of cells undergoing apoptotic cell death induced by CD4+CTLs and CD8+CTLs followed by macrophage-mediated clearing and finally tissue remodeling driven by cytokines released by CD4+CTLs, activated B cells, and M2 macrophages may contribute to the activation of fibroblasts and collagen production. In IgG4-RD, this process likely involves the apoptosis of non-immune, non-endothelial cells of mesenchymal origin and subsequent tissue remodeling. In summary, CD4+CTLs infiltrate affected tissues where they may cooperate with activated B cells, CD8+CTLs, and M2 macrophages, to induce apoptosis by secreting cytotoxic cytokines. These immune cells also drive fibrosis by secreting pro-fibrotic molecules in IgG4-RD.</jats:p>

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  • Neutralizing anti–IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease

    Jarrell J.A., Baker M.C., Perugino C.A., Liu H., Bloom M.S., Maehara T., Wong H.H., Lanz T.V., Adamska J.Z., Kongpachith S., Sokolove J., Stone J.H., Pillai S.S., Robinson W.H.

    Journal of Allergy and Clinical Immunology   149 ( 1 )   358 - 368   2022.1   ISSN:00916749

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    Background: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. Objective: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. Methods: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti–IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. Results: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti–IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti–IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti–IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti–IL-1RA autoantibodies compared with those of the controls. Conclusion: A subset of patients with IgG4-RD have anti–IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti–IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.

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  • Distinct disease-specific Tfh cell populations in two different fibrotic diseases: IgG4-related disease and Kimura's disease. Reviewed International coauthorship

    宗村 龍祐, 前原 隆, 中村 誠司

    Journal of Allergy and Clinical Immunology   in press   2022

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  • CD163+ M2 macrophages promote fibrosis in IgG4-related disease via TLR7/IRAK4/NF-κB signaling. Reviewed International journal

    2021.12

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  • Association of circulating SLAMF7+Tfh1 cells with IgG4 levels in patients with IgG4-related disease Reviewed

    Kazuhiko Higashioka, Yuri Ota, Takashi Maehara, Masafumi Moriyama, Masahiro Ayano, Hiroki Mitoma, Mitsuteru Akahoshi, Yojiro Arinobu, Takahiko Horiuchi, Seiji Nakamura, Koichi Akashi, Hiroaki Niiro

    BMC Immunology   21 ( 1 )   2020.6

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    DOI: 10.1186/s12865-020-00361-0

  • 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 Reviewed

    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

    Modern Rheumatology   30 ( 2 )   379 - 384   2020.3

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    DOI: 10.1080/14397595.2019.1576271

  • Review of a novel disease entity, immunoglobulin G4-related disease Reviewed

    Takashi Maehara, Masafumi Moriyama, Seiji Nakamura

    Journal of the Korean Association of Oral and Maxillofacial Surgeons   46 ( 1 )   3 - 11   2020.2

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  • Activated M2 macrophage contributes to the pathogenesis of IgG4-related disease via TLR7/IL-33 signaling Invited Reviewed International journal

    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

    Arthritis & Rheumatology   2020.1

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  • Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-like Receptor 7/Interleukin-33 Signaling Reviewed

    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

    Arthritis and Rheumatology   72 ( 1 )   166 - 178   2020.1

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  • Association of circulating SLAMF7+Tfh1 cells with IgG4 levels in patients with IgG4-related disease. Reviewed International journal

    Kazuhiko Higashiosa, Yuri Ota, Takashi Maehara, Masafumi Moriyama, Masahiro Ayano, Hiroki Mitoma, Mitsuteru Akahoshi, Yojiro Arinobu, Takahiko Horiuchi, Seiji Nakamura, Koichi Akashi, Hiroaki Niiro.

    BMC Immunology   2020.1

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  • CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease Reviewed

    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

    Journal of Allergy and Clinical Immunology   2020

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  • CD206+ tumor-associated macrophages promote proliferation and invasion in oral squamous cell carcinoma via EGF production Invited Reviewed International journal

    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

    Scientific reports   2019.12

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  • CD206+ tumor-associated macrophages promote proliferation and invasion in oral squamous cell carcinoma via EGF production Reviewed

    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

    Scientific reports   9 ( 1 )   2019.12

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    DOI: 10.1038/s41598-019-51149-1

  • Osteoid osteoma of mandibular bone Case report and review of the literature Reviewed

    Takashi Maehara, Yuka Murakami, Shintaro Kawano, Yurie Mikami, Tamotsu Kiyoshima, Toru Chikui, Noriko Kakizoe, Ryusuke Munemura, Seiji Nakamura

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   31 ( 5 )   322 - 326   2019.9

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  • Clinical features and mechanistic insights regarding IgG4-related dacryoadenitis and sialoadenitis a review Reviewed

    T. Maehara, S. Pillai, J. H. Stone, S. Nakamura

    International Journal of Oral and Maxillofacial Surgery   48 ( 7 )   908 - 916   2019.7

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  • Pathogenesis of IgG4-related disease a critical review Reviewed

    Takashi Maehara, Masafumi Moriyama, Seiji Nakamura

    Odontology   107 ( 2 )   127 - 132   2019.4

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    DOI: 10.1007/s10266-018-0377-y

  • Tissue-infiltrating immune cells contribute to understanding the pathogenesis of Kimura disease A case report Reviewed

    Takashi Maehara, Ryusuke Munemura, Mayumi Shimizu, Noriko Kakizoe, Naoki Kaneko, Yuka Murakami, Moriyama Masafumi, Tamotsu Kiyoshima, Shintaro Kawano, Seiji Nakamura

    Medicine (United States)   98 ( 50 )   2019

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  • High-frequency, functional HIV-specific T-follicular helper and regulatory cells are present within germinal centers in children but not adults Reviewed

    Frontiers in Immunology   9 ( SEP )   2018.9

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    DOI: 10.3389/fimmu.2018.01975

  • CD163+CD204+ tumor-associated macrophages contribute to T cell regulation via interleukin-10 and PD-L1 production in oral squamous cell carcinoma Reviewed

    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

    Scientific reports   7 ( 1 )   2017.12

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  • CD163+CD204+ tumor-associated macrophages contribute to T cell regulation via interleukin-10 and PD-L1 production in oral squamous cell carcinoma Reviewed International journal

    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

    Scientific Reports   2017.12

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  • Emerging Treatment Models in Rheumatology IgG4-Related Disease: Insights Into Human Immunology and Targeted Therapies Reviewed

    Cory A. Perugino, Hamid Mattoo, Vinay S. Mahajan, Takashi Maehara, Zachary S. Wallace, Shiv Pillai, John H. Stone

    Arthritis and Rheumatology   69 ( 9 )   1722 - 1732   2017.9

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    DOI: 10.1002/art.40168

  • Myeloid dendritic cells stimulated by thymic stromal lymphopoietin promote Th2 immune responses and the pathogenesis of oral lichen planus Reviewed

    Masaki Yamauchi, Masafumi Moriyama, Jun Nosuke Hayashida, Takashi Maehara, Noriko Ishiguro, Keigo Kubota, Sachiko Furukawa, Miho Ohta, Mizuki Sakamoto, Akihiko Tanaka, Seiji Nakamura

    PloS one   12 ( 3 )   2017.3

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  • Myeloid dendritic cells stimulated by thymic stromal lymphopoietin promote Th2 immune responses and the pathogenesis of oral lichen planus Reviewed International journal

    Masaki Yamauchi, Masafumi Moriyama, Hayashida Jun-Nosuke, Takashi Maehara, Noriko Ishiguro, Keigo Kubota, Sachiko Furukawa, Miho Ohta, Mizuki Sakamoto, Akihiko Tanaka, Seiji Nakamura

    PLoS One, 0173017, 12, 3, 2017.03   2017.3

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  • Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease Reviewed International journal

    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

    Scientific Reports   2017.2

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  • Lesional CD4+ IFN-γ+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis Reviewed

    76 ( 2 )   377 - 385   2017.2

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    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.

    DOI: 10.1136/annrheumdis-2016-209139

  • Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease Reviewed

    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

    Scientific reports   7   2017.2

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    DOI: 10.1038/srep42413

  • IgG4-related disease – mechanistic insights from both clinical and immunologic understanding of this condition– Reviewed

    40 ( 3 )   206 - 212   2017.1

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    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.

    DOI: 10.2177/jsci.40.206

  • The diagnostic utility of labial salivary gland biopsy in IgG4-related disease Reviewed International journal

    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

    Modern Rheumatology   2016.9

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  • The diagnostic utility of labial salivary gland biopsy in IgG4-related disease Reviewed

    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

    Modern Rheumatology   26 ( 5 )   725 - 729   2016.9

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    DOI: 10.3109/14397595.2016.1148225

  • Clonal expansion of CD4+ cytotoxic T lymphocytes in patients with IgG4-related disease Reviewed

    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

    Journal of Allergy and Clinical Immunology   138 ( 3 )   825 - 838   2016.9

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    DOI: 10.1016/j.jaci.2015.12.1330

  • Molecular analysis of fungal populations in patients with oral candidiasis using next-generation sequencing Reviewed

    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

    Scientific reports   6   2016.6

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    DOI: 10.1038/srep28110

  • Molecular analysis of fungal populations in patients with oral candidiasis using next-generation sequencing Reviewed International journal

    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

    Scientific Reports   2016.6

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  • DNA microarray analysis of submandibular glands in IgG4-related disease indicates a role for MARCO and other innate immune-related proteins Reviewed International journal

    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

    Medicine   2016.1

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  • DNA microarray analysis of submandibular glands in IgG4-related disease indicates a role for MARCO and other innate immune-related proteins Reviewed

    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

    Medicine (United States)   95 ( 7 )   e2853   2016

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    DOI: 10.1097/MD.0000000000002853

  • A case of mantle cell lymphoma presenting as IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease Invited Reviewed International journal

    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

    World Journal of Surgical Oncology   2015.7

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  • A case of mantle cell lymphoma presenting as IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease Reviewed

    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

    World Journal of Surgical Oncology   13 ( 1 )   2015.7

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    DOI: 10.1186/s12957-015-0644-0

  • Cytokine profiles contribute to understanding the pathogenic difference between Good syndrome and oral lichen planus two case reports and literature review Invited Reviewed International journal

    Takashi Maehara, Masafumi Moriyama, Shintarou Kawano, Hayashida Jun-Nosuke, Sachiko Furukawa, Miho Ohta, Akihiko Tanaka, Masaki Yamauchi, Yukiko Ohyama, Tamotsu Kiyoshima, Seiji Nakamura.

    Medicine (Baltimore). 2015 Apr;94(14):e704. doi: 10.1097/MD.0000000000000704.   2015.4

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  • Cytokine profiles contribute to understanding the pathogenic difference between good syndrome and oral lichen planus Reviewed

    Takashi Maehara, Masafumi Moriyama, Shintaro Kawano, Jun Nosuke Hayashida, Sachiko Furukawa, Miho Ohta, Akihiko Tanaka, Masaki Yamauchi, Yukiko Ohyama, Tamotsu Kiyoshima, Seiji Nakamura

    Medicine (United States)   94 ( 14 )   2015.4

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    DOI: 10.1097/MD.0000000000000704

  • Saliva as a potential tool for diagnosis of dry mouth including Sjögren's syndrome Reviewed

    21 ( 2 )   224 - 231   2015.3

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

    DOI: 10.1111/odi.12252

  • Clinical relevance of Küttner tumour and IgG4-related dacryoadenitis and sialoadenitis Reviewed

    21 ( 2 )   257 - 262   2015.3

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

    DOI: 10.1111/odi.12259

  • Clinical relevance of Küttner tumour and IgG4-related dacryoadenitis and sialoadenitis Reviewed International journal

    2015.3

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  • Saliva as a potential tool for diagnosis of dry mouth including Sjögren's syndrome Reviewed International journal

    2015.3

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  • A case of marginal zone B cell lymphoma mimicking IgG4-related dacryoadenitis and sialoadenitis Reviewed International journal

    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

    World Journal of Surgical Oncology   2015.2

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  • A case of marginal zone B cell lymphoma mimicking IgG4-related dacryoadenitis and sialoadenitis Reviewed

    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

    World Journal of Surgical Oncology   13 ( 1 )   2015.2

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    DOI: 10.1186/s12957-015-0459-z

  • Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease Reviewed International journal

    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

    2015.1

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  • Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease Reviewed

    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

    Clinical Immunology   156 ( 1 )   9 - 18   2015.1

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    DOI: 10.1016/j.clim.2014.10.008

  • Differences of stimulated and unstimulated salivary flow rates in patients with dry mouth Reviewed

    Hayashida Jun-Nosuke, Sakae Minami, Masafumi Moriyama, Takeshi Toyoshima, Shouichi Shinozaki, Akihiko Tanaka, takashi maehara, Seiji Nakamura

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   27 ( 1 )   96 - 101   2015.1

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    DOI: 10.1016/j.ajoms.2014.04.011

  • Differences of stimulated and unstimulated salivary flow rates in patients with dry mouth Reviewed International journal

    Hayashida Jun-Nosuke, Sakae Minami, Masafumi Moriyama, Takeshi Toyoshima, Shouichi Shinozaki, Akihiko Tanaka, Takashi Maehara, Seiji Nakamura

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   2015.1

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  • T helper subsets in Sjogren’s syndrome and IgG4-related dacryoadenitis and sialoadenitis: a critical review. Invited Reviewed International journal

    2014.6

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  • T helper subsets in Sjögren's syndrome and IgG4-related dacryoadenitis and sialoadenitis A critical review Reviewed

    51   81 - 88   2014.6

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    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.

    DOI: 10.1016/j.jaut.2013.07.007

  • Molecular analysis of fungal populations in patients with oral candidiasis using internal transcribed spacer region Reviewed

    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

    PloS one   9 ( 6 )   2014.6

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    DOI: 10.1371/journal.pone.0101156

  • Molecular analysis of fungal populations in patients with oral candidiasis using internal transcribed spacer region Reviewed International journal

    Shinsuke Ieda, Masafumi Moriyama, Toru Takeshita, Takashi Maehara, Yumi Imabayashi, Shoichi Shinozaki, Akihiko Tanaka, Jun-Nosuke Hayashida, Sachiko Furukawa, Miho Ohta, Seiji Nakamura

    PLoS One   2014.5

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  • The diagnostic utility of biopsies from the submandibular and labial salivary glands in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease Reviewed

    Masafumi Moriyama, S. Furukawa, Shintarou Kawano, Y. Goto, Tamotsu Kiyoshima, A. Tanaka, takashi maehara, Hayashida Jun-Nosuke, M. Ohta, Seiji Nakamura

    International Journal of Oral and Maxillofacial Surgery   43 ( 10 )   1276 - 1281   2014.1

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    DOI: 10.1016/j.ijom.2014.06.014

  • The diagnostic utility of biopsies from the submandibular and labial salivary glands in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease Reviewed International journal

    Masafumi Moriyama, S. Furukawa, Shintarou Kawano, Y. Goto, Tamotsu Kiyoshima, A. Tanaka, T. Maehara, Hayashida Jun-Nosuke, M. Ohta, Seiji Nakamura

    International Journal of Oral and Maxillofacial Surgery   2014.1

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  • Clinical characteristics of Mikulicz's disease as an IgG4-related disease Reviewed

    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 Oral Investigations   17 ( 9 )   1995 - 2002   2013.12

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    DOI: 10.1007/s00784-012-0905-z

  • Clinical characteristics of Mikulicz's disease as an IgG4-related disease Reviewed International journal

    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 Oral Investigations   2013.12

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  • Close association between oral Candida species and oral mucosal disorders in patients with xerostomia Reviewed International journal

    S. Shinozaki, Masafumi Moriyama, Hayashida Jun-Nosuke, A. Tanaka, T. Maehara, S. Ieda, Seiji Nakamura

    Oral Diseases   2012.12

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  • Close association between oral Candida species and oral mucosal disorders in patients with xerostomia Reviewed

    S. Shinozaki, M. Moriyama, J. N. Hayashida, A. Tanaka, T. Maehara, S. Ieda, S. Nakamura

    Oral Diseases   18 ( 7 )   667 - 672   2012.10

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    DOI: 10.1111/j.1601-0825.2012.01923.x

  • Selective localization of T helper subsets in labial salivary glands from primary Sjögren's syndrome patients Reviewed

    169 ( 2 )   89 - 99   2012.8

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

    DOI: 10.1111/j.1365-2249.2012.04606.x

  • Cytokine/chemokine profiles contribute to understanding the pathogenesis and diagnosis of primary Sjögren's syndrome Reviewed International journal

    2012.7

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  • Cytokine/chemokine profiles contribute to understanding the pathogenesis and diagnosis of primary Sjögren's syndrome Reviewed

    169 ( 1 )   17 - 26   2012.7

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

    DOI: 10.1111/j.1365-2249.2012.04587.x

  • Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease Reviewed International journal

    Akihiko Tanaka, Masafumi Moriyama, Hitoshi Nakashima, Katsuhisa Miyake, Hayashida Jun-Nosuke, Takashi Maehara, Shouichi Shinozaki, Yoshiaki Kubo, Seiji Nakamura

    Arthritis and Rheumatology   2012.1

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  • Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease Reviewed

    Akihiko Tanaka, Masafumi Moriyama, Hitoshi Nakashima, Katsuhisa Miyake, Jun Nosuke Hayashida, Takashi Maehara, Shouichi Shinozaki, Yoshiaki Kubo, Seiji Nakamura

    Arthritis and rheumatism   64 ( 1 )   254 - 263   2012.1

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    DOI: 10.1002/art.33320

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Books

  • IgG4関連疾患の代替療法

    前原隆、中村誠司( Role: Joint author)

    2020.6 

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    IgG4 関連疾患は、高IgG4 血症と罹患臓器へのIgG4 陽性形質細胞の著明な浸潤, 特徴的な臓器線維化を呈する慢性炎症性疾患で, 罹患臓器は多彩で全身性である. 病態形成に関わる免疫担当細胞や, 何を治療標的とするべきなのか未だ詳細は不明である. 本疾患に対する治療にはステロイド薬が使用されるが、治療抵抗性や再燃する症例が問題となる. 一方, 本疾患が B 細胞系の疾患であることが明らかとなり,リツキシマブ治療が有効であることが報告されている.ここ数年で本疾患の病態解明に関する研究が進み, 獲得免疫を主とした免疫異常が存在していることがわかった. その中でも特に細胞障害性T 細胞と活性化B 細胞が罹患臓器に浸潤していることが明らかになってきている. そこで本稿では, ステロイドやリツキシマブの代替療法として, 現在本疾患で明らかになっている免疫細胞やその免疫関連分子を標的とした分子標的薬の可能性について考察したい.

  • 特集IgG4関連疾患:全身から肝胆膵の病態に迫る 「T細胞 subsets と clonality 解析」

    前原隆、Hamid Mattoo、Shiv Pillai( Role: Joint author)

    肝胆膵  2016.4 

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    Responsible for pages:73(4): 507 -512 2016   Language:Japanese   Book type:Scholarly book

  • ミクリッツ病/IgG4関連疾患の病態におけるIL-21の役割

    前原隆、森山雅文、中村誠司( Role: Joint author)

    リウマチ科  2013.10 

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

  • IgG4 関連疾患と木村病における 疾患特異的な濾胞性T細胞

    前原 隆, 中村 誠司

    臨床免疫・アレルギー科  2023 

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    Total pages:9  

    CiNii Research

  • Cytotoxic T cell

    前原 隆, 中村 誠司

    先端医学社  2022 

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    Total pages:2  

    CiNii Research

Presentations

  • Single cell interrogation of T-lymphocytes infiltrating IgG4-related disease affected tissues: a novel perspective into the pathogenesis of IgG4-related disease. Invited International conference

    TAKASHI MAEHARA

    The 5th international symposium on IgG4-related disease  2024.4 

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    Event date: 2024.4

    Language:English   Presentation type:Oral presentation (general)  

    Country:Japan  

  • IgG4関連疾患における疾患特異的なリンパ球サブセットのエンハンサーRNA解析 Invited

    前原隆、村川泰裕

    理研-九大科学技術ハブ共同研究プログラム  2020.1 

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    Event date: 2020.1

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:福岡   Country:Japan  

  • Clonally Expanded CD4+ Cytotoxic T Cells, Endothelial Cell Apoptosis and the Pathogenesis of Early Systemic Sclerosis International conference

    American College of Rheumatology (2019 ACR/ARP annual meeting)  2019.11 

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    Event date: 2019.11

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

    Country:United States  

  • Clonal Expansion of a Specific Subset of Cytotoxic CD4+T Cells and Tissue Apoptosis in Patients with IgG4-related Disease International conference

    Perugino Cory, Naoki Kaneko, Takashi Maehara, Hamid Mattoo, ... John Stone, Shiv Pillai.

    American College of Rheumatology (2019 ACR/ARP annual meeting)  2019.11 

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    Event date: 2019.11

    Language:English   Presentation type:Oral presentation (general)  

    Country:United States  

  • CD8+ Cytotoxic T Lymphocytes Are Clonally-expanded in IgG4-related Disease and Home to Affected Tissues International conference

    Perugino Cory, Naoki Kaneko, Takashi Maehara, ... , John Stone, Shiv Pillai

    American College of Rheumatology (2019 ACR/ARP annual meeting)  2019.11 

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    Event date: 2019.11

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

    Country:United States  

  • A novel disease entity, IgG4-related disease: Immunological insights into the pathogenesis Invited International conference

    Takashi Maehara, Seiji Nakamura

    The 9th Japan-Thailand-Korea Joint Symposium  2019.11 

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    Event date: 2019.10

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

    Country:Korea, Republic of  

  • IgG4関連疾患の病態と治療へ向けて Invited

    前原隆

    第28回 日本シェーグレン症候群学会  2019.9 

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    Event date: 2019.9

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

    Venue:徳島   Country:Japan  

  • 次世代シークエンサー解析が紐解く,全身性強皮症の病態における Clonal に増殖した CD4+T 細胞 -国際共同研究-

    前原隆、PERUGINO Cory、金子直樹、MATTOO Hamid、宗村龍祐、山元英崇、PILLAI Shiv、中村誠司

    第73回NPO 法人日本口腔科学会学術集会  2019.4 

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    Event date: 2019.4

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

    Venue:川越   Country:Japan  

  • 根治的頸部郭清術変法

    前原隆

    第5回九州地区口腔顎顔面手術手技研究会  2019.3 

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    Event date: 2019.3

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:福岡   Country:Japan  

  • A Novel diseases discovered and established in 21st Century: IgG4-related disease - Mechanistic insights from both clinical and immunologic understanding of this condition - Invited

    Takashi Maehara

    Kyudai Oral Bioscience & OBT Research Center Joint International Symposium 2019  2019.3 

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    Event date: 2019.3 - 2019.4

    Language:English   Presentation type:Oral presentation (general)  

    Country:Japan  

  • Interleukin-21 contribute to germinal centers formation and IgG4 production in IgG4-related dacryoadenitis and sialoadenitis,so called Mikulicz’s disease. Invited International conference

    2012.11 

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    Event date: 2019.1

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Bali   Country:Indonesia  

  • シェーグレン症候群の病変局所における Th サブセットの局在に関する検討

    前原隆

    第 56 回(社)日本口腔外科学会総会・学術大会  2011.10 

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    Event date: 2019.1

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:大阪   Country:Japan  

  • ミクリッツ病/IgG4 関連疾患の胚中心過形成における IL-21 の関与.

    前原隆

    第 57 回(社)日本口腔外科学会総会・学術大会  2012.10 

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    Event date: 2019.1

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:横浜   Country:Japan  

  • ミクリッツ病の病態形成および IgG4 産生における IL-21 の関与. International conference

    前原隆

    第 21 回日本シェーグレン症候群学会  2012.9 

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    Event date: 2019.1

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:京都   Country:Japan  

  • Localization of Th subsets in lesions of Sjögren’s syndrome. International conference

    2010.7 

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    Event date: 2019.1

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

    Venue:Barcelona   Country:Spain  

  • Localization of Th subsets in lesions of Sjögren’s syndrome. International conference

    2011.3 

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    Event date: 2019.1

    Language:English   Presentation type:Oral presentation (general)  

    Venue:San Diego   Country:United States  

  • Localization of Th subsets in salivary glands of Sjögren’s syndrome. International conference

    2011.10 

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    Event date: 2019.1

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Hiroshima, Japan   Country:Japan  

  • Localization of Th subsets in salivary glands of Sjögren’s syndrome. International conference

    2011.10 

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    Event date: 2019.1

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Athens   Country:Greece  

  • シェーグレン症候群の病変局所におけるThサブセットの局在に関する検討

    前原隆

    第19回日本シェーグレン症候群学会  2010.9 

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    Event date: 2019.1

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:千葉   Country:Japan  

  • シェーグレン症候群の病変局所におけるThサブセットの局在

    前原隆

    第64回日本口腔科学会総会  2010.6 

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    Event date: 2019.1

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:北海道   Country:Japan  

  • Clonalに増殖したCD4+CTLとTfh細胞はIgG4関連疾患の病態形成に関与する

    前原隆

    第46回 日本臨床免疫学会総会  2018.11 

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    Event date: 2018.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Country:Japan  

  • Clonalに増殖したCD4+CTLとTfh細胞はIgG4関連疾患の病態形成に関与する

    前原隆、MATTOO Hamid、森山雅文、柿添乃理子、坂本瑞樹、佐伯敬子、山元英崇、STONE John、PILLAI Shiv、中村誠司

    第63回日本口腔外科学会・総会  2018.11 

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    Event date: 2018.11

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:千葉   Country:Japan  

  • IgG4関連疾患の病態 –免疫学的アプローチ- Invited

    前原隆、Mattoo Hamid、Emanuel Della Torre、森山雅文、佐伯敬子、山元英崇、Stone John、Pillai Shiv、中村誠司

    日本シェーグレン症候群学会  2018.9 

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    Event date: 2018.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:福岡   Country:Japan  

  • IgG4関連疾患の up to date -臨床研究と基礎研究のコラボレートから病態解明へのアプローチ- Invited

    前原隆

    2018.9 

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    Event date: 2018.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:福岡   Country:Japan  

  • The expansion in lymphoid organs of IL-4+BATF+TFH cells is linked to IgG4 class switching in vivo International conference

    TAKASHI Maehara1, HAMID Mattoo2, NORIKO Ishiguro1, MASAFUMI Moriyama1, SEIJI Nakamura1, SHIV Pillai2. 1. Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science Kyushu University, Fukuoka, Japan 2. Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    IADR  2018.7 

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    Event date: 2018.7 - 2018.8

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

    Country:United Kingdom  

  • IgG4関連疾患の国際共同研究成果 - 基礎研究と臨床研究のコラボレート - Invited

    前原隆1、Hamid Mattoo2、Vinay S Mahajan2、Emanuel Della Torre4、森山雅文1、太田美穂1、柿添乃理子1、坂本瑞樹1、山元英崇5、佐伯敬子6、佐藤康晴7、山本元久8、新納宏昭9、John Stone3、Shiv Pillai2、中村誠司1. 1 九州大学大学院歯学研究院 口腔顎顔面病態学講座 顎顔面腫瘍制御学 2 Ragon Institute of MGH, MIT and Harvard 3 Massachusetts General Hospital 4 San Raffaele Scientific Institute 5 九州大学大学院 医学研究院 形態機能病理学 6 長岡赤十字病院 腎臓・膠原病内科 7 岡山大学医学部保険学科・大学院保険学研究科 8 札幌医科大学 医学部 免疫・リウマチ内科学 9 九州大学大学院医学研究院 医学教育学

    第17回 九州シェーグレン研究会  2018.5 

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    Event date: 2018.5 - 2018.8

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:福岡   Country:Japan  

  • Human BATF+IL-4+ T follicular helper cells are linked to polarized IgG4 switching event and accumulate primarily outside germinal centers in IgG4-related disease Invited International conference

    Maehara Takashi

    International symposium on IgG4-RD & Fibrosis  2017.2 

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    Event date: 2017.2

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

    Country:United States  

  • Human BATF+ IL-4+ T follicular helper cells are linked to a polarized IgG4 switching event and accumulate primarily IgG4-related disease lesions. Invited International conference

    Takashi Maehara and Shiv Pillai

    Kyushu-University Oral Bio Science  2017.2 

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    Event date: 2017.2

    Language:English   Presentation type:Oral presentation (general)  

    Country:Japan  

  • Tissue-infiltrating CD4+SLAMF7+ cytotoxic T cells and endothelial cell apoptosis in systemic sclerosis - New therapy targets for disease specific T cells in SSc -

    Takashi Maehara, Naoki Kaneko, Ryusuke Minemura, Yuka Murakami, Seiji Nakamura

    2019.11 

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    Event date: 2019.10

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

    Country:Japan  

  • CD4+ cytotoxic T cells dominate the immune infiltrate in systemic sclerosis and IgG4-related disease. International conference

    IADR  2019.6 

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    Event date: 2019.6

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

    Country:Canada  

  • IgG4関連疾患における濾胞性制御性T細胞の同定

    青柳 龍一, 前原 隆, 村上 祐香, 宗村 龍祐, 古賀 理沙子, 中村 誠司

    日本口腔科学会雑誌  2022.7  (NPO)日本口腔科学会

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  • IgG4関連疾患における濾胞性制御性T細胞の同定

    青柳 龍一, 前原 隆, 村上 祐香, 宗村 龍祐, 古賀 理沙子, 中村 誠司

    日本口腔科学会雑誌  2022.3  (NPO)日本口腔科学会

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  • IgG4関連疾患の罹患臓器に浸潤する全B細胞サブセットのシングルセル遺伝子発現解析

    古賀 理紗子, 前原 隆, 青柳 龍一, 宗村 龍祐, 村上 祐香, 中村 誠司

    日本口腔科学会雑誌  2023.7  (NPO)日本口腔科学会

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  • IgG4関連疾患・IgG4関連腎臓病の最新理解 IgG4関連疾患における特異なT細胞について

    前原 隆, ピライ・シブ , 中村 誠司

    日本腎臓学会誌  2022.5  (一社)日本腎臓学会

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  • コロナ禍で輝くライジングスター COVID-19の病態に関与する特異なT・B細胞サブセット(Specific T cell and B cell subsets in COVID-19)

    金子 直樹, 森山 雅文, 前原 隆, 中村 誠司, Pillai Shiv

    Journal of Oral Biosciences Supplement  2022.9  (一社)歯科基礎医学会

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    Language:Japanese  

  • シェーグレン症候群におけるTph細胞の病態形成への関与

    古賀 理紗子, 前原 隆, 宗村 龍祐, 村上 祐香, 青柳 龍一, 金子 直樹, 森山 雅文, 中村 誠司

    日本口腔科学会雑誌  2022.7  (NPO)日本口腔科学会

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  • シングルセル解析を用いたIgG4関連疾患の唾液腺における疾患特異的T・B細胞の探索

    村上 祐香, 前原 隆, 金子 直樹, 宗村 龍祐, 森山 雅文, 青柳 龍一, 古賀 理紗子, 中村 誠司

    日本口腔診断学会雑誌  2022.2  (一社)日本口腔診断学会

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  • 口腔扁平上皮癌におけるCD3+T細胞のシングルセル遺伝子発現解析と新規治療標的となりうるグランザイムK産生細胞傷害性T細胞の同定

    古賀 理紗子, 前原 隆, 青柳 龍一, 宗村 龍祐, 村上 祐香, 中村 誠司, 川野 真太郎

    日本口腔診断学会雑誌  2024.2  (一社)日本口腔診断学会

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  • 口腔扁平上皮癌におけるCD3+T細胞のシングルセル遺伝子発現解析と新規治療標的となりうるグランザイムK産生細胞傷害性T細胞の同定

    古賀 理紗子, 前原 隆, 青柳 龍一, 宗村 龍祐, 村上 祐香, 中村 誠司, 川野 真太郎

    日本口腔内科学会雑誌  2023.12  (一社)日本口腔内科学会

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  • 口腔扁平上皮癌における浸潤CD3+T細胞のシングルセル遺伝子発現解析

    前原 隆, 古賀 理紗子, 青柳 龍一, 宗村 龍祐, 川野 真太郎, 中村 誠司

    頭頸部癌  2023.5  (一社)日本頭頸部癌学会

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  • 当科における下顎骨関節突起骨折に対する観血的整復固定術の治療成績の検討 Risdon approachとhigh perimandibular approachとの比較

    濱 栞音, 丸瀬 靖之, 森山 雅文, 前原 隆, 坂本 泰基, 柿添 乃理子, 坂本 瑞樹, 塩川 裕之, 大部 一成, 川野 真太郎, 中村 誠司

    口腔顎顔面外傷  2022.10  日本口腔顎顔面外傷学会

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  • 当科における口腔癌手術症例の再発リスクについての後ろ向き検討

    濱田 栄樹, 金子 直樹, 樋渡 萌美, 鮫島 潤星, 末吉 智貴, 長野 晴紀, 坂本 泰基, 前原 隆, 大部 一成, 川野 真太郎

    日本口腔診断学会雑誌  2024.2  (一社)日本口腔診断学会

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  • 当科における口腔癌手術症例の再発リスクについての後ろ向き検討

    濱田 栄樹, 金子 直樹, 樋渡 萌美, 鮫島 潤星, 末吉 智貴, 長野 晴紀, 坂本 泰基, 前原 隆, 大部 一成, 川野 真太郎

    日本口腔内科学会雑誌  2023.12  (一社)日本口腔内科学会

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  • 成人の側頭下窩に発生した横紋筋肉腫の画像所見

    山内 恵利佳, 清水 真弓, 岡村 和俊, 前原 隆, 吉浦 一紀

    日本口腔科学会雑誌  2022.3  (NPO)日本口腔科学会

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  • 腓骨皮弁採取部に下肢コンパートメント症候群を発症した下顎歯肉癌の1例

    坂本 瑞樹, 前原 隆, 坂本 泰基, 金子 直樹, 上加世田 泰久, 吉田 聖, 門田 英輝, 川野 真太郎

    日本口腔科学会雑誌  2024.3  (NPO)日本口腔科学会

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MISC

  • 新規疾患概念;IgG4関連疾患の免疫学的特徴から病態解明へのアプローチ Reviewed

    前原隆、宗村龍祐、村上祐香

    アレルギーの臨床   2020.9

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  • IgG4関連疾患の代替療法 Reviewed

    前原隆、中村誠司

    カレントテラピー   2020.7

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  • IgG4関連疾患-臨床研究と基礎研究のコラボレートから病態解明へのアプローチ- IgG4-related disease –Mechanistic insights from both clinical and immunologic understanding of this condition–

    前原隆

    日本臨床免疫学会会誌   2017.6

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    Language:Japanese   Publishing type:Article, review, commentary, editorial, etc. (scientific journal)  

    IgG4関連疾患は,高IgG4血症と罹患臓器へのIgG4陽性形質細胞の著明な浸潤,特徴的な花筵用線維化ならびに閉塞性静脈炎を呈する慢性炎症性疾患である.現在その治療にはステロイドが第一選択薬で有効である反面,再燃しやすいことも広く知られている.そして再燃例などの重症例にはリツキシマブなどの生物学的製剤の有効性が立証されている.IgG4関連疾患に関する重要なMechanistic-insightsの多くが,リツキシマブ治療により寛解した臨床研究の経験から得られている.欧米では既にこれらの治療による多くの知見があり,最先端の科学技術による基礎研究とのコラボレートによる研究成果が報告されている.実際に,米国のRagon Institute of MGH, MIT, and HarvardとMassachusetts General Hospital(MGH)との共同研究により,最近になってIgG4関連疾患患者の病態形成における5つの重要な知見が報告されている.1)IgG4+形質芽細胞とCD4+細胞障害性T細胞(CD4+cytotoxic T lymphocyte: CD4+CTLs)がクローナルに増殖.2)罹患臓器にCD4+CTLsが多数浸潤.3)組織のCD4+CTLsは細胞障害性・炎症性サイトカインを産生.4)リツキシマブ治療によるCD4+CTLs細胞数の減少は臨床的寛解と相関.5)IL-4+濾胞性ヘルパーT細胞(T follicular helper T: TFH)が濾胞外に多数浸潤し,IgG4へのクラススイッチに関与.これらの事実より活性化した形質芽細胞,CD4+CTLs, TFH細胞のクロストークがIgG4関連疾患の特異な病態を形成しているものと推察される.</p>

    <p> 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.</p>

  • T細胞 subsets と clonality 解析 Reviewed

    前原隆、Hamid Mattoo、Shiv Pillai

    肝胆膵   2016.4

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  • ミクリッツ病/IgG4関連疾患の病態における IL-21の役割 Reviewed

    前原隆、森山雅文、中村誠司

    科学評論社   2013.10

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  • 【IgG4関連疾患と鑑別疾患】B細胞とT細胞から紐解くIgG4関連疾患の病態形成メカニズム

    坂本 瑞樹, 金子 直樹, 森山 雅文, 前原 隆, 中村 誠司

    病理と臨床   42 ( 2 )   0127 - 0133   2024.2   ISSN:0287-3745

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  • Immune dysregulation in immunoglobulin G4-related disease(タイトル和訳中)

    Maehara Takashi, Koga Risako, Nakamura Seiji

    The Japanese Dental Science Review   59   1 - 7   2023.12   ISSN:1882-7616

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    Language:English   Publisher:日本歯科医学会  

  • IgG4関連疾患と木村病における疾患特異的な濾胞性T細胞

    前原 隆, 宗村 龍祐, 古賀 理紗子, 中村 誠司

    臨床免疫・アレルギー科   79 ( 3 )   339 - 347   2023.3   ISSN:1881-1930

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  • 新規疾患概念 IgG4関連疾患の免疫学的特徴から臓器線維化と炎症の病態解明へ向けて

    古賀 理紗子, 前原 隆, 中村 誠司

    アレルギーの臨床   43 ( 1 )   53 - 56   2023.1   ISSN:0285-6379

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    IgG4関連疾患(IgG4-Related Disease:IgG4-RD)は,免疫グロブリンのIgG4への特異的なクラススイッチと罹患臓器への多数のリンパ球の浸潤を伴う重度の臓器線維化を特徴とする全身性の慢性炎症性疾患である。病態機序は未だ明らかになっていないが,最近では自己抗原の存在もいくつか報告があり,自己免疫学的機序による病態形成が示唆されている。また,近年の解析技術の進歩により,本疾患患者の末梢血でオリゴクローナルに増殖した形質芽細胞がIgG4を産生していることや,T細胞についても特徴的に増加しているサブセットが明らかになってきた。本稿では,獲得免疫に着目しこれまでの研究で明らかになってきた免疫担当細胞から,本疾患の病態形成について概説する。(著者抄録)

  • Key Wordキーワード(No.62) Cytotoxic T cell

    前原 隆, 古賀 理紗子, 中村 誠司

    消化器病学サイエンス   6 ( 4 )   252 - 253   2022.12   ISSN:2432-7549

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    Language:Japanese   Publisher:(株)先端医学社  

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Professional Memberships

  • 日本口腔外科学会

  • 日本口腔科学会

  • 日本臨床免疫学会

  • 日本シェーグレン学会

  • International Association of Dental Research

  • 日本口腔顎顔面外傷学会

  • 日本口腔内科学会

  • 日本口腔インプラント学会

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Committee Memberships

  • Frontiers in Immunology   編集委員  

    2018.1 - Present   

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    Committee type:Academic society

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  • Frontiers in Medicine 編集委員  

    2018.1 - Present   

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Academic Activities

  • シンポジスト International contribution

    2020.10

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    Type:Competition, symposium, etc. 

  • シンポジスト International contribution

    2019.11

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    Type:Competition, symposium, etc. 

  • シンポジスト International contribution

    2019.10 - 2019.11

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    Type:Competition, symposium, etc. 

  • シンポジスト

    第28回 日本シェーグレン症候群学会  ( 徳島 ) 2019.9

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    Type:Competition, symposium, etc. 

  • 日本学術振興会審査委員

    Role(s): Review, evaluation

    2019.4 - 2020.5

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    Type:Scientific advice/Review 

  • シンポジスト

    第27回 日本シェーグレン症候群学会  ( 福岡 ) 2018.9

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    Type:Competition, symposium, etc. 

  • シンポジスト

    第17回 九州シェーグレン研究会  ( 福岡 ) 2018.5

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    Type:Competition, symposium, etc. 

  • Frontiers in Medicine 【-Research Topic- IgG4-Related Disease. Dissecting a novel fibrotic disorder through the identification of pathogenic mechanisms, reliable biomarkers, and targeted therapeutic strategies.】 International contribution

    2018.1 - 2018.10

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    Type:Academic society, research group, etc. 

  • Frontiers in Immunology 【-Research Topic- IgG4-Related Disease. Dissecting a novel fibrotic disorder through the identification of pathogenic mechanisms, reliable biomarkers, and targeted therapeutic strategies.】 International contribution

    2018.1 - 2018.10

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    Type:Academic society, research group, etc. 

  • Screening of academic papers

    Role(s): Peer review

    2018

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:3

  • シンポジスト、座長 International contribution

    2017.2

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    Type:Competition, symposium, etc. 

  • Screening of academic papers

    Role(s): Peer review

    2017

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    Type:Peer review 

    Number of peer-reviewed articles in foreign language journals:3

  • Screening of academic papers

    Role(s): Peer review

    2016

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    Type:Peer review 

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

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Other

  • IgG4-RDの罹患臓器に浸潤する全T細胞と全B細胞をシングルセル遺伝子発現解析とTCR/BCRレパトア解析により、IgG4-RDに特異に浸潤する細胞群として、IL10+LAG3+Tfh細胞、GZMK+GZMA+CTL、Doubule negative B(DN2、DN3)、MKI67+B細胞群を同定した。 (1) J Allergy Clin Immunol. 2023 Dec 11:S0091-6749(23)02412-0. (2) J Allergy Clin Immunol. 2023 Aug 29:S0091-6749(23)01072-2. (3) J Allergy Clin Immunol. 2022 Aug;150(2):440-455.e17.

    2024.2

  • 2015年3月より、ハーバード大学 Ragon Instituteへ留学し、ミシガン大学と共同研究を開始した。その結果、全身性強皮症の罹患臓器においてCD4+CTLとCD8+CTLが増加し、血管内皮細胞のアポトーシスと線維化に関与していることを明らかとした。この研究成果は、(1) J Clin Invest に掲載さらに、2020年3月に Nature レビュー誌で (2) Research Highlight として紹介された。 (1) J Clin Invest. 2020 May 1;130(5):2451-2464. (2) Nat Rev Rheumatol. 2020 May;16(5):253-254. doi: 10.1038/s41584-020-0404-6.

    2020.5

  • 2015年3月より、ハーバード大学 Ragon Instituteへ留学し、九州大学、長岡赤十字病院との国際共同研究を開始した。その結果IgG4を産生する活性化したB細胞、CD4+細胞障害性T細胞、IL-4産生濾胞性T細胞のクロストークがIgG4関連疾患の特異な病態を形成していることを明らかとした。この研究成果は、アレルギー学のトップジャーナルである (1) J Allergy Clin Immunol とリウマチ学のトップジャーナルである (2) Annals of Rheumatic Diseases に掲載され、さらに (3) Nature レビュー誌で Research Highlight として紹介された。 (1) J Allergy Clin Immunol. 2016 Sep;138(3):825-38., 2016.09. (2) Ann. Rheum. Dis. 2017 Feb;76(2):377-385., 2017.02. (3) Nat Rev Rheumatol. 2016 Sep;12(9):500. doi: 10.1038/nrrheum.2016.124.

    2018.4

  • IgG4関連疾患の罹患臓器である唾液腺には、胚中心過形成が生じており特異なTfh細胞が浸潤し、IgG4産生へのクラススイッチに関与している可能性を (1) Annals of Rheumatic Disease に報告した。さらにこの研究成果は、(2)同誌にリサーチハイライトされた。 (1) Ann Rheum Dis. 2012 Dec;71(12):2011-19. doi: 10.1136/annrheumdis-2012-201477. (2) Ann Rheum Dis. 2012 Dec;71(12):1919-20. doi: 10.1136/annrheumdis-2012-201866.

    2015.3

Research Projects

  • 口腔扁平苔癬の創薬ターゲットの探索〜病因T細胞と関連エンハンサーRNAの同定〜

    2023

    日本学術振興会  科学研究費助成事業  挑戦的研究(開拓)

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  • 口腔扁平苔癬の創薬ターゲットの探索~病因T細胞と関連エンハンサーRNAの同定~

    Grant number:22K18401  2022.6 - 2025.3

    科学研究費助成事業  挑戦的研究(開拓)

    中村 誠司, 前原 隆, 森山 雅文, 村川 泰裕

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    口腔扁平苔癬(OLP) は、口腔粘膜の角化異常を伴う原因不明で難治性の慢性炎症性疾患であり、発症頻度も比較的高い疾患である。病理学的には基底膜直下へT 細胞を主体としたリンパ球の浸潤を特徴とすることから、このT 細胞が病因となり上皮下の基底細胞が障害の標的と考えられている。しかし、未だに病因は不明で、完全治癒は期待できず、ステロイドによる治療に終始するしかない。さらに、OLP は癌化する可能性があることから根治的な治療法の開発が求められている。そこで本研究では、シングルセル遺伝子発現解析を駆使して疾患関連細胞のスイッチ遺伝子を特定し、それらを標的とした次世代ゲノム医療への応用に繋げる。

    CiNii Research

  • IgG4関連疾患の異所性胚中心オルガノイドから病因解明と新規モデル動物の樹立

    Grant number:23K24549  2022.4 - 2026.3

    科学研究費助成事業  基盤研究(B)

    前原 隆, 川野 充弘, 山元 英崇, 中村 誠司

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    IgG4-RDの唾液腺炎と末梢血に浸潤するT/B細胞を分離採取してシングルセル遺伝子発現解析を行い、B細胞と関連するT細胞について詳細に解析する。この成果を踏まえて、① 疾患に特異的なT細胞とB細胞を明らかにする。② IgG4-RDの異所性胚中心の3次元臓器を作成し、T-B細胞の相互連間を解明する。③ IgG4-RDの新規動物モデルを樹立する。④ IgG4-RDの病態の全容解明と、臨床応用できるバイオマーカーや新規治療薬開発の基盤を整える。

    CiNii Research

  • IgG4関連疾患の異所性胚中心オルガノイドから病因解明と新規モデル動物の樹立

    Grant number:22H03291  2022 - 2025

    日本学術振興会  科学研究費助成事業  基盤研究(B)

    前原 隆, 川野 充弘, 山元 英崇, 中村 誠司

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    IgG4-RDの唾液腺炎と末梢血に浸潤するT/B細胞を分離採取してシングルセル遺伝子発現解析を行い、B細胞と関連するT細胞について詳細に解析する。この成果を踏まえて、①IgG4-RDの異所性胚中心の3次元臓器を作成し、T-B細胞の相互連間を解明する。②IgG4-RDの新規動物モデルを樹立する。③IgG4-RDの病態の全容解明と、臨床応用できるバイオマーカーや新規治療薬開発の基盤を整える。

    CiNii Research

  • IgG4関連疾患の創薬ターゲットとなり得る病因関連エンハンサーRNAの探索

    Grant number:21K19607  2021 - 2023

    日本学術振興会  科学研究費助成事業  挑戦的研究(萌芽)

    前原 隆, 村川 泰裕, 中村 誠司

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    従前に我々は、本疾患に特異的な細胞群を明らかにしているため、本研究では、この細胞群を分離採取し遺伝子発現制御に働く上流のゲノム転写ネットワークを明らかにする。ヒト疾患の疾患関連細胞のスイッチ遺伝子を世界初に特定することができ、新規の次世代ゲノム医療の基盤を築ける本疾患の臓器障害に対する新規治療法の開発が求められており、この免疫学的特異性が標的になると期待される。

    CiNii Research

  • IgG4関連疾患のシングルセル・エンハンサーRNA解析による次世代ゲノム医療への基盤構築

    2021 - 2022

    QRプログラム わかばチャレンジ

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  • Immunologic specificity based pathogenesis of IgG4-related diseases and validation in mouse models of the disease

    Grant number:20H00553  2020.4 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (A)

    Nakamura Seiji

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    IgG4-related diseases is a unique systemic disease characterized by mass formation and consequent dysfunction of multiple organs, as well as severe fibrosis with infiltrating T cells, B cells, and macrophages. Currently, no effective treatment is available. In this study, we focused on a subset of unique T cells, B cells, and macrophages and performed single-cell RNA sequencing as well as T-B receptor sequencing to obtain a comprehensive, unbiased view of tissue infiltrating cells. As a result, we identified characteristic T and B cell subsets. We also focused on macrophages expressing Toll-like receptor 7 and tested whether it is possible to generate mice that can reproduce the pathology by stimulating them with TLR7 agonist.

    CiNii Research

  • 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 - 2022

    日本学術振興会  科学研究費助成事業  基盤研究(A)

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  • 口腔扁平上皮癌の免疫担当細胞ネットワークの解明と治療標的分子の探索

    2020 - 2021

    九州大学 QRプログラム「わかばチャレンジ」

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  • 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

    Grant number:19K22723  2019.6 - 2024.3

    科学研究費助成事業  挑戦的研究(萌芽)

    中村 誠司, 前原 隆, 森山 雅文

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    我々のこれまでの研究ではIgG4 の過剰産生には特異なT 細胞とそれらが産生するサイトカインが関与していることを明らかにしており、それらの疾患関連分子をマーカーとして検索することは病因・病態の本質により迫ることになり、特異的で精度が高い新たな診断法の開発に繋がると期待できる。
    本研究では、非侵襲性で繰り返して実施できることも検査の重要な要件であると考え、最も罹患頻度が高いのが唾液腺であること、さらには唾液腺内で産生される可溶性分子は唾液中にも検出可能であることに着目し、唾液中の可溶性マーカーを用いた新たなIgG4-RDの診断法の確立を目指す。

    CiNii Research

  • Elucidation of the mechanisms of orang fibrosis using patients with IgG4-related disease and their mouse models

    Grant number:19H03854  2019 - 2022

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Maehara Takashi

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    IgG4-related diseases, which were first proposed in Japan and are now attracting worldwide attention, are diseases characterized by lesions in organs throughout the body and irreversible organ fibrosis associated with infiltration of T and B cells into the affected organs. However, the molecular mechanism of organ fibrosis that characterizes this disease is still unknown, and the disease is intractable with no effective treatment. Because fibrosis is irreversible and leads to deterioration of organ function, the development of novel therapeutic methods is required. In this study, we identified lymphocytes involved in organ fibrosis and investigated their relationship with characteristic macrophages involved in organ fibrosis.

    CiNii Research

  • 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 - 2022

    日本学術振興会  科学研究費助成事業  基盤研究(B)

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  • 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 - 2021

    日本学術振興会  科学研究費助成事業  挑戦的研究(萌芽)

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  • 武田科学振興財団 「医学系研究助成」 -国際共同研究- IgG4関連疾患におけるクラススイッチの分子機序解明と新規治療戦略

    2019 - 2021

    科学研究費助成事業 

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    Authorship:Principal investigator  Grant type:Competitive funding other than Grants-in-Aid for Scientific Research

  • IgG4関連疾患における疾患特異的なリンパ球サブセットのエンハンサーRNA解析

    2019 - 2020

    2019年度 理研-九大 科学技術ハブ 共同研究プログラム

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  • New therapy targets for IgG4-RD and other human autoimmune disease focused on clonal expanded T and B cells.

    Grant number:18KK0260  2018.10 - 2023.3

    Grants-in-Aid for Scientific Research  Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))

    MAEHARA TAKASHI

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    Grant type:Scientific research funding

    IgG4-related disease (IgG4-RD) is a disease characterized by systemic organ involvement, T- and B-cell infiltration of affected organs, and specific immunoglobulin class switching (mainly IgG4). In this study, we identified IL10+IL21+LAG3+Tfh cells involved in the specific class switching of IgG4-RD by single-cell gene expression analysis of T cells infiltrating affected organs with IgG4-RD. We also found that many of the class-switched B cells expressing AID also express high levels of IL10 and IL21 receptors.

    CiNii Research

  • 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

    2018.8 - 2020.3

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    Authorship:Coinvestigator(s)  Grant type:Other funds from industry-academia collaboration

  • 国際共同研究 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- International coauthorship

    2018.7 - 2022.7

    九州大学大学院 歯学研究院 口腔顎顔面病態学講座 顎顔面腫瘍制御学分野(日本) 

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    Authorship:Principal investigator 

  • 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-

    2018 - 2022

    日本学術振興会  科学研究費助成事業  国際共同研究強化(B)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 上原記念生命科学財団 研究奨励 (臨床研究) 「日米共同研究 IgG4 関連疾患の病因解明への新戦略」

    2018 - 2020

    科学研究費助成事業 

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    Authorship:Principal investigator  Grant type:Competitive funding other than Grants-in-Aid for Scientific Research

  • 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」

    2017.4 - 2020.3

    京都大学(日本) 

  • IgG4関連疾患の病態解明に向けた Th2 型自然免疫応答の新戦略

    2016 - 2018

    日本学術振興会  海外特別研究員

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    Authorship:Principal investigator  Grant type:Joint research

  • 持田記念医学薬学振興財団留学補助金

    2016 - 2017

    科学研究費助成事業 

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    Authorship:Principal investigator  Grant type:Competitive funding other than Grants-in-Aid for Scientific Research

  • かなえ医薬振興財団 Clonally expand CD4+ cytotoxic T lymphocytes in IgG4-related disease

    2015 - 2016

    科学研究費助成事業 

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    Authorship:Principal investigator  Grant type:Competitive funding other than Grants-in-Aid for Scientific Research

  • IgG4関連疾患の病態解明に向けた免疫学的研究―異所性胚中心形成とTh細胞―

    2014 - 2016

    科学研究費助成事業  若手研究(B)

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    Authorship:Principal investigator  Grant type:Scientific research funding

  • 臨床医学振興財団 ミクリッツ病の病態形成におけるM2マクロファージとIL33の関与に関する研究

    2013 - 2015

    科学研究費助成事業 

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    Authorship:Principal investigator  Grant type:Competitive funding other than Grants-in-Aid for Scientific Research

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Class subject

  • 口腔感染・炎症治療学

    2023.10 - 2024.3   Second semester

FD Participation

  • 2019.5   Role:Participation   Title:臨床実習後臨床能力試験の実施に向けて

    Organizer:Undergraduate school department

  • 2018.5   Role:Participation   Title:臨床実習後臨床能力試験の実施に向けて

    Organizer:Undergraduate school department

Other educational activity and Special note

  • 2019  Class Teacher 

  • 2018  Class Teacher 

Outline of Social Contribution and International Cooperation activities

  • 社会貢献:学外の医療系専門学校における講義、開業歯科医院での口腔外科手術指導
    国際連携活動:自己免疫疾患の病態解明に向けた国際共同研究 (ハーバード大学、マサチューセッツ総合病院、Ragon Institute of MGH, MIT and Harvard)

Social Activities

  • 非常勤講師

    福岡医健専門学校  2020.4

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    Audience: General, Scientific, Company, Civic organization, Governmental agency

    Type:Lecture

  • 非常勤講師

    福岡医健専門学校  2019.4

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    Audience: General, Scientific, Company, Civic organization, Governmental agency

    Type:Lecture

  • 非常勤講師

    福岡医健専門学校  2018.4

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    Audience: General, Scientific, Company, Civic organization, Governmental agency

    Type:Lecture

Travel Abroad

  • 2019.6

    Staying countory name 1:Canada   Staying institution name 1:International Association for Dental Research

  • 2018.7

    Staying countory name 1:United Kingdom   Staying institution name 1:International Association for Dental Research

  • 2017.2

    Staying countory name 1:United States   Staying institution name 1:Third International symposium of IgG4-RD & Fibrosis

  • 2015.3 - 2018.3

    Staying countory name 1:United States   Staying institution name 1:ハーバード大学 Ragon Institute of MGH, MIT and Harvard

  • 2012.11

    Staying countory name 1:Indonesia   Staying institution name 1:10th Asian Congress on Oral and Maxillofacial Surgery

  • 2011.10

    Staying countory name 1:Greece   Staying institution name 1:11th International Symposium on Sjogren's Syndrome

  • 2011.3

    Staying countory name 1:United States   Staying institution name 1:International Association for Dental Research

  • 2010.7

    Staying countory name 1:Spain   Staying institution name 1:International Association for Dental Research

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Specialized clinical area

  • Biology / Medicine, Dentistry and Pharmacy / Dentistry / Surgical Dentistry

Clinician qualification

  • Certifying physician

    日本口腔外科学会

  • Specialist

    日本口腔外科学会

Year of medical license acquisition

  • 2007