Elucidation of mechanism on IgG4-related disease and establishment of disease model mouse

• Project/Area Number: 17H01603
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Kyushu University
• Principal Investigator: Nakamura Seiji 九州大学, 歯学研究院, 教授 (60189040)
• Co-Investigator(Kenkyū-buntansha): 新納 宏昭 九州大学, 医学研究院, 教授 (20380636) ; 森山 雅文 九州大学, 歯学研究院, 助教 (20452774) ; 柴田 琢磨 東京大学, 医科学研究所, 助教 (30554505) ; 安河内 友世 (川久保友世) 福岡大学, 薬学部, 准教授 (70507813) ; 坪井 洋人 筑波大学, 医学医療系, 講師 (80580505)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥42,900,000 (Direct Cost: ¥33,000,000、Indirect Cost: ¥9,900,000); Fiscal Year 2019: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000); Fiscal Year 2018: ¥12,740,000 (Direct Cost: ¥9,800,000、Indirect Cost: ¥2,940,000); Fiscal Year 2017: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000)
• Keywords: IgG4関連疾患 / 疾患モデルマウス / T細胞サブセット / マクロファージ / B細胞 / 濾胞性T細胞 / Toll様受容体 / B細胞サブセット / モデルマウス / 自然免疫 / M2マクロファージ / CCL16 / マクロファージサブセット / Toll 様受容体

Outline of Final Research Achievements

1) Establishment of IgG4-related disease (IgG4-RD) model mice: In huTLR7-transgenic mice, the focus and fibrosis scores in submandibular glands, pancreas, and lungs were significantly higher than those in wild-type mice. Moreover, the concentration of serum IgG, IgG1, and IL-33 in huTLR7-transgenic mice was distinctly increased upon stimulation with a TLR7 agonist.
2) Expansion of IL-4+ BATF+ T follicular helper (Tfh) cells is linked to IgG4 class switching in IgG4-RD: In IgG4-RD, most Tfh cells in tertiary and secondary lymphoid organs (SLOs) make IL-4. Human IL-4+ Tfh cells do not express GATA-3 but express nuclear BATF, and the transcriptomes of IL-4-secreting Tfh cells differ from both PD1hi Tfh cells that do not secrete IL-4 and IL-4-secreting non-Tfh cells.

Academic Significance and Societal Importance of the Research Achievements

本研究の予想される結果と意義は、T 細胞とB 細胞に抗原特異性があれば抗原ペプチドが分子標的薬となり得るし、抗原に非特異的であれば抗サイトカイン抗体や抗受容体抗体などが考えられ、既にかなり多くの分子標的薬が開発されて臨床応用されていることから、その中に適切な分子標的薬が含まれている可能性は高い。また、本研究の推進により病態を忠実に再現する疾患モデルマウスが作製できれば、上記の分子標的薬の治療薬としても効果を検討でき、新規治療法の開発に極めて有用な疾患モデルマウスになると期待できる。

Research Products

• [Journal Article] RORγt antagonist improves Sj?gren's syndrome‐like sialadenitis through downregulation of CD25 (2020)
  • Author(s): Ono Yuko、Tsuboi Hiroto、Moriyama Masafumi、Asashima Hiromitsu、Kudo Hanae、Takahashi Hiroyuki、Honda Fumika、Abe Saori、Kondo Yuya、Takahashi Satoru、Matsumoto Isao、Nakamura Seiji、Sumida Takayuki
  • Journal Title: Oral Diseases Volume: - Issue: 4 Pages: 766-777
  • DOI: 10.1111/odi.13255
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activated M2 macrophage contributes to the pathogenesis of IgG4-related disease via TLR7/IL-33 signalin. (2019)
  • Author(s): Ishiguro N, Moriyama M, Furusho K, Furukawa S, Shibata T, Murakami Y, Chinju A, Haque ASMR, 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
  • Journal Title: Arthritis Rheumatol. Volume: Jan;72(1) Issue: 1 Pages: 166-178
  • DOI: 10.1002/art.41052
  • Peer Reviewed / Open Access
• [Journal Article] 2.Tissue-infiltrating immune cells contribute to understanding the pathogenesis of Kimura disease: A case report (2019)
  • Author(s): Maehara T, Munemura R, Shimizu M, Kakizoe N, Kaneko N, Murakami Y, Moriyama M, Kiyoshima T, Kawano S, Nakamura S.
  • Journal Title: Medicine Volume: in press Issue: 50 Pages: e18300-e18300
  • DOI: 10.1097/md.0000000000018300
  • Peer Reviewed / Open Access
• [Journal Article] CD206+ tumor-associated macrophages promote proliferation and invasion in oral squamous cell carcinoma via EGF production. (2019)
  • Author(s): Haque ASMR, Moriyama M, Kubota K, Ishiguro N, Sakamoto M, Chinju A, Mochizuki K, Sakamoto T, Kaneko N, Munemura R, Maehara T, Tanaka A, Hayashida JN, Kawano S, Kiyoshima T, Nakamura S.
  • Journal Title: Sci Rep. Volume: Oct 10;9(1) Issue: 1 Pages: 14611-14611
  • DOI: 10.1038/s41598-019-51149-1
  • Peer Reviewed / Open Access
• [Journal Article] Upregulation and pathogenic roles of CCL18-CCR8 axis in IgG4-related disease (2019)
  • Author(s): Tsuboi Hiroto、Iizuka-Koga Mana、Asashima Hiromitsu、Takahashi Hiroyuki、Kudo Hanae、Ono Yuko、Honda Fumika、Iizuka Akira、Segawa Seiji、Abe Saori、Yagishita Mizuki、Yokosawa Masahiro、Kondo Yuya、Moriyama Masafumi、Matsumoto Isao、Nakamura Seiji、Sumida Takayuki
  • Journal Title: Modern Rheumatology Volume: - Issue: 4 Pages: 1-9
  • DOI: 10.1080/14397595.2019.1632061
  • Peer Reviewed / Open Access
• [Journal Article] 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 (2019)
  • Author(s): Sakamoto Mizuki、Moriyama Masafumi、Shimizu Mayumi、Chinju Akira、Mochizuki Keita、Munemura Ryusuke、Ohyama Keiko、Maehara Takashi、Ogata Kenichi、Ohta Miho、Yamauchi Masaki、Ishiguro Noriko、Matsumura Mayu、Ohyama Yukiko、Kiyoshima Tamotsu、Nakamura Seiji
  • Journal Title: Modern Rheumatology Volume: - Issue: 2 Pages: 1-6
  • DOI: 10.1080/14397595.2019.1576271
  • Peer Reviewed / Open Access
• [Journal Article] Cytidine deaminase enables Toll-like receptor 8 activation by cytidine or its analogs. (2019)
  • Author(s): Furusho K, Shibata T, Sato R, Fukui R, Motoi Y, Zhang Y, Saitoh SI, Ichinohe T, Moriyama M, Nakamura S, Miyake, K.
  • Journal Title: International immunology. Volume: 31 Issue: 3 Pages: 167-173
  • DOI: 10.1093/intimm/dxy075
  • Peer Reviewed / Open Access
• [Journal Article] Pathogenesis of IgG4-related disease: a critical review (2018)
  • Author(s): Maehara Takashi、Moriyama Masafumi、Nakamura Seiji
  • Journal Title: Odontology Volume: 107 Issue: 2 Pages: 127-132
  • DOI: 10.1007/s10266-018-0377-y
  • Peer Reviewed / Open Access
• [Journal Article] The expansion in lymphoid organs of IL-4+ BATF+ T follicular helper cells is linked to IgG4 class switching in vivo (2018)
  • Author(s): Maehara T, Mattoo H, Mahajan VS , Murphy SJH , Yuen GJ, Ishiguro N, Ohta M, Moriyama M, Saeki T, Yamamoto H, Yamauchi M, Daccache J, Kiyoshima T, Nakamura S, Stone JH, Pillai S.
  • Journal Title: Life Science Alliance Volume: 印刷中 Issue: 1 Pages: e201800050-e201800050
  • DOI: 10.26508/lsa.201800050
  • Peer Reviewed / Open Access
• [Journal Article] Factors in glucocorticoid regimens associated with treatment response and relapses of IgG4-related disease: a multicentre study (2018)
  • Author(s): Shirakashi Mirei、Yoshifuji Hajime、Kodama Yuzo、Chiba Tsutomu、Yamamoto Motohisa、Takahashi Hiroki、Uchida Kazushige、Okazaki Kazuichi、Ito Tetsuya、Kawa Shigeyuki、Yamada Kazunori、Kawano Mitsuhiro et al.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 10262-10262
  • DOI: 10.1038/s41598-018-28405-x
  • NAID: 120007134012
  • Peer Reviewed / Open Access
• [Journal Article] Clinical practice guideline for Sj?gren’s syndrome 2017 (2018)
  • Author(s): Sumida Takayuki、Azuma Naoto、Moriyama Masafumi、Takahashi Hiroyuki、Asashima Hiromitsu、Honda Fumika、Abe Saori、Ono Yuko、Hirota Tomoya、Hirata Shintaro、Tanaka Yoshiya、Shimizu Toshimasa、Nakamura Hideki、Kawakami Atsushi、Sano Hajime、Ogawa Yoko、Tsubota Kazuo、Ryo Koufuchi、Saito Ichiro、Tsuboi Hiroto
  • Journal Title: Modern Rheumatology Volume: 28 Issue: 3 Pages: 383-408
  • DOI: 10.1080/14397595.2018.1438093
  • Peer Reviewed / Open Access
• [Journal Article] Cytokine mixtures mimicking secretomes from mesenchymal stem cells improve medication-related osteonecrosis of the jaw in a rat model. (2018)
  • Author(s): Ogata K, Matsumura M, Moriyama M, Katagiri W, Hibi H and Nakamura S
  • Journal Title: JBMR PLUS Volume: Vol2 (2) Issue: 2 Pages: 69-80
  • DOI: 10.1002/jbm4.10013
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease. (2017)
  • Author(s): Furukawa S, Moriyama M, Miyake K, Nakashima H, Tanaka A, Maehara T, Iizuka-Koga M, Tsuboi H, Hayashida JN, Ishiguro N, Yamauchi M, Sumida T, Nakamura S
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 42413-42413
  • DOI: 10.1038/srep42413
  • NAID: 120007135019
  • Peer Reviewed / Open Access
• [Journal Article] Th1/Th2 Immune Balance and Other T Helper Subsets in IgG4-Related Disease. (2017)
  • Author(s): Moriyama M, Nakamura S.
  • Journal Title: Curr Top Microbiol Immunol Volume: 401 Pages: 75-83
  • DOI: 10.1007/82_2016_40
  • ISBN: 9783319525419, 9783319525426
  • Peer Reviewed / Open Access
• [Journal Article] CD163+CD204+ tumor-associated macrophages contribute to T cell regulation via interleukin-10 and PD-L1 production in oral squamous cell carcinoma. (2017)
  • Author(s): Kubota K, Moriyama M, Furukawa S, Rafiul HASM, Maruse Y, Jinno T, Tanaka A, Ohta M, Ishiguro N, Yamauchi M, Sakamoto M, Maehara T, Hayashida JN, Kawano S, Kiyoshima T, Nakamura S.
  • Journal Title: Scientific Reports Volume: 7(1) Issue: 1 Pages: 1755-1755
  • DOI: 10.1038/s41598-017-01661-z
  • Peer Reviewed / Open Access
• [Journal Article] cDNA microarray analysis identifies NR4A2 as a novel molecule involved in the pathogenesis of Sjogren's syndrome (2017)
  • Author(s): Takahashi H, Tsuboi H, Asashima H, Hirota T, Kondo Y, Moriyama M, Matsumoto, Nakamura S, Sumida T.
  • Journal Title: Clinical & Experimental Immunology Volume: 190 Issue: 1 Pages: 96-109
  • DOI: 10.1111/cei.13000
  • Peer Reviewed / Open Access
• [Journal Article] Lesional CD4+ IFN-γ+ cytotoxic T lymphocytes in IgG4-related dacryoadenitis and sialoadenitis. (2017)
  • Author(s): Maehara T, Mattoo H, Ohta M, Mahajan VS, Moriyama M, Yamauchi M, Drijvers J, Nakamura S, Stone JH, Pillai SS.
  • Journal Title: Ann Rheum Dis Volume: 76(2) Issue: 2 Pages: 377-385
  • DOI: 10.1136/annrheumdis-2016-209139
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Recent topics of my researches in the field of oral and maxillofacial surgery ～A novel salivary gland disease entity and oral potentially malignant disorders～ (2019)
  • Author(s): Nakamura Seiji
  • Organizer: Research Symposium in Taipei Medical University
  • Int'l Joint Research / Invited
• [Presentation] シェーグレン症候群とIgG4関連疾患の新しい理解 (2019)
  • Author(s): 中村誠司
  • Organizer: 第29回日本口腔内科学会・第３２回日本口腔診断学会・第２８回日本口腔検査学会・第３０回日本臨床口腔病理学会合同シンポジウム
  • Invited
• [Presentation] IgG4 関連涙腺・唾液腺炎の診断における口唇腺生検および超音波検査の有用性 (2019)
  • Author(s): 坂本瑞樹、森山雅文、中村誠司
  • Organizer: 第１2回IgG4研究会
  • Invited
• [Presentation] M2マクロファージはToll様受容体7-IRF8シグナルを介してIgG4関連疾患におけるIL-1誘導型炎症を惹起する (2019)
  • Author(s): 鎮守晃、森山雅文、中村誠司
  • Organizer: 第73回 日本口腔科学会 学術集会
  • Invited
• [Presentation] Activated M2 macrophage via its Toll-like receptor 7 contributes to the pathogenesis of IgG4-related disease (2018)
  • Author(s): Noriko Ishiguro, Masafumi Moriyama, Miho Ohta, Masaki Yamauchi, Haque A. S. M. Rafiul, Mizuki Sakamoto, Keita Mochizuki, Ryusuke Munemura, Jun-Nosuke Hayashida, and Seiji Nakamura
  • Organizer: 14th International Sjogren's Symposium
  • Int'l Joint Research
• [Presentation] Clinicopathological analysis of labial salivary gland tissues from patients with IgG4-related disease (2018)
  • Author(s): Akira Chinju, Masafumi Moriyama, Noriko Ishiguro, Yurie Mikami, Akihiko Tanaka, Takashi Maehara, Sachiko Furukawa, Miho Ohta, Masaki Yamauchi, Haque A. S. M. Rafiul, Mizuki Sakamoto, Keita Mochizuki, Ryusuke Munemura, Jun-Nosuke Hayashida, and Seiji Nakamura
  • Organizer: 14th International Sjogren's Symposium
  • Int'l Joint Research
• [Presentation] 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 (2018)
  • Author(s): 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
  • Organizer: 第63回日本口腔外科学会・総会
  • Invited
• [Presentation] IgG4関連涙腺・唾液腺炎（ミクリッツ病）の病態と診断 (2018)
  • Author(s): 森山雅文、清水真弓、坂本瑞樹、鎮守晃、望月敬太、宗村龍祐、前原隆、山内昌樹、石黒乃理子、中村誠司
  • Organizer: 第27回 日本シェーグレン症候群学会
  • Invited
• [Presentation] IgG4 関連涙腺・唾液腺炎の診断における口唇腺生検および超音波検査の有用性 (2018)
  • Author(s): 坂本瑞樹、森山雅文、清水真弓、鎮守晃、望月敬太、宗村龍佑、大山恵子、前原隆、緒方謙一、太田美穂、山内昌樹、石黒乃理子、松村万由、中村誠司
  • Organizer: 第28回日本口腔内科学会・第31回日本口腔診断学会 合同学術大会
• [Presentation] Possible involvement of innate immunity in the pathogenesis of IgG4-RD (2017)
  • Author(s): Seiji Nakamura, Masafumi Moriyama, Noriko Ishiguro, Akihiko Tanaka, Takashi Maehara, Sachiko Furukawa, Miho Ohta, Masaki Yamauchi, Mizuki Sakamoto, and Jun-Nosuke Hayashida
  • Organizer: Third International Symposium on IgG4-Related Disease and Fibrosis
  • Int'l Joint Research / Invited
• [Presentation] Activating mechanism of innate immunity via toll-like receptors in IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) (2017)
  • Author(s): Noriko Ishiguro, Masafumi Moriyama, Sachiko Furukawa, Akihiko Tanaka, Takashi Maehara, Miho Ohta, Masaki Yamauchi, Mizuki Sakamoto, Jun-Nosuke Hayashida, and Seiji Nakamura
  • Organizer: Third International Symposium on IgG4-Related Disease and FibrosisThird International Symposium on IgG4-Related Disease and Fibrosis
  • Invited
• [Presentation] The diagnostic utility of labial salivary gland biopsy in IgG4-related disease (2017)
  • Author(s): Mizuki Sakamoto, Masafumi Moriyama, Akihiko Tanaka, Takashi Maehara, Sachiko Furukawa, Miho Ohta, Masaki Yamauchi, Noriko Ishiguro, Jun-Nosuke Hayashida, and Seiji Nakamura
  • Organizer: Third International Symposium on IgG4-Related Disease and Fibrosis
  • Invited
• [Presentation] Interleukin-33 produced by M2 macrophages and other immune cells contributes to Th2 immune reaction of IgG4-related disease (2017)
  • Author(s): Masafumi Moriyama, Sachiko Furukawa, Takashi Maehara, Akihiko Tanaka, Miho Ohta, Noriko Ishiguro, Masaki Yamauchi, Mizuki Sakamoto, and Seiji Nakamura
  • Organizer: Third International Symposium on IgG4-Related Disease and Fibrosis
  • Invited
• [Presentation] DNA microarray analysis of submandibular glands in IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) indicates a role for macrophage receptor with collagenous structure (MARCO) (2017)
  • Author(s): Miho Ohta, Masafumi Moriyama, Akihiko Tanaka, Takashi Maehara, Sachiko Furukawa, Jun-Nosuke Hayashida, Masaki Yamauchi, Noriko Ishiguro, Mizuki Sakamoto, and Seiji Nakamura
  • Organizer: Third International Symposium on IgG4-Related Disease and Fibrosis
  • Invited
• [Book] 臨床医必読 最新IgG4関連疾患 改訂第2版 (2019)
  • Author(s): 岡崎 和一
  • Total Pages: 240
  • Publisher: 診断と治療社
  • ISBN: 9784787824394
• [Book] シェーグレン症候群の診断と治療マニュアル (2018)
  • Author(s): 日本シェーグレン症候群学会
  • Total Pages: 268
  • Publisher: 診断と治療社
  • ISBN: 9784787823694
• [Book] 別冊 BIO Clinica 慢性炎症と疾患 通巻20号 第7巻第3巻 (2018)
  • Author(s): 森 良之
  • Total Pages: 146
  • Publisher: 北隆館
• [Book] 「臨床免疫・アレルギー科 第67巻 第4号」 IgG4関連疾患の病態形成における自然免疫活性化機構 (2017)
  • Author(s): 森山雅文、中村誠司
  • Total Pages: 448
  • Publisher: 科学評論社