Japan-U.S. joint Research for establishment of international disease concept and new diagnostic criteria of IgG4-related disease

• Project/Area Number: 17H04671
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 海外学術
• Research Field: Surgical dentistry
• Research Institution: Kyushu University
• Principal Investigator: Moriyama Masafumi 九州大学, 歯学研究院, 助教 (20452774)
• Co-Investigator(Kenkyū-buntansha): 佐藤 康晴 岡山大学, 保健学研究科, 教授 (00579831) ; 中村 誠司 九州大学, 歯学研究院, 教授 (60189040)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2019: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
• Keywords: IgG4関連疾患 / 日米国際共同研究 / 診断基準 / 国際共同研究 / 国際的疾患概念 / 日米共同研究 / ヘルパーT細胞 / 自然免疫 / 病態

Outline of Final Research Achievements

We performed the exhaustive gene expression analysis using by the salivary glands from Japanese and American IgG4-related disease. MMP9 and CCL18 were extracted as differentially expressed genes. PCR validated significantly higher expression of CCL18. Immunohistochemical analysis confirmed that the expression pattern of CCL18 was similar to that of the M2 macrophage marker CD163.
CCL18 was identified as a disease-associated molecule in IgG4-RD by DNA microarray. Moreover, M2 macrophages might contribute to the initiation of IgG4-RD via CCL18

Academic Significance and Societal Importance of the Research Achievements

IgG4関連疾患は新規疾患であることから、その研究拠点はきわめて限定的であり、さらに臨床所見および研究結果にも本邦と海外では差異がある。そこで本研究では、欧米の研究拠点である米国のRagon 研究所と共同で、人種間の臨床統計および免疫学的検討を行った。その結果、日米共通の疾患関連分子（CCL18）を同定しており、今後は再発の多いステロイド治療に代わる新しい分子標的治療の開発が期待される。

Research Products

• [Int'l Joint Research] Ragon研究所(米国)
• [Journal Article] CD4+ and CD8+ cytotoxic T lymphocytes may induce mesenchymal cell apoptosis in IgG4-related disease (2021)
  • Author(s): Perugino Cory A., Moriyama Masafumi（28名中24番目）, et al.
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 147 Issue: 1 Pages: 368-382
  • DOI: 10.1016/j.jaci.2020.05.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Secreted factors from dental pulp stem cells improve sjogre’s syndrome via regulatory T cell-mediated immunosuppression (2021)
  • Author(s): Matsumura-Kawashima et al.
  • Journal Title: Stem Cell Research & Therapy Volume: 2021 Issue: 1 Pages: 1-16
  • DOI: 10.1186/s13287-021-02236-6
  • Peer Reviewed / Open Access
• [Journal Article] Dental pulp-derived stem cell-conditioned media attenuates secondary Sj?gren's syndrome via suppression of inflammatory cytokines in the submandibular glands (2021)
  • Author(s): Ogata Kenichi、Matsumura-Kawashima Mayu、Moriyama Masafumi、Kawado Tatsuya、Nakamura Seiji
  • Journal Title: Regenerative Therapy Volume: 16 Pages: 73-80
  • DOI: 10.1016/j.reth.2021.01.006
  • Peer Reviewed / Open Access
• [Journal Article] Association of circulating SLAMF7+Tfh1 cells with IgG4 levels in patients with IgG4-related disease. (2020)
  • Author(s): Higashioka K, Ota Y, Maehara T, et. al.
  • Journal Title: BMC Immunol. Volume: 21 Issue: 1 Pages: 31-31
  • DOI: 10.1186/s12865-020-00361-0
  • Peer Reviewed / Open Access
• [Journal Article] Review of a novel disease entity, immunoglobulin G4-related disease (2020)
  • Author(s): Maehara Takashi、Moriyama Masafumi、Nakamura Seiji
  • Journal Title: Journal of the Korean Association of Oral and Maxillofacial Surgeons Volume: 46 Issue: 1 Pages: 3-3
  • DOI: 10.5125/jkaoms.2020.46.1.3
  • Peer Reviewed / Open Access
• [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] シェーグレン症候群患者におけるM3 型ムスカリン受容体アゴニスト長期投与による治療効果の検討 (2020)
  • Author(s): 坂本瑞樹、森山雅文、清水真弓、緒方謙一、石黒乃理子、鎮守晃、太田美穂、中村誠司
  • Journal Title: 日本口腔内科学会雑誌 Volume: 26 Pages: 77-83
  • NAID: 130008059510
  • Peer Reviewed / Open Access
• [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] 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] 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] 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] 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] 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] 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] IL-1 inducing inflammation by CD163+ M2 macrophages contributes to the fibrosis of IgG4-related disease via TLR7/IRAK4/NFkB signaling. (2021)
  • Author(s): Akira Chinju, Masafumi Moriyama, Noriko Ishiguro, Miho Ohta, Takashi Maehara, Akihiko Tanaka, Mizuki Sakamoto, Haque A.S.M. Rafiul, Keita Mochizuki, Yuko Ono, Ryusuke Munemura, Jun-Nosuke Hayashida, Seiji Nakamura
  • Organizer: Oral Bioscience & OBT Research Center Joint International Symposium 2021
  • Int'l Joint Research / Invited
• [Presentation] Toll様受容体7（TLR7）に着目したIgG4関連疾患モデルマウスの樹立 (2020)
  • Author(s): 森山雅文、石黒乃理子、鎮守晃、坂本瑞樹、古庄克宏、太田美穂、望月敬太、宗村龍祐、前原隆、中村誠司
  • Organizer: 第65回 （公社）日本口腔外科学会総会・学術大会
• [Presentation] IgG4関連疾患においてTLR7はIRAK4/NFκBシグナルを介して線維化を惹起する (2020)
  • Author(s): 鎮守晃、森山雅文、柿添乃理子、古庄克宏、前原隆、伊東美穂、坂本瑞樹、望月敬太、宗村 龍祐、中村誠司
  • Organizer: 第65回 （公社）日本口腔外科学会総会・学術大会
• [Presentation] ヒト歯髄幹細胞培養上清を用いたシェーグレン症候群に対する免疫抑制能の検討 (2020)
  • Author(s): 川島（松村） 万由、緒方謙一、森山雅文、川戸達也、中村誠司
  • Organizer: 第65回 （公社）日本口腔外科学会総会・学術大会
• [Presentation] 口腔扁平苔癬の病態形成に関わるヘルパーT細胞とその活性機序について (2020)
  • Author(s): 森山雅文
  • Organizer: 第33回 日本口腔診断学会・第30回日本口腔内科学会・第10回日本口腔検査学会 合同学術大会
  • Invited
• [Presentation] Usefulness of labial salivary gland biopsy for the diagnosis and estimation of disease activity of IgG4-related disease (2018)
  • Author(s): Mizuki Sakamoto, Masafumi Moriyama, Noriko Ishiguro, Yurie Mikami, Akihiko Tanaka, Takashi Maehara, Sachiko Furukawa, Miho Ohta, Masaki Yamauchi, Haque A. S. M. Rafiul, Akira Chinju, Keita Mochizuki, Ryusuke Munemura, Jun-Nosuke Hayashida, and Seiji Nakamura
  • Organizer: 14th International Sjogren's Symposium
  • Int'l Joint Research
• [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
  • Organizer: 第27回 日本シェーグレン症候群学会
  • Invited
• [Presentation] TLR7+CD163+ M2 macrophages promote the initiation of IgG4-related disease. (2017)
  • Author(s): Noriko ISHIGURO, Masafumi MORIYAMA, and Seiji NAKAMURA
  • Organizer: 第 65 回 国際歯科研究学会日本部会
• [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 Fibrosis
  • Int'l Joint Research
• [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] 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
  • Int'l Joint Research
• [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
  • Int'l Joint Research
• [Book] 新臨床内科学 ［デスク判］ 第10版 (2020)
  • Author(s): 森山雅文
  • Total Pages: 2002
  • Publisher: 医学書院
  • ISBN: 9784260038065
• [Book] 「別冊BIO Clinica 第7巻 第3号」5. 唾液腺炎・IgG4関連疾患. (2018)
  • Author(s): 森山雅文、中村誠司
  • Total Pages: 146
  • Publisher: 北隆館
• [Book] 「日本医事新報 No. 4939」 特集 唾液腺・涙腺病変からみたIgG4関連疾患の進歩 3. IgG4関連疾患の病態形成機序 -涙腺・唾液腺より (2018)
  • Author(s): 森山雅文、中村誠司
  • Total Pages: 100
  • Publisher: 日本医事新報社
• [Book] 臨床免疫・アレルギー科 第67巻 第4号 (2017)
  • Author(s): 森山 雅文、中村 誠司
  • Total Pages: 448
  • Publisher: 科学評論社