An investigation of the pathogenic mechanism of IgG4-related disease focusing on the scavenger receptor "MARCO"

• Project/Area Number: 17K17265
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Surgical dentistry
• Research Institution: Kyushu University
• Principal Investigator: ITO Miho 九州大学, 大学病院, 医員 (20778857)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: IgG4 関連疾患 / コラーゲン様構造マクロファージ 受容体 / 自然免疫 / IgG4関連疾患 / コラーゲン様構造マクロファージ受容体 / MARCO / Toll様受容体 / Toll-like Receptor / TLR / スカベンジャー受容体

Outline of Final Research Achievements

IgG4-related disease (IgG4-RD) is a novel systemic disease entity characterized by elevated serum IgG4 and tissue infiltration of IgG4-positive plasma cells accompanied by severe fibrosis. Although recent studies demonstrated that innate immune cells including monocytes and macrophages might promote local fibrosis and IgG4 production, the pathological mechanism remains unclear.
Macrophage receptor with collagenous structure (MARCO) and Toll-like Receptor (TLR) 7 were identified as disease-associated molecule in IgG4-RD by DNA microarray in submandibular glands from patients with IgG4-RD. Immunohistochemical analysis confirmed that these molecules expression co-localized with CD163+ M2 macrophages. Moreover, M2 macrophages might contribute to the initiation of IgG4-RD via MARCO and TLR7.

Academic Significance and Societal Importance of the Research Achievements

IgG4-RD 発症に MARCO や TLR 7 を介した機序が示唆され、これにより今後、難航しているIgG4-RDモデルマウスの確立、現在の治療の第一選択薬であるステロイドに代わる新しい分子標的治療にも繋がる可能性が多いに期待される。

Research Products

• [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] 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): Mizuki Sakamoto, Masafumi Moriyama, Mayumi Shimizu, Akira Chinju, Keita Mochizuki, Ryusuke Munemura, Keiko Ohyama, takashi maehara, Kenichi Ogata, Miho Ohta, Masaki Yamauchi, Noriko Ishiguro, Mayu Matsumura, Yukiko Ohyama, Tamotsu Kiyoshima, Seiji Nakamura
  • Journal Title: Modern Rheumatology Volume: 30 Pages: 379-384
  • 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
• [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(招待講演)(国際学会)
  • 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] M3型ムスカリン受容体アゴニストの長期投与による唾液分泌量の経時的変化と治療効果に関わる因子についての検討 (2019)
  • Author(s): 坂本瑞樹、森山雅文、林田淳之介、大山恵子、前原隆、緒方謙一、石黒乃理子、松村万由、 鎮守晃、望月敬太、宗村龍祐、太田美穂、中村誠司
  • Organizer: 第73回 日本口腔科学会 学術集会
• [Presentation] 口唇腺生検と顎下腺超音波検査は、IgG4 関連涙腺・唾液腺炎の診断に有用か? (2019)
  • Author(s): 坂本瑞樹、森山雅文、清水真弓、鎮守晃、望月敬太、前原 隆、太田美穂、石黒乃理子、林田淳之將、中村誠司
  • Organizer: 第64回日本口腔外科学会総会・学術集会
• [Presentation] シェーグレン症候群患者に対するM3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 (2019)
  • Author(s): 坂本瑞樹、森山雅文、林田淳之介、清水真弓、大山恵子、前原隆、緒方謙一、石黒乃理子、松村万由、鎮守 晃、望月敬太、宗村龍祐、太田美穂、中村誠司
  • Organizer: 第28回日本シェーグレン症候群学会
• [Presentation] IgG4 関連疾患において M2 マクロファージはToll 様受容体 7-IRAK4 シグナルを介してIL-1 誘導型炎症を惹起する (2019)
  • Author(s): 鎮守晃、森山雅文、石黒乃理子、古庄克宏、前原隆、坂本瑞樹、田中昭彦、古川祥子、山内昌樹、太田美穂、望月敬太、宗村龍祐、林田淳之將、中村誠司
  • Organizer: 第28回日本シェーグレン症候群学会
• [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、石黒乃理子、古庄克宏、前原隆、坂本瑞樹、田中昭彦、古川祥子、山内昌樹、太田美穂、望月敬太、宗村龍祐、林田淳之將、中村誠司
  • Organizer: 第73回日本口腔科学会学術集会
• [Presentation] CD68+ monocyte/macrophage via TLR8/TNF-α signaling contributes to the pathogenesis of Sjogren’s syndrome (2019)
  • Author(s): Mizuki SAKAMOTO, Masafumi MORIYAMA, Keiko OYAMA, Takashi MAEHARA, Kenichi OGATA, Miho OHTA, Noriko ISHIGURO, Haque A. S. M. RAFIUL, Akira CHINJU, Keita MOCHIZUKI, Mayu MATSUMURA, Ryusuke MUNEMURA, and Seiji NAKAMURA
  • Organizer: The 60th Congress of Korean Association of Oral & Maxillofacial Surgeons
  • Int'l Joint Research
• [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、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11回 IgG４研究会
• [Presentation] シェーグレン症候群の病態形成におけるToll様受容体を介した自然免疫の関与 (2018)
  • Author(s): 坂本 瑞樹、森山 雅文、大山 恵子、田中 昭彦、前原 隆、緒方 謙一、古川 祥子、太田 美穂、山内 昌樹、石黒 乃理子、Haque A. S. M. Rafiul、鎮守 晃、望月 敬太、松村 万由、宗村 龍祐、林田 淳之將、中村 誠司
  • Organizer: 第72回口腔科学会学術集会
• [Presentation] Involvement of innate immune responses in the pathogenesis ofSjogren’s syndrome via Toll like receptor 8 (2018)
  • Author(s): Mizuki SAKAMOTO, Masafumi MORIYAMA, Keiko OYAMA, Akihiko TANAKA, Takashi MAEHARA, Kenichi OGATA, Sachiko FURUKAWA, Miho OHTA, Masaki YAMAUCHI, Noriko ISHIGURO, Haque A. S. M. RAFIUL, Akira CHINJU, Keita MOCHIZUKI, Mayu MATSUMURA, Ryusuke MUNEMURA, Jun-Nosuke HAYASHIDA, and Seiji NAKAMURA
  • Organizer: The 59th Congress of Korean Association of Oral & Maxillofacial Surgeons
  • Int'l Joint Research
• [Presentation] DNA microarray analysis of labial salivary gland in Sjogren’s syndrome indicates a role for innate immune responses in its pathogenesis via Toll like receptor 8 (2018)
  • Author(s): Mizuki Sakamoto, Masafumi Moriyama, Keiko Oyama, Akihiko Tanaka, Takashi Maehara,、Sachiko Furukawa, Miho Ohta, Masaki Yamauchi, Noriko Ishiguro, Miho Ohta, Masaki Yamauchi, Haque A. S. M. Rafiul, Akira Chinju, Keita Mochizuki, Ryusuke Munemura Jun-Nosuke Hayashida, and Seiji Nakamura
  • Organizer: 第14回国際シェーグレン症候群学会
  • 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, Mizuki Sakamoto, Haque A. S. M. Rafiul, Keita Mochizuki, Ryusuke Munemura, Jun-Nosuke Hayashida, and Seiji Nakamura
  • Organizer: 第14回国際シェーグレン症候群学会
  • Int'l Joint Research