New strategy targeted at innate immunity for the pathologic clarification of new disease concept "IgG4-related disease"

• Project/Area Number: 26293430
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• 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): 中村 誠司 九州大学, 歯学研究院, 教授 (60189040) ; 中島 衡 福岡大学, 医学部, 教授 (70188960) ; 坪井 洋人 筑波大学, 医学医療系, 講師 (80580505)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2017: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2014: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: IgG4関連疾患 / 自然免疫 / Toll様受容体 / IL-33 / マクロファージ / Toll 様受容体 / M2 マクロファージ / ミクリッツ病

Outline of Final Research Achievements

IgG4-related disease (IgG4-RD) is a unique inflammatory disorder. In addition, recent studies have also implicated the Toll-like receptor (TLR) pathway. Here, we examined the expression of TLRs in salivary glands (SGs) from patients with IgG4-RD. In patients with IgG4-RD, TLR7 was overexpressed compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of TLR7-positive cells in the SGs of patients with IgG4-RD. Double immunohistochemical staining showed that TLR7 expression co-localized with CD163+ M2 macrophages. In huTlr7 Tg mice, the focus and fibrosis score in SMGs, pancreas, and lungs were significantly higher than those in wild-type mice. Moreover, the concentration of serum IgG in huTlr7 Tg mice was significantly higher than that in wild-type mice and distinctly increased upon stimulation with TLR7 agonist. Thus, huTlr7 Tg mice could lead to the establishment of a mouse model of IgG4-RD.

Research Products

• [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] 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] 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] Comparison of performance of the 2016 ACR-EULAR classification criteria for primary Sjogren’s syndrome with other sets of criteria in Japanese patients. (2017)
  • Author(s): Tsuboi H., Hagiwara S., Asashima H., Takahashi H., Harota T., Noma H., Umehara H., Kawakami A., Nakamura H., Sano H., Tsubota K., Ozawa Y., Takamura E., Saito I., Inoue H., Nakamura S., Moriyama M., Takeuchi T., Tanaka Y., Hirata S., Mimori T., Matsumoto I., Sumida T.
  • Journal Title: Ann. Rheum. Dis. Volume: 3 Issue: 12 Pages: 2016-210758
  • DOI: 10.1136/annrheumdis-2016-210758
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
• [Journal Article] DNA microarray analysis of submandibular glands in IgG4-related disease indicates a role for MARCO and other innate immune related proteins (2016)
  • Author(s): Ohta M, Moriyama M, Maehara T, Gion Y, Furukawa S, Tanaka A, Hayashida JN, Yamauchi M, Ishiguro N, Mikami Y, Tsuboi H, Iizuka-Koga M, Kawano S, Sato Y, Kiyoshima T, Sumida T, Nakamura S.
  • Journal Title: Medicine Volume: 97 Issue: 7 Pages: e2853-e2853
  • DOI: 10.1097/md.0000000000002853
  • NAID: 120007135530
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The diagnostic utility of labial salivary gland biopsy in IgG4-related disease (2016)
  • Author(s): Moriyama M, Ohta M, Furukawa S, Mikami Y, Tanaka A, Maehara T, Yamauchi M, Ishiguro N, Hayashida JN, Kawano S, Ohyama Y, Kiyoshima T, Nakamura S.
  • Journal Title: Mod Rheumatol Volume: 3 Issue: 5 Pages: 1-5
  • DOI: 10.3109/14397595.2016.1148225
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] IgG4関連疾患の病態形成おける自然免疫の関与 －特にM2マクロファージに注目して－ (2016)
  • Author(s): 森山 雅文
  • Journal Title: アレルギーの臨床 Volume: 36 Pages: 1273-1277
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Saliva as a potential tool for diagnosis of dry mouth including Sjogren's syndrome. (2015)
  • Author(s): Ohyama K, Moriyama M et al.
  • Journal Title: Oral Dis Volume: 21(2) Issue: 2 Pages: 224-231
  • DOI: 10.1111/odi.12252
  • Peer Reviewed / Open Access
• [Journal Article] A case of marginal zone B cell lymphoma mimicking IgG4-related dacryoadenitis and sialoadenitis. (2015)
  • Author(s): Ohta M, Moriyama M, Goto Y, Kawano S, Tanaka A, Maehara T, Furukawa S, J Hayashida JN, Kiyoshima T, Shimizu M, Arinobu Y, Nakamura S.
  • Journal Title: World J Surg Oncol Volume: 13 Issue: 1 Pages: 67-67
  • DOI: 10.1186/s12957-015-0459-z
  • Peer Reviewed / Open Access
• [Journal Article] A case of mantle cell lymphoma presenting as IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease (2015)
  • Author(s): Hayashi Y, Moriyama M, M Takashi, Goto Y, Kawano S, Ohta M, Tanaka A, Furukawa S, Hayashida JN, Kiyoshima T, Shimizu M, Chikui T, Nakamura S.
  • Journal Title: World J Surg Oncol Volume: 13 Issue: 1 Pages: 225-225
  • DOI: 10.1186/s12957-015-0644-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effectiveness of imaging modalities for screening IgG4-related dacryoadenitis and sialadenitis (Mikulicz’s disease) and for differentiating it from Sjögren’s syndrome (SS), with an emphasis on sonography. (2015)
  • Author(s): Shimizu M, Okamura K, Kise Y, Takeshita Y, Furuhashi H, Weerawanich W, Moriyama M, Ohyama Y, Furukawa S, Nakamura S, Yoshiura K
  • Journal Title: Arthritis Res Ther Volume: 17 Issue: 1 Pages: 223-223
  • DOI: 10.1186/s13075-015-0751-x
  • Peer Reviewed / Open Access
• [Journal Article] Clinical relevance of Kuttner tumour and IgG4-related dacryoadenitis and sialoadenitis. (2014)
  • Author(s): Furukawa S1, Moriyama M, Kawano S, Tanaka A, Maehara T, Hayashida JN, Goto Y, Kiyoshima T, Shiratsuchi H, Ohyama Y, Ohta M, Imabayashi Y, Nakamura S.
  • Journal Title: Oral Dis Volume: 21(2) Issue: 2 Pages: 257-62
  • DOI: 10.1111/odi.12259
  • Peer Reviewed / Open Access
• [Journal Article] Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz’s disease. (2014)
  • Author(s): Furukawa S, Moriyama M, Tanaka A, Maehara T, Tsuboi H, Iizuka M, Hayashida JN, Ohta M, Saeki T, Notohara K, Nakamura S.
  • Journal Title: Clinical Immnology Volume: 156 Issue: 1 Pages: 9-18
  • DOI: 10.1016/j.clim.2014.10.008
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] DNA microarray analysis of labial salivary glands in IgG4-related disease. Comparison with Sjögren’s syndrome. (2014)
  • Author(s): Tsuboi H, Nakai Y, Iizuka1 M, Asashima H, Hagiya C, Tsuzuki S, Hirota T, Miki H, Hagiwara S, Kondo Y, Tanaka A, Moriyama M, Matsumoto I, Nakamura S, Yoshihara T, Abe K, Sumida T.
  • Journal Title: Arthritis and Rheumatology Volume: 66 Issue: 10 Pages: 2892-2899
  • DOI: 10.1002/art.38748
  • Peer Reviewed / Open Access
• [Journal Article] The diagnostic utility of biopsies from the submandibular and labial salivary glands in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz’s disease (2014)
  • Author(s): Moriyama M, Furukawa S, Kawano S, Goto Y, Kiyoshima T, Tanaka A, Maehara T, Hayashida JN, Ohta M, Nakamura S
  • Journal Title: Int J Oral Maxillofac Surg Volume: 43 Issue: 10 Pages: 1276-1281
  • DOI: 10.1016/j.ijom.2014.06.014
  • Peer Reviewed / Open Access
• [Journal Article] T helper subsets in Sjogren’s syndrome and IgG4-related dacryoadenitis and sialoadenitis: A critical review. (2013)
  • Author(s): Moriyama M, et al.
  • Journal Title: J Autoimmun. Volume: in press Pages: 81-88
  • DOI: 10.1016/j.jaut.2013.07.007
  • Peer Reviewed / Open Access
• [Presentation] TLR7を標的としたIgG4関連疾患モデルマウスの検証 (2018)
  • Author(s): 石黒乃理子、森山雅文、古庄克宏、祇園由佳、田中昭彦、前原隆、古川祥子、太田美穂、 坂本瑞樹、鎮守晃、望月敬太、宗村龍祐、林田淳之將、佐藤康晴、三宅健介、中村誠司
  • Organizer: IgG4研究会
• [Presentation] IgG4関連疾患の世界トップレベル IgG4関連疾患の病因 -免疫学的アプローチ- (2016)
  • Author(s): 森山 雅文、田中 昭彦、前原 隆、古川 祥子、太田 美穂、石黒 乃理子、中村 誠司
  • Organizer: 第31回日本臨床リウマチ学会
  • Place of Presentation: 東京
  • Year and Date: 2016-10-30
  • Invited
• [Presentation] Diagnostic utility of labial salivary gland biopsy in IgG4-related disease (2016)
  • Author(s): Moriyama M, Tanaka A, Ohta M, Furukawa S, Maehara T, Yamauchi M, Ishiguro N, Hayashida JN, Nakamura S
  • Organizer: The Annual Meeting of American Academy of Oral Medicine (AAOM) 2016
  • Place of Presentation: Atlanta, USA
  • Year and Date: 2016-04-07
  • Int'l Joint Research
• [Presentation] Management of Xerostomia ~focus on M3 muscarinic receptor agonist~ (2015)
  • Author(s): Masafumi Moriyama
  • Organizer: The 63rd Annual Meeting of Japanese for Dental Research
  • Place of Presentation: Fukuoka
  • Year and Date: 2015-10-30
  • Int'l Joint Research / Invited
• [Presentation] IgG4関連疾患の診断における口唇腺生検の有用性 (2015)
  • Author(s): 森山 雅文、太田 美穂、古川 祥子、三上 友理恵、山内 昌樹、石黒 乃理子、川野 真太郎、大山 順子、清島 保、中村 誠司
  • Organizer: 第60回 日本口腔外科学会総会・学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-16
• [Presentation] IgG4関連疾患の唾液腺病変 ～病態形成に関わるTh細胞の活性化機構～ (2015)
  • Author(s): 森山 雅文、田中 昭彦、前原 隆、古川 祥子、太田美穂、中村 誠司
  • Organizer: 第25回日本口腔内科学会学術大会
  • Place of Presentation: 大阪
  • Year and Date: 2015-09-18
  • Invited
• [Presentation] シェーグレン症候群：診療ガイドラインについて 口腔病変の診断と治療 (2015)
  • Author(s): 森山 雅文、田中 昭彦、前原 隆、古川 祥子、太田美穂、中村 誠司
  • Organizer: 第24回日本シェーグレン症候群学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-09-18
  • Invited
• [Presentation] 当科における口腔乾燥症の診断とマネージメント － M3型ムスカリン受容体アゴニストによるドライマウス治療 － (2015)
  • Author(s): 森山 雅文
  • Organizer: Salivary gland disease ~Summer Seminar in Tenjin~
  • Place of Presentation: 福岡
  • Year and Date: 2015-07-09
  • Invited
• [Presentation] シェーグレン症候群の病態形成におけるＴ細胞サブセットの関与 (2015)
  • Author(s): 森山 雅文、古川 祥子、田中 昭彦、前原 隆、太田 美穂、山内 昌樹、林田 淳之將、中村 誠司
  • Organizer: 第59回 日本リウマチ学会総会・学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-04-23
  • Invited
• [Presentation] IL-33 produced by macrophages promote the pathogenesis of IgG4-related disease (2015)
  • Author(s): S. Furukawa, M. Moriyama, A.Tanaka, T. Maehara, J.-N. Hayashida, M. Ohta, M. Yamauchi and S. Nakamura.
  • Organizer: International Association for Dental Research
  • Place of Presentation: 米国、ボストン
  • Year and Date: 2015-03-12
  • Invited
• [Presentation] IgG4 関連涙腺・唾液腺の疾患概念と免疫学的特徴 (2014)
  • Author(s): 森山 雅文、田中 昭彦、前原 隆、古川 祥子、中村 誠司
  • Organizer: 第24回 日本口腔内科学会・第27回 日本口腔診断学会 合同学術大会
  • Place of Presentation: 福岡
  • Year and Date: 2014-09-20
  • Invited
• [Presentation] Küttner 腫瘍と IgG4 関連涙腺・唾液腺炎の臨床的意義 (2014)
  • Author(s): 古川 祥子、森山 雅文、川野 真太郎、田中 昭彦、前原 隆、林田 淳之介、後藤 雄一、大山 順子、太田 美穂、中村 誠司
  • Organizer: 第23回日本シェーグレン症候群学会学術集会
  • Place of Presentation: 長崎
  • Year and Date: 2014-09-14
• [Presentation] IgG4 関連疾患の病態形成におけるTh 細胞および自然免疫細胞の関与 (2014)
  • Author(s): 森山 雅文、田中 昭彦、前原 隆、古川 祥子、太田 美穂、中村 誠司
  • Organizer: 第55回 日本神経学会学術大会
  • Place of Presentation: 福岡
  • Year and Date: 2014-05-21
  • Invited
• [Book] 臨床免疫・アレルギー科 「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: 6
  • Publisher: 科学評論社
• [Book] ドライシンドロームの基礎と臨床 (2016)
  • Author(s): 中元 雅史、森山 雅文、石原 宏、中尾 光善
  • Total Pages: 7
  • Publisher: メディカルレビュー社
• [Book] 分子リウマチ治療 (2016)
  • Author(s): 森山 雅文
  • Total Pages: 4
  • Publisher: 先端医学社
• [Book] IgG4-Related Kidney Disease (2016)
  • Author(s): Moriyama M, Nakamura S
  • Total Pages: 12
  • Publisher: Springer
• [Book] IgG4関連疾患 実践的臨床から病因へ (2015)
  • Author(s): Th2細胞・制御性T細胞とIgG4関連疾患 (1)
  • Total Pages: 6
  • Publisher: 前田書店
• [Book] 臨床医必読 最新IgG4関連疾患 (2015)
  • Author(s): 3. 唾液腺病変
  • Total Pages: 3
  • Publisher: 診断と治療社
• [Book] 見逃すと怖い膠原病 Q&A100 (2014)
  • Author(s): 森山 雅文
  • Total Pages: 6
  • Publisher: メディカルレビュー社
• [Book] 「臨床放射線 第59巻第8号 8月号」、ミクリッツ病／IgG4関連疾患とシェーグレン症候群の新しい理解 (2014)
  • Author(s): 森山 雅文、中村 誠司
  • Total Pages: 11
  • Publisher: 金原出版株式会社
• [Book] 「IgG4-related disease」、<Imaging> Salivary glands in Mikulicz’s disease (2014)
  • Author(s): Moriyama M, Nakamura S
  • Total Pages: 8
  • Publisher: Springer社