Mast cells can produce transforming growth factor b1 and promote tissue fibrosis during the development of Sjogren's syndrome-related sialadenitis

• Project/Area Number: 19K08898
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Kurume University
• Principal Investigator: Kaieda Shinjiro 久留米大学, 医学部, 准教授 (20330798)
• Co-Investigator(Kenkyū-buntansha): 星野 友昭 久留米大学, 医学部, 教授 (00261066)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: シェーグレン症候群 / マスト細胞 / 唾液腺炎 / 組織線維化 / TGFβ / HMC-1 / 線維芽細胞 / Type I collgen

Outline of Research at the Start

シェーグレン症候群は自己免疫が病因として考えられるが、その発症機序には未解明な部分が多く、根本治療は未だ確立されていない。眼および口腔乾燥症状により患者のQOLは著しく低下し、慢性に経過することから新規治療法の確立は急務である。本研究で、マスト細胞のシェーグレン症候群における唾液腺炎への関与について注目している。先行実験でマスト細胞は唾液腺炎局所で増殖し、マスト細胞数と唾液分泌能低下が有意に相関することを明らかにした。本研究で唾液腺炎におけるマスト細胞の機能解析を行い、マスト細胞およびその関連分子を標的とした新規治療法の確立を目標に本研究を立案した。

Outline of Final Research Achievements

This study investigated the associations of mast cells with immune-mediated inflammation and fibrosis in patients with primary　Sjogren’s syndrome (pSS). Mast cell numbers in labial salivary glands were significantly greater in pSS than in control individuals. In salivary glands from patients with pSS, mast cell number was significantly correlated with fibrosis extent; moreover, mast cells were located　near fibrous tissue and expressed TGFβ1. Col1a and TGFβ1 mRNAs were upregulated in cocultured fibroblasts and HMC-1 cells, respectively. Fibroblasts cultured in HMC-1 conditioned medium exhibited upregulation of Col1a mRNA; this was abrogated by TGFβ1 neutralizing antibodies.　 Mast cell numbers were elevated in patients with pSS-related sialadenitis; these cells were located near fibroblasts and expressed TGFβ1. TGFβ1 could induce collagen synthesis in fibroblasts, which might contribute to fibrosis.

Academic Significance and Societal Importance of the Research Achievements

シェーグレン症候群は唾液や涙液分泌が障害され慢性的に乾燥症状が持続し、QOLが低下する難治性疾患である。唾液腺炎症を抑制する根本治療は確立されておらず対症療法が主となっている。本研究ではマスト細胞が唾液腺炎症部位で増殖し、TGFβ1を産生を介して線維芽細胞によるコラーゲン線維産生を促進することを明らかにした。シェーグレン症候群においてマスト細胞およびTGFβ1を阻害することで組織線維化を抑制し唾液分泌能低下を軽減させる新規治療法の確立が期待される。

Research Products

• [Journal Article] Cancer-associated Dermatomyositis with Histiocytic Sarcoma (2022)
  • Author(s): Masahiro Tsutsumi, Yasumasa Shimasaki, Takuma Koga, Shinjiro Kaieda
  • Journal Title: Internal Medicine Volume: 61 Issue: 2 Pages: 277-278
  • DOI: 10.2169/internalmedicine.7995-21
  • NAID: 130008141772
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-01-15
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Characteristics of Anti-TIF-1γ Antibody-Positive Dermatomyositis Associated with Malignancy (2022)
  • Author(s): Yumi Harada, Masaki Tominaga, Eriko Iitoh, Shinjiro Kaieda, Takuma Koga, Kiminori Fujimoto, Tomonori Chikasue, Hitoshi Obara, Tatsuyuki Kakuma, Hiroaki Ida, Totmoaka Kawayama, Tomoaki Hoshino
  • Journal Title: Journal of Clinical Medicine Volume: 11 Issue: 7 Pages: 1-10
  • DOI: 10.3390/jcm11071925
  • Peer Reviewed / Open Access
• [Journal Article] Subcutaneous Cheek Nodule Associated with Granulomatosis with Polyangiitis (2021)
  • Author(s): Makiko Hayashi, Shinjiro Kaieda, Aya Kawaguchi, Masahiro Tsutsumi, Yumi Harada, Takuma Koga , Jun Akiba, Tomoaki Hoshino, Hiroaki Ida
  • Journal Title: Internal Medicine Volume: 60 Issue: 23 Pages: 3823-3826
  • DOI: 10.2169/internalmedicine.6541-20
  • NAID: 130008123627
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-12-01
  • Peer Reviewed / Open Access
• [Journal Article] Mast cells can produce transforming growth factor β1 and promote tissue fibrosis during the development of Sjogren's syndrome-related sialadenitis. (2021)
  • Author(s): Kaieda S, Fujimoto K, Todoroki K, Abe Y, Kusukawa J, Hoshino T, Ida H
  • Journal Title: Modern Rheumatology Volume: in press Issue: 4 Pages: 761-769
  • DOI: 10.1093/mr/roab051
  • Peer Reviewed / Open Access
• [Journal Article] Epstein-Barr Virus-Related Lymphoproliferative Disorders-Associated Polymyositis in a Patient With Rheumatoid Arthritis (2021)
  • Author(s): Shinjiro Kaieda, Takuma Koga, Kyohei Yamada, Hiroaki Ida
  • Journal Title: Journal of Clinical Rheumatology Volume: 27
  • Peer Reviewed
• [Journal Article] MEFV E148Q variant is more associated with familial Mediterranean fever when combined with other non-exon 10 MEFV variants in Japanese patients with recurrent fever (2021)
  • Author(s): Fujimoto K, Hidaka Y, Koga T, Kaieda S, Yamasaki S, Nakashima M, Hoshino T, Yamamoto K, Nishikomori R, Ida H
  • Journal Title: Modern Rheumatology Volume: in Press Issue: 6 Pages: 1208-1214
  • DOI: 10.1080/14397595.2021.1880534
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and Genetic Analysis of 22 Japanese Patients with Familial Mediterranean Fever: An Examination of <i>MEFV</i> and 10 Other Genes Related to Autoinflammatory Syndromes (2020)
  • Author(s): Fujimoto K, Hidaka Y, Koga T, Kaieda S, Yamasaki S, Nakashima M, Hoshino T, Ida H
  • Journal Title: Internal Medicine Volume: 59 Issue: 11 Pages: 1373-1378
  • DOI: 10.2169/internalmedicine.3778-19
  • NAID: 130007850356
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-06-01
  • Peer Reviewed / Open Access
• [Journal Article] CD163 deficiency facilitates lipopolysaccharide-induced inflammatory responses and endotoxin shock in mice (2020)
  • Author(s): Fujiwara Y, Ohnishi K, Horlad H, Saito Y, Shiraishi D, Takeya H, Yoshii D, Kaieda S, Hoshino T, Komohara Y.
  • Journal Title: Clinical Translational Immunology Volume: 25 Issue: 9
  • DOI: 10.1002/cti2.1162
  • Peer Reviewed / Open Access
• [Journal Article] Share Epstein-Barr Virus-Related Lymphoproliferative Disorders-Associated Polymyositis in a Patient With Rheumatoid Arthritis (2020)
  • Author(s): Kaieda S, Koga T, Yamada K, Ida H
  • Journal Title: Journal of Clinical Rheumatology Volume: in Press
  • Peer Reviewed
• [Journal Article] Evaluation of usefulness in surfactant protein D as a predictor of mortality in myositis-associated interstitial lung disease (2020)
  • Author(s): Kaieda S, Gono T, Masui K, Sato S, Kuwana M, JAMI Investigators
  • Journal Title: PLoS One Volume: 15 Issue: 6 Pages: e0234523-e0234523
  • DOI: 10.1371/journal.pone.0234523
  • Peer Reviewed / Open Access
• [Journal Article] 肥満細胞は関節リウマチの疾患活動性と相関し自己抗体産生に寄与する (2020)
  • Author(s): 海江田信二郎
  • Journal Title: リウマチ科 Volume: 63 Pages: 325-328
• [Journal Article] 関節炎におけるマスト細胞の関与 (2020)
  • Author(s): 海江田信二郎
  • Journal Title: 久留米医学会雑誌 Volume: 83 Pages: 124-127
• [Journal Article] Juxta-vertebral Lesions Associated with Granulomatosis with Polyangiitis (2019)
  • Author(s): Yoshida Y, Kaieda S, Furuta T, Ida H
  • Journal Title: Internal Medicine Volume: 58 Issue: 17 Pages: 2587-2588
  • DOI: 10.2169/internalmedicine.2903-19
  • NAID: 130007700178
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2019-09-01
  • Peer Reviewed / Open Access
• [Journal Article] Elevation of Pulmonary CD163 + and CD204 + Macrophages Is Associated With the Clinical Course of Idiopathic Pulmonary Fibrosis Patients (2019)
  • Author(s): Nouno T, Okamoto M, Ohnishi K, Kaieda S, Tominaga M, Zaizen Y, Ichiki M, Momosaki S, Nakamura M, Fujimoto K, Fukuoka J, Shimizu S, Komohara Y, Hoshino T.
  • Journal Title: Journal of Thoracic Disease Volume: 11 Issue: 9 Pages: 4005-4017
  • DOI: 10.21037/jtd.2019.09.03
  • Peer Reviewed / Open Access
• [Journal Article] A Retrospective Study of the Tolerability of Nintedanib for Severe Idiopathic Pulmonary Fibrosis in the Real World (2019)
  • Author(s): Nakamura M, Okamoto M, Fujimoto K, Ebata T, Tominaga M, Nouno T, Zaizen Y, Kaieda S, Tsuda T, Kawayama T, Hoshino T
  • Journal Title: Annals of Translational Medicine Volume: 7 Issue: 12 Pages: 262-270
  • DOI: 10.21037/atm.2019.05.33
  • Peer Reviewed / Open Access
• [Journal Article] Signal intensity of superb micro-vascular imaging associates with the activity of vascular inflammation in Takayasu arteritis. (2019)
  • Author(s): Ito S, Tahara N, Hirakata S, Kaieda S, Tahara A, Maeda-Ogata S, Bekki M, Sugiyama Y, Honda A, Igata S, Kuromatsu R, Nakashima O, Fukumoto Y.
  • Journal Title: J Nucl Cardiol Volume: in press Issue: 3 Pages: 1063-1065
  • DOI: 10.1007/s12350-019-01665-4
  • Peer Reviewed / Int'l Joint Research
• [Presentation] シェーグレン症候群における唾液腺炎に対するマスト細胞の関与 (2021)
  • Author(s): 海江田信二郎 井田弘明
  • Organizer: 日本シェーグレン症候群学会学術集会
• [Presentation] Mast Cells Contribute to the Development of Lung Fibrosis via Inducing Myofibroblast Differentiation by TGF-β Production (2021)
  • Author(s): Kaieda S, Okamoto M, Tominaga M, Hoshino T
  • Organizer: 2021 アメリカリウマチ学会年次総会
  • Int'l Joint Research
• [Presentation] Mast Cells Contribute to the Development of Sialadenitis Associated with Soogren’s Syndrome via Inducing Tissue Fibrosis by TGFβ Production (2020)
  • Author(s): Shinjiro Kaieda1, Kyoko Fujimoto1 and Hiroaki Ida
  • Organizer: 2020 American College of Rheumatology annual meeting
  • Int'l Joint Research
• [Presentation] シェーグレン症候群に対するマスト細胞の関与 (2019)
  • Author(s): 海江田信二郎
  • Organizer: 第63回日本リウマチ学会総会
• [Presentation] Surfactant Protein D as a Useful Predictor for Mortality in Myositis-associated Interstitial Lung Disease: A Dimorphic Model Based on anti-MDA5 Antibody (2019)
  • Author(s): Shinjiro Kaieda, Takahisa Gono , Kenichi Masui , Naoshi Nishina , Shinji Sato and Masataka Kuwana
  • Organizer: 2019 ACR/ARP Annual Meeting
  • Int'l Joint Research