Analysis of pathogenesis of oral lichen planus -Cytokine network connecting dendritic cells and T cells-

• Project/Area Number: 17K11846
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Kyushu University
• Principal Investigator: Hayashida Junnosuke 九州大学, 歯学研究院, 共同研究員 (80432920)
• Co-Investigator(Kenkyū-buntansha): 中村 誠司 九州大学, 歯学研究院, 教授 (60189040)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: カテプシンK / pDC / mDC / 自己免疫性炎症 / Th17 / TLR9 / 口腔扁平苔癬 / サイトカイン / ヘルパーT細胞 / 樹状細胞 / ＴＳＬＰ / リンパ球

Outline of Final Research Achievements

For the purpose of identifying epithelial-derived disease-related molecules involved in the pathogenesis of oral lichen plan (OLP), pathological sections of patients were comprehensively analyzed by DNA microarray. As a result, cathepsin K (CTSK) was extracted as a humoral factor involved in the activation of Th (helper T) cells. CTSK was strongly expressed in the epithelium of the lesion and the infiltration of inflammatory cells immediately below it. Dendritic cells were extracted from human peripheral blood and stimulated with CTSK. As a result, it was suggested that dendritic cells such as mDC and pDC play an important role in the activation of Th subset of OLP.

Academic Significance and Societal Importance of the Research Achievements

WHOはOLPをpremalignant conditionからpotentially malignant disorderと位置づけたが、実際一部のOLP症例では扁平上皮癌への悪性転化が認められるため、OLPの病態進展をいかに抑制するかが治療上重要と考えられた。今回の研究によってカテプシンKがIL-6やIL-23などの炎症性サイトカイン産生を制御することが示唆され、Th17細胞分化を誘導することで自己免疫性炎症を引き起こすことが示唆された。これらの細胞に関与するDCサブセットをさらに明らかにすることで疾患の発症や重症化のメカニズム解明および新規治療薬の開発が期待される。

Research Products

• [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] 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] Oral Methotrexate-related Lymphoproliferative Disease Presenting with Severe Osteonecrosis of the Jaw: A Case Report and Literature Review (2018)
  • Author(s): Furukawa S, Oobu K, Moriyama M, Kawano S, Sako S, Hayashida JN, Matsubara R, Ogata KI, Kiyoshima T, Nakamura S.
  • Journal Title: Internal Medicine Volume: 57 Issue: 4 Pages: 575-581
  • DOI: 10.2169/internalmedicine.8946-17
  • NAID: 130006351523
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Myeloid dendritic cells stimulated by thymic stromal lymphopoietin promote Th2 immune responses and the pathogenesis of oral lichen planus (2017)
  • Author(s): Yamauchi M, Moriyama M, Hayashida JN, Maehara T, Ishiguro N, Kubota K, Furukawa S, Ohta M, Sakamoto M, Tanaka A, Nakamura S
  • Journal Title: PLoS One Volume: 12(3) Issue: 3 Pages: e0173017-e0173017
  • DOI: 10.1371/journal.pone.0173017
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 口腔扁平苔癬の病態形成に関わるヘルパー T細胞と活性化機構 (2020)
  • Author(s): 森山雅文、山内昌樹、望月敬太、A.S.M Rafiul Haque、中村誠司
  • Organizer: 第30回日本口腔内科学会
• [Presentation] Clinicopathological analysis of labial salivary gland tissues from patients with IgG4-related disease (2018)
  • Author(s): Akira Chinju, 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, Mizuki Sakamoto, Keita Mochizuki, Ryusuke Munemura, Jun-Nosuke Hayashida, and Seiji Nakamura.
  • Organizer: 14th International Sjogren’s Syndrome Symposium
  • 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: 14th International Sjogren’s Syndrome Symposium
  • Int'l Joint Research