Analysis of disease specific T cell receptors in autoimmune liver diseases

• Project/Area Number: 17K09416
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Shinshu University
• Principal Investigator: Umemura Takeji 信州大学, 学術研究院医学系, 准教授 (30419345)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: AIH / PBC / HLA / KIR / Autotaxin / sCD14 / IL-8 / HLA-DPB1 / オートタキシン / SH2B3 / T細胞受容体 / 自己免疫性肝炎 / 原発性胆汁性胆管炎

Outline of Final Research Achievements

We revealed several genes are associated with susceptibility and resistant to AIH. Moreover, combined KIR/HLA pair and cirrhosis at diagnosis related to AIH progression. Serum autotaxin are correlated with fibrosis in PBC. High sCD14 and IL-8 levels are associated with poor outcome of PBC.

Academic Significance and Societal Importance of the Research Achievements

本研究を通して原因不明の難病である自己免疫性肝炎と原発性胆汁性胆管炎の患者検体を用いて幾つかの血中バイオマーカー、ケモカイン、HLAやNK細胞の受容体などの宿主因子が発症、線維化の程度、病態の進展、生命予後に関連するという新たな研究成果を発表することができた。発見した因子を診断時に測定する事で予後を予測することが可能となれば早期から集約的な治療介入を開始することで患者さんの生命予後を延長することが可能となり得る。

Research Products

• [Int'l Joint Research] INOVA Diagnostics(米国)
• [Journal Article] KIR/HLA genotypes confer susceptibility and progression in patients with autoimmune hepatitis (2019)
  • Author(s): Umemura Takeji、Joshita Satoru、Saito Hiromi、Yoshizawa Kaname、Norman Gary L.、Tanaka Eiji、Ota Masao
  • Journal Title: JHEP Reports Volume: 1 Issue: 5 Pages: 353-360
  • DOI: 10.1016/j.jhepr.2019.09.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical utility of FibroScan as a non‐invasive diagnostic test for primary biliary cholangitis (2019)
  • Author(s): Joshita Satoru、Yamashita Yuki、Sugiura Ayumi、Uehara Takeshi、Usami Yoko、Yamazaki Tomoo、Fujimori Naoyuki、Matsumoto Akihiro、Tanaka Eiji、Umemura Takeji
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: - Issue: 7 Pages: 1208-1214
  • DOI: 10.1111/jgh.14929
  • Peer Reviewed
• [Journal Article] Biochemical and plasma lipid responses to pemafibrate in patients with primary biliary cholangitis (2019)
  • Author(s): Joshita Satoru、Umemura Takeji、Yamashita Yuki、Sugiura Ayumi、Yamazaki Tomoo、Fujimori Naoyuki、Matsumoto Akihiro、Tanaka Eiji
  • Journal Title: Hepatology Research Volume: 49 Issue: 10 Pages: 1236-1243
  • DOI: 10.1111/hepr.13361
  • Peer Reviewed
• [Journal Article] POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33 (2019)
  • Author(s): Hitomi, Y. Ueno, K. Kawai, Y. Nishida, N. , Umemura, T. et al
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 102-102
  • DOI: 10.1038/s41598-018-36490-1
  • NAID: 120006715480
  • Peer Reviewed / Open Access
• [Journal Article] Genetics and epigenetics in the pathogenesis of primary biliary cholangitis (2018)
  • Author(s): Joshita Satoru、Umemura Takeji、Tanaka Eiji、Ota Masao
  • Journal Title: Clinical Journal of Gastroenterology Volume: 11 Issue: 1 Pages: 11-18
  • DOI: 10.1007/s12328-017-0799-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serum Autotaxin Is a Useful Disease Progression Marker in Patients with Primary Biliary Cholangitis (2018)
  • Author(s): Joshita, S. Umemura, T. Usami, Y. Yamashita, Y. Norman, G. L. Sugiura, A. Yamazaki, T. Fujimori, N. Kimura, T. Matsumoto, A. Igarashi, K. Yoshizawa, K. Ota, M. Tanaka, E.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 8159-8159
  • DOI: 10.1038/s41598-018-26531-0
  • NAID: 120007099792
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features of autoimmune hepatitis with acute presentation: class FormattedString { value: a Japanese nationwide survey } (2018)
  • Author(s): Joshita, S. Yoshizawa, K. Umemura, T. Ohira, H. Takahashi, A. Harada, K. Hiep, N. C. Tsuneyama, K. Kage, M. Nakano, M. Kang, J. H. Koike, K. Zeniya, M. Yasunaka, T. Takaki, A. Torimura, T. Abe, M. Yokosuka, O. Tanaka, A. Takikawa, H. Japan Autoimmune Hepatitis Study, Group
  • Journal Title: J Gastroenterol Volume: 53 Issue: 9 Pages: 1079
  • DOI: 10.1007/s00535-018-1444-4
  • URL: https://localhost/en/publications/b17c2b89-a4c6-4f62-8ac7-d607063c34a9
  • Peer Reviewed
• [Journal Article] A cis-eQTL of HLA-DPB1 Affects Susceptibility to Type 1 Autoimmune Hepatitis (2018)
  • Author(s): Yamazaki, T. Umemura, T. Joshita, S. Yoshizawa, K. Tanaka, E. Ota, M.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 11924-11924
  • DOI: 10.1038/s41598-018-30406-9
  • NAID: 120007179056
  • Peer Reviewed / Open Access
• [Journal Article] Association between KIR-HLA combination and ulcerative colitis and Crohn's disease in a Japanese population (2018)
  • Author(s): Saito, H. Hirayama, A. Umemura, T. Joshita, S. Mukawa, K. Suga, T. Tanaka, E. Ota, M.
  • Journal Title: PLoS One Volume: 13 Issue: 4 Pages: e0195778-e0195778
  • DOI: 10.1371/journal.pone.0195778
  • NAID: 120007179054
  • Peer Reviewed / Open Access
• [Journal Article] Association between serum soluble CD14 and IL-8 levels and clinical outcome in primary biliary cholangitis (2017)
  • Author(s): Umemura, T. Sekiguchi, T. Joshita, S. Yamazaki, T. Fujimori, N. Shibata, S. Ichikawa, Y. Komatsu, M. Matsumoto, A. Shums, Z. Norman, G. L. Tanaka, E. Ota, M.
  • Journal Title: Liver International Volume: 印刷中 Issue: 6 Pages: 897-905
  • DOI: 10.1111/liv.13316
  • NAID: 120007100137
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Association of autoimmune hepatitis with Src homology 2 adaptor protein 3 gene polymorphisms in Japanese patients (2017)
  • Author(s): Umemura, T. Joshita, S. Hamano, H. Yoshizawa, K. Kawa, S. Tanaka, E. Ota, M.
  • Journal Title: Journal of Human genetics Volume: 62 Issue: 11 Pages: 963-967
  • DOI: 10.1038/jhg.2017.74
  • NAID: 120007179053
  • Peer Reviewed
• [Presentation] Noninvasive Prediction of Liver Fibrosis in Autoimmune Liver Disease (2019)
  • Author(s): Umemura Takeji
  • Organizer: Asian Pacific Association for the Study of the Liver Single Topics Conference
  • Int'l Joint Research
• [Presentation] Killer cell immunoglobulin-like receptors/human leukocyte antigen genotypes confer s usceptibility and progression in patients with autoimmune hepatitis (2019)
  • Author(s): Umemura Takeji, et al.
  • Organizer: American Association for the Study of Liver Diseases
  • Int'l Joint Research
• [Presentation] 慢性肝疾患におけるATXおよびM2BPGiの非侵襲的病気診断マーカーとしての有用性とその臨床的意義 (2019)
  • Author(s): 城下智、梅村武司、田中榮司
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] Clinical significance of M2BPGi in patients with autoimmune liver disease (2019)
  • Author(s): Umemura T
  • Organizer: The Asian Pacific Association for the Study of the Liver STC
  • Int'l Joint Research / Invited
• [Presentation] Noninvasive Prediction of Liver Fibrosis in Autoimmune Liver Disease (2019)
  • Author(s): Umemura T
  • Organizer: The Asian Pacific Association for the Study of the Liver STC
  • Int'l Joint Research / Invited
• [Presentation] 自己免疫性肝疾患におけるKIR-HLAの検討 (2018)
  • Author(s): 梅村武司、他
  • Organizer: 第27回日本組織適合性学会大会
• [Presentation] 自己免疫性肝炎におけるHLA-DPB1の遺伝子多型とHLA-DP発現量の検討 (2018)
  • Author(s): 梅村武司、山崎智生、城下智、田中榮司
  • Organizer: 第54回日本肝臓学会総会
• [Presentation] 次世代シークエンサーによるHLAゲノム解析：自己免疫性肝疾患における検討 (2018)
  • Author(s): 梅村武司、城下智、田中榮司
  • Organizer: 第42回日本肝臓学会東部会
• [Presentation] ウルソデオキシコール酸治療開始前の血清IL-8とsCD14は原発性胆汁性胆管炎の予後予測因子である (2017)
  • Author(s): 梅村武司、関口智裕、城下智、田中榮司
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] 原発性胆汁性胆管炎における血中Autotaxinの臨床的意義の検討 (2017)
  • Author(s): 城下智、梅村武司、田中榮司
  • Organizer: 第21回日本肝臓学会大会
• [Presentation] Association of Serum Autotaxin Levels with Disease Stages in Patients with Primary Biliary Cholangitis in Japanese patients (2017)
  • Author(s): Joshita S, Umemura T, Usami Y, Sugiura A, Yamazaki T, Fujimori N, Komatsu M, Matsumoto A, Igarashi K, Ota M, Tanaka E
  • Organizer: Asian Pacific Digestive Week
  • Int'l Joint Research