Metabolomic analysis in IgG4-related disease

• Project/Area Number: 15K09511
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kanazawa Medical University
• Principal Investigator: IWAO Haruka 金沢医科大学, 医学部, 助教 (10612244)
• Co-Investigator(Kenkyū-buntansha): 河南 崇典 金沢医科大学, 医学部, 講師 (20350762) ; 正木 康史 金沢医科大学, 医学部, 教授 (40238895)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: IgG4関連疾患 / メタボロミクス / 脂質メディエーター / 12-HETE

Outline of Final Research Achievements

IgG4-related disease is indicated by increased infiltration of IgG4-positive plasma cells, typically elevated IgG4 serum levels and the formation of lymphoplasmacytic infiltrate in one or more organs. We explored the metabolome of >400 small molecules in serum from 10 matched pair IgG4-related disease subjects prior to (PRE) and following (POST) steroid treatment and contrast these profiles with a cohort of 10 normal non-diseased subjects (NORM). The polyunsaturated fatty acid arachidonate is involved in pro-inflammatory activities through its metabolism to the pro-inflammatory prostaglandins via cyclooxygenase activity and HETEs via lipoxygenases. Individuals with PRE IgG4-related disease had elevated arachidonate and the 12-lipoxygenase product, 12-HETE, as compared to NORM subjects. The higher levels of the pro-inflammatory arachidonate and 12-HETE was unaffected by steroid treatment as POST subjects had similar levels of these biochemicals as was observed in PRE subjects.

Academic Significance and Societal Importance of the Research Achievements

脂質メディエーターは極めて微量であること、半減期が短いこと、直接遺伝子にコードされないことなどから、横断的・総論的な研究はなされていなかった。本研究では、IgG4関連疾患の慢性炎症、炎症の遷延化に果たす脂質メディエーターに着目し、解析を行った。本研究で得られた知識は、IgG4関連疾患という一病変の解明だけに留まらず、炎症・代謝疾患に果たす、脂質メディエーターの制御の解析にも繋がると思われる。

Research Products

• [Journal Article] Sjogren’s syndrome manifesting as clinicopathological features of TAFRO syndrome: A case report. (2017)
  • Author(s): Fujimoto S, Kawabata H, Kurose N, Kawanami-Iwao H, Sakai T, Kawanami T, Fujita Y, Fukushima T, Masaki Y.
  • Journal Title: Medicine (Baltimore) Volume: 96(50) Issue: 50 Pages: e9220-e9220
  • DOI: 10.1097/md.0000000000009220
  • Peer Reviewed / Open Access
• [Journal Article] IgG4関連疾患のプロテオーム解析 (2017)
  • Author(s): 河南崇典、河南（岩男）悠、正木康史
  • Journal Title: 臨床免疫・アレルギー科 Volume: 67(4) Pages: 343-348
  • Peer Reviewed
• [Journal Article] A multicenter phase II prospective clinical trial of glucocorticoid for patients with untreated IgG4-related disease. (2016)
  • Author(s): Masaki Y, Matsui S, Saeki T, Tsuboi H, Dobashi H, Susaki K, Morimoto H, Takagi K, Kawano M, Origuchi T, Wada Y, Takahashi N, Horikoshi M, Ogishima, H, Suzuki Y, Kawanami T, Kawanami (Iwao) H, Sakai T, Suzuki R, Morikawa Y, Yoshino T, Nakamura S, Kojima M, Kurose N, Sugai S, Sumida T.
  • Journal Title: Mod Rheumatol Volume: 15 Issue: 5 Pages: 1-6
  • DOI: 10.1080/14397595.2016.1259602
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Proposed diagnostic criteria, disease severity classification and treatment strategy for TAFRO syndrome, 2015 version. (2016)
  • Author(s): Masaki Y, Kawabata H, Takai K, Kojima M, Tsukamoto N, Ishigaki Y, Kurose N, Ide M, Murakami J, Nara K, Yamamoto H, Ozawa Y, Takahashi H, Miura K, Miyauchi T, Yoshida S, Momoi A, Awano N, Ikushima S, Ohta Y, Furuta N, Fujimoto S, Kawanami H, Sakai T, Kawanami T, Fujita Y, Fukushima T, Nakamura S, Kinoshita T, Aoki S.
  • Journal Title: Int J Hematol. Volume: in press Issue: 6 Pages: 686-92
  • DOI: 10.1007/s12185-016-1979-1
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Isolation of vascular smooth muscle antigen-reactive CD4(+)αβTh1 clones that induce pulmonary vasculitis in MRL/Mp-Fas(+/+) mice. (2016)
  • Author(s): Fujita Y, Fujii T, Shimizu H, Sato T, Nakamura T, Iwao H, Nakajima A, Miki M, Sakai T, Kawanami T, Tanaka M, Masaki Y, Fukushima T, Okazaki T, Umehara H, Mimori T.
  • Journal Title: Cell Immunol. Volume: 303 Pages: 50-54
  • DOI: 10.1016/j.cellimm.2016.03.004
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Prospective clinical study of R-CMD therapy for indolent B cell lymphoma and mantle cell lymphoma from the Hokuriku Hematology Oncology Study Group (2015)
  • Author(s): Sakai T, Masaki Y, Otsuki N, Sakamaki I, Kishi S, Miyazono T, Urasaki Y, Murakami J, Satoh T, Nakamura T, Iwao H, Nakajima A, Kawanami T, Miki M, Fujita Y, Tanaka M, Fukushima T, Okazaki T, Ueda T.
  • Journal Title: Medical Oncology Volume: 32 Issue: 9 Pages: 232-238
  • DOI: 10.1007/s12032-015-0677-9
  • Peer Reviewed / Open Access
• [Journal Article] <b>CD14</b>^<b>+</b><b> follicular dendritic cells in lymphoid follicles may play a role in the pathogenesis of IgG4-related </b><b>disease </b> (2015)
  • Author(s): Tomomi Satoh-Nakamura, Nozomu Kurose, Takafumi Kawanami, Takuji Nakamura, Haruka Iwao-Kawanami, Akio Nakajima, Miyuki Miki, Tomoyuki Sakai, Yoshimasa Fujita, Masao Tanaka, Toshihiro Fukushima, and Yasufumi Masaki
  • Journal Title: Biomedical Research Volume: 36 Issue: 2 Pages: 143-153
  • DOI: 10.2220/biomedres.36.143
  • NAID: 130005065277
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Decreased Expression of Innate Immunity-Related Genes in Peripheral Blood Mononuclear Cells from Patients with IgG4-Related Disease (2015)
  • Author(s): Nakajima A, Masaki Y, Nakamura T,et al.
  • Journal Title: Pros One Volume: １０ Issue: 5 Pages: e0126582-e0126582
  • DOI: 10.1371/journal.pone.0126582
  • Peer Reviewed / Open Access