Identification of new biomarkers about Langerhans cell histiocytosis using mass spectrometry

• Project/Area Number: 26460451
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Kochi University (2015-2016); Tottori University (2014)
• Principal Investigator: MURAKAMI Ichiro 高知大学, 教育研究部医療学系連携医学部門, 教授 (80548701)
• Co-Investigator(Renkei-kenkyūsha): OKA Takashi 岡山大学, 医歯薬総合研究科, 講師 研究者 (50160651)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2014: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: ランゲルハンス細胞組織球症 / 質量分析 / 血清タンパク / ITIH4 / MS-LCH / SS-LCH / 質量分析器 / 血漿

Outline of Final Research Achievements

Plasma sample from 12 patients with LCH-RO (－) (5 MS-LCH and 7 SS-LCH) and 5 non-LCH patients were analyzed by peptidomics. Mass spectrometry (MS) spectra were　acquired and peptides exhibiting quantitative differences between MS-LCH and SS-LCH patients were targeted.
One new candidate biomarker, m/z 3145 was selected and identified after obtaining a MS/MS fragmentation pattern using liquid chromatography-MS/MS. This peak was　identified as a proteolytic fragment derived from interalpha-trypsin inhibitor heavy chain 4 (ITIH4, [PDB: Q14624]).
Peptidomics of LCH have revealed that the level of acute-phase ITIH4 distinguishes MS-LCH-RO (－) from SS-LCH-RO (－). Acute-phase proteins serve non-specific,　physiological immune functions within the innate immune system. LCH may be a　reactive disorder with both underlying neoplastic potential of antigen presenting　cells harboring BRAF mutations and hyper-immunity of other inflammatory cells　against MCPyV infection.

Research Products

• [Journal Article] Thyrotropin receptor antibody (TRAb)-IgM levels are markedly higher than TRAb-IgG levels in Graves’ disease patients and controls, and TRAb-IgM production is related to EBV reactivation. (2016)
  • Author(s): K Kumata, K Nagata, M Matsushita, S Kuwamoto, M Kato, I Murakami, S Fukata, K Hayashi
  • Journal Title: Viral Immunol. Volume: 29 Issue: 8 Pages: 459-463
  • DOI: 10.1089/vim.2016.0043
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma peptidomics (2015)
  • Author(s): Murakami I, Oh Y, Morimoto A, Sano H, Kanzaki S, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Nagata K, Hayashi K, Imashuku S, Gogusev J, Jaubert F, Oka T, Yoshino T.
  • Journal Title: Clin Proteomics. Volume: 12 Issue: 1 Pages: 16-16
  • DOI: 10.1186/s12014-015-9089-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interleukin-1 loop model for pathogenesis of Langerhans cell histiocytosis (2015)
  • Author(s): Murakami I, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Nagata K, Horie Y, Hayashi K, Imamura T, Morimoto A, Imashuku S, Gogusev J, Jaubert F, Takata K, Oka T, Yoshino T.
  • Journal Title: Cell Commun Signal Volume: 13 Issue: 1 Pages: 13-13
  • DOI: 10.1186/s12964-015-0092-z
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a Langerhans cell histiocytosis lesion cell line with dermal dendritic cell characteristics. (2015)
  • Author(s): Murakami I, Gogusev J, Jaubert F, Matsushita M, Hayashi K, Miura I, Tanaka T, Oka T, Yoshino T.
  • Journal Title: Oncol Rep. Volume: 33 Issue: 1 Pages: 171-8
  • DOI: 10.3892/or.2014.3567
  • Peer Reviewed
• [Presentation] ECOLOGY OF MERKEL CELL POLYOMAVIRUS IN HEALTHY SKIN SHOWS A CLOSE AGREEMENT WITH INTERLEUKIN-1 LOOP MODEL IN LANGERHANS CELL HISTIOCYTOSIS (2016)
  • Author(s): Ichiro Murakami, Junko Nakashima, Yumiko Hashida, Masanori Daibata, Michiko Matsushita, Takeshi Iwasaki, Satoshi Kuwamoto, Masako Kato, Keiko Nagata, Kazuhiko Hayashi, Takashi Oka, Tadashi Yoshino, Toshihiko Imamura, Akira Morimoto, Shinsaku Imashuku, Jean Gogusev, Francis Jaubert
  • Organizer: 32nd Annual Meeting of the Histiocyte Society
  • Place of Presentation: Dublin, Ireland
  • Year and Date: 2016-10-17
  • Int'l Joint Research
• [Presentation] 診療領域別講習特別プログラム 研究講演会 組織球・樹状細胞腫瘍の病理診断アップデート ランゲルハンス細胞腫瘍の病理診断と最新知見 (2016)
  • Author(s): 村上 一郎
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-05-12
• [Presentation] ランゲルハンス細胞組織球症の病態について (2016)
  • Author(s): 村上一郎
  • Organizer: 第41回 LCH研究会
  • Place of Presentation: ヤクルトホール（東京都港区）
  • Year and Date: 2016-03-20
  • Invited
• [Presentation] ランゲルハンス細胞組織球症患者血清の質量分析器による解析 (2015)
  • Author(s): 村上一郎、松下倫子、岩崎 健、桑本聡史、加藤雅子、堀江 靖、林 一彦、岡 剛史、吉野 正
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2015-04-30 – 2015-05-02
• [Remarks] ランゲルハンス細胞組織球症発症仮説
  • URL: http://www.kochi-ms.ac.jp/~ff_pthl2/dop/LCH1.htm
• [Remarks] ランゲルハンス細胞組織球症発症仮説
  • URL: http://www.med.tottori-u.ac.jp/molepath/1934/1935/12319.html
• [Remarks] A hypothesis of Langerhans cell histiocytosis
  • URL: http://www.med.tottori-u.ac.jp/molepath/1934/1935/12320.html