Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma peptidomics

Ichiro Murakami, Yukiko Oh, Akira Morimoto, Hitoshi Sano, Susumu Kanzaki, Michiko Matsushita, Takeshi Iwasaki, Satoshi Kuwamoto, Masako Kato, Keiko Nagata, Kazuhiko Hayashi, Shinsaku Imashuku, Jean Gogusev, Francis Jaubert, Takashi Oka, Tadashi Yoshino

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: Langerhans cell histiocytosis (LCH) is a proliferative disorder in which abnormal Langerhans cell (LC)-like cells (LCH cells) intermingle with inflammatory cells. Whether LCH is reactive or neoplastic remains a controversial matter. We recently described Merkel cell polyomavirus (MCPyV) as a possible causative agent of LCH and proposed interleukin-1 loop model: LCH is a reactive disorder with an underlying oncogenic potential and we now propose to test this theory by looking for acute markers of inflammation. We detected MCPyV-DNA in the peripheral blood cells of patients with high-risk organ-type (LCH-risk organ (RO) (+)) but not those with non-high-risk organ-type LCH (LCH-RO (-)); this difference was significant. LCH-RO (-) is further classified by its involvement of either a single organ system (SS-LCH) or multiple organ systems (MS-LCH). In patients with LCH-RO (-), MCPyV-DNA sequences were present in LCH tissues, and significant differences were observed between LCH tissues and control tissues associated with conditions such as dermatopathic lymphadenopathy and reactive lymphoid hyperplasia. Although MCPyV causes subclinical infection in nearly all people and 22 % of healthy adults will harbor MCPyV in their buffy coats, circulating monocytes could serve as MCPyV reservoirs and cause disseminated skin lesions. Methods: 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. Results: 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 inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4, [PDB: Q14624]). Conclusions: 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. Among LCH-RO (-), MCPyV-DNA sequences were present in both MS-LCH tissues and SS-LCH tissues without significant differences. ITIH4 may show that LCH activity or LCH subtypes correlates with the systemic or localized reactions of MCPyV infection.

Original languageEnglish
Article number16
JournalClinical Proteomics
Volume12
Issue number1
DOIs
Publication statusPublished - Jun 18 2015

Fingerprint

Langerhans Cell Histiocytosis
Mass spectrometry
Plasmas
Merkel cell polyomavirus
Tissue
DNA sequences
Mass Spectrometry
Acute-Phase Proteins
Immune system
Polyomavirus Infections
Liquid chromatography
Biomarkers
Ports and harbors
Interleukin-1
Adjustment Disorders
Skin
Blood
Cells
Tandem Mass Spectrometry

Keywords

  • Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) [PDB: Q14624]
  • Interleukin-1 loop model
  • Langerhans cell histiocytosis
  • Peptidomics

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine
  • Clinical Biochemistry

Cite this

Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma peptidomics. / Murakami, Ichiro; Oh, Yukiko; Morimoto, Akira; Sano, Hitoshi; Kanzaki, Susumu; Matsushita, Michiko; Iwasaki, Takeshi; Kuwamoto, Satoshi; Kato, Masako; Nagata, Keiko; Hayashi, Kazuhiko; Imashuku, Shinsaku; Gogusev, Jean; Jaubert, Francis; Oka, Takashi; Yoshino, Tadashi.

In: Clinical Proteomics, Vol. 12, No. 1, 16, 18.06.2015.

Research output: Contribution to journalArticle

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 2015, 'Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma peptidomics', Clinical Proteomics, vol. 12, no. 1, 16. https://doi.org/10.1186/s12014-015-9089-2
Murakami, Ichiro ; Oh, Yukiko ; Morimoto, Akira ; Sano, Hitoshi ; Kanzaki, Susumu ; Matsushita, Michiko ; Iwasaki, Takeshi ; Kuwamoto, Satoshi ; Kato, Masako ; Nagata, Keiko ; Hayashi, Kazuhiko ; Imashuku, Shinsaku ; Gogusev, Jean ; Jaubert, Francis ; Oka, Takashi ; Yoshino, Tadashi. / Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma peptidomics. In: Clinical Proteomics. 2015 ; Vol. 12, No. 1.
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abstract = "Background: Langerhans cell histiocytosis (LCH) is a proliferative disorder in which abnormal Langerhans cell (LC)-like cells (LCH cells) intermingle with inflammatory cells. Whether LCH is reactive or neoplastic remains a controversial matter. We recently described Merkel cell polyomavirus (MCPyV) as a possible causative agent of LCH and proposed interleukin-1 loop model: LCH is a reactive disorder with an underlying oncogenic potential and we now propose to test this theory by looking for acute markers of inflammation. We detected MCPyV-DNA in the peripheral blood cells of patients with high-risk organ-type (LCH-risk organ (RO) (+)) but not those with non-high-risk organ-type LCH (LCH-RO (-)); this difference was significant. LCH-RO (-) is further classified by its involvement of either a single organ system (SS-LCH) or multiple organ systems (MS-LCH). In patients with LCH-RO (-), MCPyV-DNA sequences were present in LCH tissues, and significant differences were observed between LCH tissues and control tissues associated with conditions such as dermatopathic lymphadenopathy and reactive lymphoid hyperplasia. Although MCPyV causes subclinical infection in nearly all people and 22 {\%} of healthy adults will harbor MCPyV in their buffy coats, circulating monocytes could serve as MCPyV reservoirs and cause disseminated skin lesions. Methods: 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. Results: 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 inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4, [PDB: Q14624]). Conclusions: 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. Among LCH-RO (-), MCPyV-DNA sequences were present in both MS-LCH tissues and SS-LCH tissues without significant differences. ITIH4 may show that LCH activity or LCH subtypes correlates with the systemic or localized reactions of MCPyV infection.",
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T1 - Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma peptidomics

AU - Murakami, Ichiro

AU - Oh, Yukiko

AU - Morimoto, Akira

AU - Sano, Hitoshi

AU - Kanzaki, Susumu

AU - Matsushita, Michiko

AU - Iwasaki, Takeshi

AU - Kuwamoto, Satoshi

AU - Kato, Masako

AU - Nagata, Keiko

AU - Hayashi, Kazuhiko

AU - Imashuku, Shinsaku

AU - Gogusev, Jean

AU - Jaubert, Francis

AU - Oka, Takashi

AU - Yoshino, Tadashi

PY - 2015/6/18

Y1 - 2015/6/18

N2 - Background: Langerhans cell histiocytosis (LCH) is a proliferative disorder in which abnormal Langerhans cell (LC)-like cells (LCH cells) intermingle with inflammatory cells. Whether LCH is reactive or neoplastic remains a controversial matter. We recently described Merkel cell polyomavirus (MCPyV) as a possible causative agent of LCH and proposed interleukin-1 loop model: LCH is a reactive disorder with an underlying oncogenic potential and we now propose to test this theory by looking for acute markers of inflammation. We detected MCPyV-DNA in the peripheral blood cells of patients with high-risk organ-type (LCH-risk organ (RO) (+)) but not those with non-high-risk organ-type LCH (LCH-RO (-)); this difference was significant. LCH-RO (-) is further classified by its involvement of either a single organ system (SS-LCH) or multiple organ systems (MS-LCH). In patients with LCH-RO (-), MCPyV-DNA sequences were present in LCH tissues, and significant differences were observed between LCH tissues and control tissues associated with conditions such as dermatopathic lymphadenopathy and reactive lymphoid hyperplasia. Although MCPyV causes subclinical infection in nearly all people and 22 % of healthy adults will harbor MCPyV in their buffy coats, circulating monocytes could serve as MCPyV reservoirs and cause disseminated skin lesions. Methods: 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. Results: 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 inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4, [PDB: Q14624]). Conclusions: 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. Among LCH-RO (-), MCPyV-DNA sequences were present in both MS-LCH tissues and SS-LCH tissues without significant differences. ITIH4 may show that LCH activity or LCH subtypes correlates with the systemic or localized reactions of MCPyV infection.

AB - Background: Langerhans cell histiocytosis (LCH) is a proliferative disorder in which abnormal Langerhans cell (LC)-like cells (LCH cells) intermingle with inflammatory cells. Whether LCH is reactive or neoplastic remains a controversial matter. We recently described Merkel cell polyomavirus (MCPyV) as a possible causative agent of LCH and proposed interleukin-1 loop model: LCH is a reactive disorder with an underlying oncogenic potential and we now propose to test this theory by looking for acute markers of inflammation. We detected MCPyV-DNA in the peripheral blood cells of patients with high-risk organ-type (LCH-risk organ (RO) (+)) but not those with non-high-risk organ-type LCH (LCH-RO (-)); this difference was significant. LCH-RO (-) is further classified by its involvement of either a single organ system (SS-LCH) or multiple organ systems (MS-LCH). In patients with LCH-RO (-), MCPyV-DNA sequences were present in LCH tissues, and significant differences were observed between LCH tissues and control tissues associated with conditions such as dermatopathic lymphadenopathy and reactive lymphoid hyperplasia. Although MCPyV causes subclinical infection in nearly all people and 22 % of healthy adults will harbor MCPyV in their buffy coats, circulating monocytes could serve as MCPyV reservoirs and cause disseminated skin lesions. Methods: 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. Results: 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 inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4, [PDB: Q14624]). Conclusions: 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. Among LCH-RO (-), MCPyV-DNA sequences were present in both MS-LCH tissues and SS-LCH tissues without significant differences. ITIH4 may show that LCH activity or LCH subtypes correlates with the systemic or localized reactions of MCPyV infection.

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KW - Interleukin-1 loop model

KW - Langerhans cell histiocytosis

KW - Peptidomics

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