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Immunopeptidomics: Isolation of Mouse and Human MHC Class I- and II-Associated Peptides for Mass Spectrometry Analysis
Published on: October 15, 2021
Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma
Ichiro Murakami1, Yukiko Oh2, Akira Morimoto2
1Division of Molecular Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago-shi, Tottori 683-8503 Japan.
Insights
Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) levels can distinguish between multisystem (MS-LCH) and single-system Langerhans cell histiocytosis (LCH) in patients. This finding may link LCH subtypes to Merkel cell polyomavirus (MCPyV) infection responses.
Area of Science:
- Oncology
- Immunology
- Virology
Background:
- Langerhans cell histiocytosis (LCH) is a proliferative disorder of abnormal Langerhans cells (LCs) with debated reactive or neoplastic origins.
- Merkel cell polyomavirus (MCPyV) is implicated in LCH pathogenesis, with MCPyV-DNA detected in high-risk LCH patients.
- LCH is proposed to be a reactive disorder with oncogenic potential, necessitating investigation into acute inflammatory markers.
Purpose of the Study:
- To identify acute inflammatory markers differentiating LCH subtypes.
- To investigate the role of MCPyV in LCH pathogenesis and its correlation with disease subtypes.
- To explore the potential of peptidomics in diagnosing LCH and its subtypes.
Main Methods:
- Plasma samples from LCH patients (multisystem LCH [MS-LCH] and single-system LCH [SS-LCH]) and non-LCH controls were analyzed using peptidomics.
- Mass spectrometry (MS) was employed to acquire spectra and identify peptides with quantitative differences between MS-LCH and SS-LCH.
- Candidate biomarkers were selected and identified via MS/MS fragmentation patterns.
Main Results:
- A novel biomarker, m/z 3145, was identified as a proteolytic fragment of inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4).
- ITIH4 levels were found to distinguish MS-LCH-RO (-) from SS-LCH-RO (-).
- MCPyV-DNA sequences were present in LCH tissues of both MS-LCH and SS-LCH patients without significant differences.
Conclusions:
- The acute-phase protein ITIH4 can differentiate between MS-LCH-RO (-) and SS-LCH-RO (-), suggesting its utility as a biomarker.
- LCH may represent a reactive disorder involving MCPyV infection, with potential neoplastic elements (e.g., BRAF mutations) and hyper-immunity.
- ITIH4 levels may correlate with LCH activity or subtypes, reflecting systemic or localized reactions to MCPyV infection.
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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