Table 1.
Extracellular vesicle marker in central demyelinating diseases related to inflammatory pathways from plasma or serum: reports from clinical studies
| Methods of EV detection (specimen) | Major findings of each disorder | Interpretation | Ref | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Multiple sclerosis | Subtypes of multiple sclerosis | NMOSD | Relapsing disease activity | |||||||
| RRMS | SPMS | PPMS | CIS | Clinical | Radiologic | |||||
| EVs classified by origin | ||||||||||
| Endothelial cells | ||||||||||
| Flow cytometry (platelet-poor plasma) | ↑ PMP ↑ CD31 ↑ CD62E |
↑ PMP ↑ CD31 ↔ CD62E |
↑ PMP ↑ CD31 ↔ CD62E |
↑ PMP ↑ CD31 ↔ CD62E |
↔ PMP ↑ CD31 ↑ CD62E |
NA | NA | NA | An increase in EMPs-CD31 involved in all courses of MS. However, PMP was associated with chronic MS but not with early stage, increased EMP-CD62E was found in the early stage of disease. | [33] |
| Flow cytometry and 3T MRI (plasma) | NA | ↑ CD31+/CD51+/CD61+/CD54+ (EMPs) | ↓CD31+/CD51-/CD61-/CD54- (PMPs) | NA | NA | NA | NA | NA | An increase in EMPs was more common in RRMS than in SPMS. PMP levels rose in SPMS but not in SPMS. | [35] |
| Flow cytometry, scanning EM (platelet-poor plasma) | ↑ CD105 | NA | NA | NA | NA | NA | NA | NA | Untreated MS had high endothelial microparticles detected from CD105. | [93] |
| Flow cytometry (platelet-poor plasma) | NA | ↑ CD51+ | NA | NA | NA | NA | ↑ CD31+ ↑ CD51+ |
↑ CD31+ | CD31+ associated with clinical and radiologic exacerbation of MS, while CD51+ was associated with natural course of MS. | [34] |
| Flow cytometry with fluorescent dye (plasma) | NA | NA | NA | NA | NA | NA | ↑ CD54+-monocyte conjugate ↑ CD63E+ |
↑ CD54+-monocyte conjugate | EMP triggered monocyte-CD54+ binding and activation. | [36] |
| Flow cytometry (plasma) | NA | NA | NA | NA | NA | NA | ↑ CD31 ↑ CD54 ↑ CD62E |
NA | EMP associated with exacerbation of MS. | [90] |
| Tandem spectrometry (plasma) | ↑ Fibrinogen alpha-chain | ↑ Fibrinogen alpha-chain | NA | NA | NA | NA | NA | NA | Fibrinogen EV associated with CD8+ activation and caused RRMS. | [58] |
| Platelet | ||||||||||
| Flow cytometry (platelet-rich plasma) | ↑ CD62p ↑ PMP ↔ Platelet surface IgG ↑ Platelet surface IgM |
NA | NA | NA | NA | NA | NA | NA | MS patients had a high level of long-platelet EV activation. | [43] |
| Flow cytometry (plasma) | ↑ CD61 ↔ CD45 ↔ CD14 |
↑ CD61 ↑ CD45 ↑ CD14 |
↔ CD61 ↔ CD45 ↔ CD14 |
NA | NA | NA | NA | NA | Platelet EV, but not leukocyte EV, played a role in early MS while SPMS reduced all PMP and LMP due to stage changes in neurodegeneration. | [42] |
| Leukocytes and microglia | ||||||||||
| Flow cytometry (plasma) | ↑ CD61 ↔ CD45 ↔ CD14 |
↑ CD61 ↑ CD45 ↑ CD14 |
↔ CD61 ↔ CD45 ↔ CD14 |
NA | NA | NA | NA | NA | Platelet EV, but not leukocyte EV, played a role in early MS while SPMS reduced all PMP and LMP due to stage changes in neurodegeneration. | [42] |
| Immunoprecipitation, NTA | ↑ AMPB (T-cell EVs) ↑ FIBB (T-cell EVs) ↑ GELS (B-cell EVs) |
NA | NA | NA | NA | NA | ↑ GELS (B-cell EVs) | NA | Both T and B cell-dervied EVs correlated with MS. Only B cell associated with active disease. | [48] |
| Oligodendrocytes | ||||||||||
| ExoQuick,NTA, Western blot, ELISA (serum) | NA | ↔ MOG | ↑ MOG | NA | NA | NA | ↑ MOG | ↑ MOG | Progressive disease activity correlated with MOG level. | [54] |
| Exo-check, immuno-gold TEM | NA | ↑ Myelin basic protein | NA | ↑ Myelin basic protein | ↑ Myelin basic protein | NA | NA | NA | Increased oligodencrocyte-dervied EVs associated with MS in all stages. | [55] |
| EVs categorized by EV surface membrane expression | ||||||||||
| Fibrinogen | ||||||||||
| Tandem spectrometry (plasma) | ↑ Fibrinogen alpha-chain | ↑ Fibrinogen alpha-chain | NA | NA | NA | NA | NA | NA | Fibrinogen EV associated with CD8+ activation and caused RRMS. | [58] |
| Glycolipids | ||||||||||
| UC, EM, NTA, Negative ion electrospray mass spectrometry (plasma) | ↑ C16:0 sulfatide | ↑ C16:0 sulfatide | ↑ C16:0 sulfatide | NA | NA | NA | NA | NA | Sulfatide C16:0 triggered CD1d and activated T cell. | [62] |
| EVs classified by containing substances | ||||||||||
| microRNAs | ||||||||||
| High throughput NGS (serum) | NA | ↑ miR-15b-5p ↑ miR-30b-5p ↑ miR-342-3p ↑ miR-451a |
↑ miR-127-3p ↑ miR-370-3p ↑ miR-409-3p ↑ miR-432-5p ↑ miR-15b-5p ↑ miR-223-3p ↑ miR-23-3p |
↑ miR-127-3p ↑ miR-370-3p ↑ miR-409-3p ↑ miR-432-5p ↑ miR-15b-5p ↑ miR-223-3p ↑ miR-23-3p |
NA | NA | ↓ miR-30b-5p ↓ miR-342-3p ↓ miR-374a-5p ↑ miR-432-5p ↑ miR-433-3p ↑ miR-485-3p |
NA | Dysregulated miRNA associated with MS subtypes. | [67] |
| NGS (serum) | NA | ↓ miR-122-5p ↓ miR-196b-5p ↓ miR-301a-3p ↓ miR-532-5p |
NA | NA | NA | NA | ↓ miR-122-5p ↓ miR-196b-5p ↓ miR-301a-3p ↓ miR-532-5p |
↓ miR-122-5p ↓ miR-196b-5p ↓ miR-301a-3p ↓ miR-532-5p |
Decreased miRNA was associated with the exacerbation of disease | [72] |
| High throughput NGS (serum) | NA | NA | NA | NA | ↑ miR-126-5p ↑ let-7f-5p ↑ let-7a-5p ↑ miR-23a-3p ↑ miR-223-3p ↓ let-7b-5p ↓ miR-24-3p ↓ let-79-5p ↓ miR-25-3p |
NA | NA | NA | CIS patients had different patterns of serum exosomes when compared with HC. | [77] |
| miScript miRNA techniques RT-PCR (serum) | NA | NA | ↑ miR-376c-3p ↑ miR-191-5p ↑ miR-26a-5p |
↑ miR-376c-3p ↑ miR-191-5p ↑ miR-26a-5p ↑ miR-128-3p ↑ miR-24-3p |
NA | NA | NA | NA | miR-128-3p and miR-24-3p were associated with PPMS. | [78] |
| NGS with RT-qPCR. EV detection by CD63, CD81 (serum) | ↔ miR-380-3p ↔ miR-216a-5p ↔ miR-548p ↔ miR-153-3p ↔ miR-448 |
↔ miR-380-3p ↔ miR-216a-5p ↔ miR-548p ↔ miR-153-3p ↔ miR-448 |
NA | NA | NA | ↑ miR-122-3p ↓ miR-4424 ↓ miR-6764-3p ↓ miR-412-3p ↓ miR-380-3p ↓ miR-216a-5p ↓ miR-548p ↓ miR-153-3p ↓ miR-448 |
↑ miR-200a-5p | NA | Mir-122-3p was unique in NMOSD and miR-200a-5p correlated with clinical NMOSD relapse. | [85] |
| Microarray, Flow cytometry (peripheral blood) | ↑ Let-7i | NA | NA | NA | NA | NA | NA | NA | Let-7i inhibited Treg differentiation by inhibiting IGF1R and TGFBR1. | [79] |
CIS, clinically isolated syndrome; EMP, endothelial microparticles; MS, multiple sclerosis; EM, electron microscope; EV, extracellular vesicles; HC, healthy controls; ICAM1, Intercellular Adhesion Molecule 1; IGF1R, insulin-like growth factor 1; LMP, leukocyte microparticles; MHC, major histocompatibility complex; miRNA, microribonucleic acid; MOG, myelin oligodendrocyte glycoprotein; NGS, next-generation sequencing; NMOSD, neuromyelitis optica spectrum disorder; NTA, nanoparticle tracking analysis; PECAM, Platelet endothelial cell adhesion molecule; PMP, platelet microparticles; PPMS; primary progressive multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; RT-PCR, reverse transcription polymerase chain reaction; RT-qPCR, quantitative reverse transcription polymerase chain reaction; SPMS, secondary progressive multiple sclerosis; TEM, transmission electron microscope; TGFBR1, Transforming Growth Factor Beta Receptor 1; UC, ultracentrifugation, WM, white matter.