Table 2.
EVs as biomarkers in MS.
| References | Patients | EV | Isolation method | Quantification method | Source | Cargo/measures | Results | Biomarker |
|---|---|---|---|---|---|---|---|---|
| Azimi et al. (2019) | RRMS, HC | Exo | Total exosome isolation kit (Invitrogen) | Elisa | T cell cultures | miRNA | miR-326 is upregulated in RRMS vs. HC. | Diagnostic |
| Bhargava et al. (2019) | RRMS, HC | Exo | Exoquick (System Biosciences) | NTA—nanosight | Serum | Concentration protein | TLR3 reduction, TLR4 increase in RRMS vs. HC. | Diagnostic |
| Ebrahimkhani et al. (2020) | RRMS | Exo | Size exclusion chromatography (qEV Izon) | NTA—nanosight | Serum | miRNA | miRNA differential expression between active vs. non-active RRMS. miRNA differential expression between FTY responders vs. non-responders. | Disease activity, response to treatment |
| Pieragostino et al. (2019) | MS, HC | EVs | FACS | FACS, Dynamic light scattering |
CSF, Tears | Proteomics | Microglial and neuronal EVs detectable in CSF and tears. Protein cargo is different between MS and HC. Protein cargo overlap (70%) between tears and CSF EV in MS. |
Diagnostic |
| Amoruso et al. (2018) | RRMS, HC | MV | Differential centrifugation | Fluorescence | Monocytes | Concentration | Increased MVs concentration in RRMS vs. HC, reduced by FTY | Diagnostic, treatment effect |
| Azimi et al. (2018) | RRMS, HC | Exo | Total exosome isolation kit (Invitrogen) | Elisa | Treg cultures | Functional assay | Treg-derived MS exo are less effective in suppressing conventional T cell proliferation and in inducing T cell apoptosis. | Diagnostic |
| Geraci et al. (2018) | RRMS, OND | EV | Differential centrifugation | FACS, NTA—nanosight |
CSF | Concentration Markers | No differences in concentration and Ib4 positivity in MS vs. OND. Increased concentration, Ib4 positivity and CD19+/CD200+ in active vs. stable MS. CCR3+ CCR5+ CD4+/CCR3+, CD4+/CCR5+ CC3+/CCR5+ are increased in MS with MRI activity. |
Disease activity |
| Kimura et al. (2018) | RRMS, PMS, HC | Exo | Differential centrifugation | NTA—nanosight | Plasma | Functional assay, miRNA |
let-7i, miR-19b, miR-25, miR-92a are upregulated in MS. No differences between disease subtype. MS exo decrease Treg cell frequency, through let-7i. |
Diagnostic |
| Manna et al. (2018) | RRMS | Exo | Exoquick (System Biosciences) |
Dynamic light scattering | Serum | miRNA | miRNA differential expression between IFNB-treated vs. naive RRMS. miRNA differential between IFN responders vs. non-responders | Treatment effect, Response to treatment |
| Pieragostino et al. (2018) | MS, c-OND, p-OND |
Exo | FACS | FACS, Dynamic light scattering | CSF | Lipids | Increased Exo concentration in MS vs. to p- and c-OND. Concentration correlates with acid sphingomyelinase activity. Exo deliver active acid sphingomyelinase cargo. Exosomal acid sphingomyelinase activity correlates with EDSS. |
Diagnostic, Disability |
| Sáenz-Cuesta et al. (2018) | RRMS, HC | EVs | Differential centrifugation | NTA—nanosight | Serum | Concentration miRNA Functional assays | FTY increases EVs concentration. FTY changes EVs miRNA expression. FTY reduces the ability of EVs to inhibit lymphocyte activation. |
Treatment effect |
| Blonda et al. (2017) | RRMS, HC | MV | Differential centrifugation | Fluorescence | Monocytes | Production | Increased MVs concentration in MS. IFNB, TFM, and FTY reduce monocyte MVs production. | Disease, Treatment effect |
| Dalla Costa et al. (2018) | RRMS, HC | MV | Differential centrifugation | FACS | Monocytes | Concentration | Increased MV concentration in RRMS vs. HC. FTY reduces concentration, NTZ increases it. No differences for IFN and GA. |
Diagnostic, Treatment effect |
| Ebrahimkhani et al. (2017) | MS (RR, PMS), HC | Exo | Size exclusion chromatography (qEV Izon) | NTA—nanosight | Serum | miRNA | miRNA are dysregulated in MS. Differential expression in disease subtype. Combination of 3 or more miRNAs predicts the clinical form. |
Disease, Disease subtype |
| Galazka et al. (2017) | MS (RR, PMS), HC | Exo | Exoquick kit (System Biosciences) | NTA—nanosight | Serum, CSF | Concentration protein, Functional assay |
MOG is increased in RRMS and SPMS. MOG correlates with MRI activity. MS exo induces proliferation of MOG-TCR transgenic T cells. |
Diagnostic, Disease activity |
| Niwald et al. (2017) | RRMS, HC | Exo | Total exosome isolation kit (Life Technologies) | None | Serum | miRNA | miR155, miR-301a decrease and miR-326 increase in MS. miR-301a and miR155 are higher in recently active RRMS. |
Diagnostic, Disease activity |
| Selmaj et al. (2017) | RRMS, HC | Exo | ExoQuick kit (System Biosciences) | NTA—nanosight | Serum, PBMC | Concentration miRNA | 4 miRNA are differentially expressed among HC, aRRMS, naRRMS. Negative correlation with MRI activity and clinical activity. These miRNA are significantly less concentrated in RRMS PMBC exo. |
Diagnostic, disease activity |
| Welton et al. (2017) | RRMS vs. IIH | Exo | Exo-spin (Cell GS) | NTA—nanosight | CSF | Concentration proteomics | Higher concentration and p/p ratio in RRMS. 50 proteins specifically enriched in RRMS exo vs. RRMS CSF. |
Diagnostic, |
| Lee et al. (2019) | MS, NMO, LETM | Exo | Differential centrifugation | FACS, NTA—nanosight | CSF | Proteomics | MS and NMO have a different exosomal protein content. | Diagnosis |
| Moyano et al. (2016) | RRMS, HC | Exo, MV | Differential centrifugation | NTA—nanosight | Plasma | Concentration size lipids |
C16:0 sulfatide is more expressed in RRMS vs. HC. Negative correlation with EDSS. |
Diagnostic, Disability |
| Zinger et al. (2016) | RRMS, HC | EV | Differential centrifugation | FACS | Plasma | Concentration markers | Total EV and CD105+ MPs are increased while CD19+ EV are reduced in untreated RRMS vs. HC. FTY restores their levels comparable to HC. |
Diagnostic, Treatment effect |
| Alexander et al. (2015) | MS (RR, SP), HC | Exo | Differential centrifugation | FACS | Plasma | Concentration markers | Exo from different sources are differently modulated in RR and SPMS. Correlation with MRI measures. | Diagnostic |
| Giovannelli et al. (2015) | RRMS, HC | Exo | Exosome-specific extraction kit (Norgen) | None | Plasma, urine | miRNA | JCV miRNA are more represented in exo of JCV + RRMS (NTZ) and HC. | Treatment side effects |
| Marcos-Ramiro et al. (2014) | MS (CIS, RR, PMS), HC | EV | Differential centrifugation | FACS | Plasma | Concentration markers | CD62+ and CD31+ are increased in all MS subtypes vs. HC | Diagnostic |
| Sáenz-Cuesta et al. (2014) | RRMS, SPMS, HC | MV | Differential centrifugation | FACS | Plasma | Concentration markers | CD61+, CD45+, CD14+ MP are increased in RRMS vs. SPMS and HC. NTZ and IFNB treatment increase their level. | Diagnostic, treatment effect |
| Verderio et al. (2012) | MS, NMO, OIND, ONIND, HC | MV | FACS | FACS | CSF | Concentration of myeloid MVs | Myeloid MVs are increased in active RRMS compared to stable RRMS and in CIS compared to HC. MVs concentration correlates with MRI activity. | Diagnostic disease activity |
| Nordberg et al. (2011) | MS | EV | FACS | FACS | Plasma | Concentration markers | CD31+ and CD54+ MPs are reduced by IFNB. Correlation with a reduction of MRI activity. |
Response to treatment |
MS, multiple sclerosis; RR, relapsing remitting; PMS, progressive multiple sclerosis; SP, secondary progressive; HC, healthy controls; OND, other neurological disorders; IIH, idiopathic intracranial hypertension; NMO, neuromyelitis optica; LETM, longitudinal extensive transverse myelitis; CIS, clinically isolated syndrome; ONIND, other non-inflammatory neurological disorders; Exo, exosomes; MV, microvesicles; NTA, Nanoparticle tracking analysis; PBMC, peripheral blood mononuclear cell; CSF, cerebrospinal fluid; miRNA, microRNA; FTY, fingolimod; IFNB, interferon-beta; TFM, teriflunomide; NTZ, natalizumab; EDSS, expanded disability status scale; MOG, myelin oligodendrocyte glycoprotein.