MicroRNAs Associated with Disability Progression and Clinical Activity in Multiple Sclerosis Patients Treated with Glatiramer Acetate.

MicroRNAs (miRNAs) are promising biomarkers in multiple sclerosis (MS). This study aims to investigate the association between a preselected list of miRNAs in serum with therapeutic response to Glatiramer Acetate (GA) and with the clinical evolution of a cohort of relapsing-remitting MS (RRMS) patients. We conducted a longitudinal study for 5 years, with cut-off points at 2 and 5 years, including 26 RRMS patients treated with GA for at least 6 months. A total of 6 miRNAs from a previous study (miR-9.5p, miR-126.3p, mir-138.5p, miR-146a.5p, miR-200c.3p, and miR-223.3p) were selected for this analysis. Clinical relapse, MRI activity, confirmed disability progression (CDP), alone or in combination (No Evidence of Disease Activity-3) (NEDA-3), and Expanded Disability Status Scale (EDSS), were studied. After multivariate regression analysis, miR-9.5p was associated with EDSS progression at 2 years (ß = 0.23; 95% CI: 0.04-0.46; p = 0.047). Besides this, mean miR-138.5p values were lower in those patients with NEDA-3 at 2 years (p = 0.033), and miR-146a.5p and miR-126.3p were higher in patients with CDP progression at 2 years (p = 0.044 and p = 0.05 respectively. These results reinforce the use of microRNAs as potential biomarkers in multiple sclerosis. We will need more studies to corroborate these data and to better understand the role of microRNAs in the pathophysiology of this disease.

microRNA Expression and Its Association With Disability and Brain Atrophy in Multiple Sclerosis Patients Treated With Glatiramer Acetate.

Background: MicroRNAs are small non-coding RNA that regulate gene expression at a post-transcriptional level affecting several cellular processes including inflammation, neurodegeneration and remyelination. Different patterns of miRNAs expression have been demonstrated in multiple sclerosis compared to controls, as well as in different courses of the disease. For these reason they have been postulated as promising biomarkers candidates in multiple sclerosis. Objective: to correlate serum microRNAs profile expression with disability, cognitive functioning and brain volume in patients with remitting-relapsing multiple sclerosis. Methods: cross-sectional study in relapsing-remitting multiple sclerosis patients treated with glatiramer acetate. Disability was measured with Expanded Disability Status Scale (EDSS) and cognitive function was studied with Symbol Digit Modalities Test (SDMT). Brain volume was analyzed with automatic software NeuroQuant®. Results: We found an association between miR.146a.5p (rs:0.434, p=0.03) and miR.9.5p (rs:0.516, p=0.028) with EDSS; and miR-146a.5p (rs:-0.476, p=0.016) and miR-126.3p (rs:-0.528, p=0.007) with SDMT. Regarding to the brain volume, miR.9.5p correlated with thalamus (rs:-0.545, p=0.036); miR.200c.3p with pallidum (rs:-0.68, p=0.002) and cerebellum (rs:-0.472, p=0.048); miR-138.5p with amygdala (rs:0.73, p=0.016) and pallidum (rs:0.64, p=0.048); and miR-223.3p with caudate (rs:0.46, p=0.04). Conclusions: These data support the hypothesis of microRNA as potential biomarkers in this disease. More studies are needed to validate these results and to better understand the role of microRNAs in the pathogenesis, monitoring and therapeutic response of multiple sclerosis.

Anti-Human Herpesvirus 6 A/B Antibodies Titers Correlate With Multiple Sclerosis-Associated Retrovirus Envelope Expression.

Human endogenous retrovirus W family envelope proteins (pHERV-W ENV/syncytin-1) have been repeatedly associated with multiple sclerosis (MS). Here, we have focused on the study of pHERV-W ENV/syncytin-1 expression levels in MS patients (relapsing and progressive forms) and in healthy donors (HD) and on exploring their possible relationship with Epstein-Barr virus (EBV) and human herpesvirus-6A/B (HHV-6A/B). We included blood samples from 101 MS patients and 37 HD to analyze antiviral antibody titers by ELISA and pHERV-W ENV/syncytin-1 expression levels by flow cytometry as well as by qPCR. Patients with relapsing MS forms showed significantly higher pHERV-W ENV/syncytin-1 protein and gene expression levels than HD. Progressive MS patients also showed significantly higher protein and gene expression levels than both HD and relapsing MS patients. Regarding antiviral antibodies titers, anti-HHV-6A/B IgM levels were positively correlated with pHERV-W ENV/syncytin-1 protein expression levels in patients with relapsing MS, while in the progressive forms patients this correlation was found with anti-HHVA/B IgG levels. Therefore, pHERV-W ENV could be involved in MS pathogenesis, playing a role in relapsing and progressive forms. Besides, anti-HHV-6A/B antibodies positively correlated with pHERV-W ENV expression. Further studies are needed to better understand this possible relationship.

MicroRNAs of Human Herpesvirus 6A and 6B in Serum and Cerebrospinal Fluid of Multiple Sclerosis Patients.

Human herpesvirus-6A (HHV-6A) and -6B (HHV-6B) might be involved in the etiopathogenesis of multiple sclerosis (MS), especially the HHV-6A. We aim at assessing, for the first time in the scientific literature, the HHV-6A/B microRNAs in MS patients. We analyzed the miRNAs of HHV-6A: miR-U86, and -6B: hhv6b-miR-Ro6-1, -2, -3-3p, -3-5p, and -4 in paired samples of serum and CSF of 42 untreated MS patients and 23 patients with other neurological diseases (OND), using Taqman MicroRNA Assays. Intrathecal HHV-6A/B antibody production and anti-HHV-6A/B IgG/IgM levels in serum were measured. MS clinical data were available. We detected the following miRNAs: hhv6b-miR-Ro6-2 (serum: MS:97.7%, OND:95.7%; CSF: MS:81%, OND:86.4%), 3-3p (serum: MS:4.8%, OND:0%; CSF: MS:2.4%, OND:4.5%), -3-5p (serum: MS:95.2%, OND:91.3%; CSF: MS:50%, OND:54.5%), and miR-U86 (serum: MS:54.8%, OND:47.8%; CSF: MS:11.9%, OND:9.1%). In the serum of the whole population (MS and OND patients) we found a significant correlation between the levels of hhv6b-miR-Ro6-2 and -3-5p (Spearman r = 0.839, pcorr = 3E-13), -2 and miR-U86 (Spearman r = 0.578, pcorr = 0.001) and -3-5p and miR-U86 (Spearman r = 0.698, pcorr = 1.34E-5); also in the CSF, between hhv6b-miR-Ro6-2 and -3-5p (Spearman r = 0.626, pcorr = 8.52E-4). These correlations remained statistically significant when both populations were considered separately. The anti-HHV-6A/B IgG levels in CSF and the intrathecal antibody production in positive MS patients for hhv6b-miR-Ro6-3-5p were statistically significant higher than in the negative ones (pcorr = 0.006 and pcorr = 0.036). The prevalence of miR-U86 (30.8%) in the CSF of individuals without gadolinium-enhancing lesions was higher (p = 0.035) than in the ones with these lesions (0%); however, the difference did not withstand Bonferroni correction (pcorr = 0.105). We propose a role of HHV-6A/B miRNAs in the maintenance of the viral latency state. Further investigations are warranted to validate these results and clarify the function of these viral miRNAs.

Correction to: Blood lymphocyte subsets identify optimal responders to IFN-beta in MS.

The author claims that his name is incorrectly listed on PubMed. It seems that the first and last name has been mixed up.

Blood lymphocyte subsets identify optimal responders to IFN-beta in MS.

Response to interferon-beta (IFN-beta) treatment is heterogeneous in multiple sclerosis (MS). We aimed to search for biomarkers predicting no evidence of disease activity (NEDA) status upon IFN-beta treatment in MS. 119 patients with relapsing-remitting MS (RRMS) initiating IFN-beta treatment were included in the study, and followed prospectively for 2 years. Neutralizing antibodies (NAb) were explored in serum samples obtained after 6 and 12 months of IFN-beta treatment. Soluble cytokines and blood lymphocytes were studied in basal samples by ELISA and flow cytometry, respectively. 9% of patients developed NAb. These antibodies were more frequent in patients receiving IFN-beta 1b than in those treated subcutaneous (p = 0.008) or intramuscular (p < 0.0001) IFN-beta 1a. No patient showing NAb remained NEDA during follow-up. Basal immunological variables are also associated with patient response. Percentages below 3% of CD19 + CD5 + cells (AUC 0.74, CI 0.63-0.84; OR 10.68, CI 3.55-32.15, p < 0.0001; Likelihood ratio 4.28) or above 2.6% of CD8 + perforin + T cells (AUC 0.79, CI 0.63-0.96; OR 6.11, CI 2.0-18.6, p = 0.0009; Likelihood ratio 5.47) increased the probability of achieving NEDA status during treatment. Basal blood immune cell subsets contribute to identify MS patients with a high probability of showing an optimal response to IFN-beta.

Study of the anti-JCV antibody levels in a Spanish multiple sclerosis cohort.

BACKGROUND: One of the risk factor to develop progressive multifocal leukoencephalopathy (PML) among natalizumab-treated patients is the presence and high levels of anti-JCV antibodies. Our purpose was to test the association of different clinical and demographic variables with the presence and levels of anti-JCV antibodies in a Spanish cohort of patients with multiple sclerosis (MS) during natalizumab treatment. MATERIALS AND METHODS: All patients with MS from two hospitals with at least one measure of the anti-JCV antibodies levels (2011-2014) were recruited, among them were two PML cases. Anti-JCV antibody levels were assessed using two-step ELISA. RESULTS: A total of 1061 patients (16·3% natalizumab-treated) participated in this study. The seropositivity rate of anti-JCV antibodies was 58·2%. It increased with age (Pcorrected = 0·00005) and was lower among HLA-DRB1*15:01 carriers (Pcorrected = 0·049). The two patients with PML were HLA-DRB1*15:01 carriers. We had at least three quarterly anti-JCV antibody measurements (index value) from 137 patients, whose levels did not increase during natalizumab treatment. However, 5·8% of these patients had an increase of the index value higher of one point in a maximum of 6 months, something that was more frequently observed (P = 0·054) among patients treated with immunosuppressant prior to natalizumab onset. CONCLUSIONS: Old age and HLA-DRB1*15:01 were the factors that influence positively and negatively, respectively, our anti-JCV antibody prevalence, although our both PML cases were HLA-DRB1*15:01carriers. Most of our patients showed a stable anti-JCV antibody index values during natalizumab treatment.