Defective structural RNA processing in relapsing-remitting multiple sclerosis

BackgroundSurveillance of integrity of the basic elements of the cell including DNA, RNA, and proteins is a critical element of cellular physiology. Mechanisms of surveillance of DNA and protein integrity are well understood. Surveillance of structural RNAs making up the vast majority of RNA in a cell is less well understood. Here, we sought to explore integrity of processing of structural RNAs in relapsing remitting multiple sclerosis (RRMS) and other inflammatory diseases.ResultsWe employed mononuclear cells obtained from subjects with RRMS and cell lines. We used quantitative-PCR and whole genome RNA sequencing to define defects in structural RNA surveillance and siRNAs to deplete target proteins. We report profound defects in surveillance of structural RNAs in RRMS exemplified by elevated levels of poly(A) + Y1-RNA, poly(A) + 18S rRNA and 28S rRNAs, elevated levels of misprocessed 18S and 28S rRNAs and levels of the U-class of small nuclear RNAs. Multiple sclerosis is also associated with genome-wide defects in mRNA splicing. Ro60 and La proteins, which exist in ribonucleoprotein particles and play different roles in quality control of structural RNAs, are also deficient in RRMS. In cell lines, silencing of the genes encoding Ro60 and La proteins gives rise to these same defects in surveillance of structural RNAs.ConclusionsOur results establish that profound defects in structural RNA surveillance exist in RRMS and establish a causal link between Ro60 and La proteins and integrity of structural RNAs.

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Investigating the role of brain-derived neurotrophic factor in relapsing-remitting multiple sclerosis

Multiple sclerosis (MS) is a common, heterogeneous disorder of the central nervous system with a complex trait composed of both genetic and environmental factors. Recently, scientific interest has increased in defining factors that possibly contribute to brain functional plasticity; the results might be useful to assess the relationship between MS lesion burden and clinical events, as well as explaining the well-known phenotypic heterogeneity of the disease. In this study, we explored the effect of the Val66Met brain-derived neurotrophic factor (BDNF) functional polymorphism on cognitive performances and volumetric measurements obtained by magnetic resonance imaging of the brain in a selected population of relapsing-remitting MS (RRMS) patients, with relatively short disease duration and minimal clinical disability, compared to gender, age and educational-level matched healthy subjects. We found that in the RRMS group, the BDNF Met-allele was significantly associated with the lower volume of cerebral grey matter (GM) (P = 0.005). Furthermore, a significant (P = 0.013) interaction effect between 'MS-status' and the BDNF genotype was found for GM volumes, with the result that patients carrying the BDNF Met-allele showed a higher risk of developing global GM atrophy than the homozygous Val/Val. No BDNF-related impact on global neuropsychological functions resulted in either RRMS patients or controls. Our data seem to be consistent with the reported influence of BDNF in neuronal plasticity, thus suggesting that the Met-allele might have a negative prognostic effect on cortical morphometry in RRMS patients.     

Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis,

ObjectivesThe primary objective was to evaluate the effect of omega-3 fatty acids (omega-3 FA) on matrix metalloproteinase-9 (MMP-9) production by immune cells in multiple sclerosis (MS). Quality of life, fatty acid levels, and safety were also evaluated.Materials and MethodsTen participants with relapsing-remitting MS (RRMS) received omega-3 FA supplementation (9.6 g/day fish oil) in an open-label study. Participants were evaluated at four time points, baseline, after 1 month of omega-3 FA supplementation, after 3 months of omega-3 FA supplementation, and after a 3-month wash out.ResultsImmune cell secretion of MMP-9 decreased by 58% after 3 months of omega-3 FA supplementation when compared with baseline levels (p<0.01). This effect was coupled with a significant increase in omega-3 FA levels in red blood cell membranes.ConclusionsOmega-3 FA significantly decreased MMP-9 levels in RRMS and may act as an immune-modulator that has potential therapeutic benefit in MS patients.     

Cutting edge: mast cells regulate disease severity in a relapsing-remitting model of multiple sclerosis

Mast cells (MCs) exert a significant pathologic influence on disease severity in C57BL/6 (B6) strain-dependent experimental allergic encephalomyelitis (EAE), a model of primary progressive multiple sclerosis (MS). However, relapsing-remitting MS, which is modeled in SJL mice, is the more prevalent form. Given genetically determined heterogeneity in numbers and responsiveness of MCs from various strains of mice, we asked whether these cells also influence this more clinically relevant MS model using SJL-Kit(W/W-v) mice. Similar to the commercially available WBB6F(1)-Kit(W/W-v) mice, SJL-Kit(W/W-v) mice are MC-deficient, anemic, and neutropenic and have normal T cell compartments. They exhibit significantly reduced disease severity, but retain the relapsing-remitting course, a phenotype reversed by selective MC reconstitution. These data confirm that MC influence is not confined to an isolated model of EAE and reveal a new system to study the effects of MC heterogeneity on relapsing-remitting EAE and other SJL strain-specific diseases.     

Association between peripheral IFN-gamma producing CD8+ T-cells and disability score in relapsing-remitting multiple sclerosis

A large body of evidence supports the involvement of the immune system in the pathogenesis of multiple sclerosis (MS). Nevertheless, how the peripheral T-cells phenotypes are associated with factors such as the disability score, the effects of immunomodulatory treatments, or the activation period is poorly understood. In this study, we have centered our attention on the presence of IFN-gamma and IL-4 producing CD4+ and CD8+ T-cells in the peripheral blood of 58 relapsing-remitting MS (RRMS) patients, 48 that were stable and 10 who were in relapse period, and 30 healthy controls (HC). Our results support the existence of an independent association between the percentage of IFN-gamma producing CD8+ lymphocytes and the increased levels of disability score. Furthermore, the number of IFN-gamma producing CD8+ lymphocytes and the disability score were not correlated in patients treated with interferon-beta, evidence of its possible benefits in combating a pro-inflammatory profile. Finally, we compared the T-cell populations in RRMS patients in the stable or active period, and we found a significant decrease of IFN-gamma producing CD4+ lymphocytes in active patients. In conclusion our study supports the hypothesis that different peripheral blood T-cell phenotypes are associated with disability score or active period of the disease.     

Oral health status and temporomandibular disorders in multiple sclerosis patients

Multiple sclerosis (MS) is an inflammatory disease of unknown etiology involving the central nervous system. Certain clinical manifestations affect the oro-facial region. Three in particular should be of interest to the dentist: trigeminal neuralgia, sensory neuropathy of the trigeminal nerve and facial palsy. The aim of this study was to determine the oral health status, the frequency of subjective symptoms and temporomandibular disorders (TMD) subtype according to Research diagnostic criteria for temporomandibular disorders (RDC/TMD) among MS patients. Examinees in this study were 50 patients suffering from MS, who were at least once treated during their disease in the Clinic Hospital Center, Rijeka, Clinic for Neurology. All examinees had to meet the diagnostic criteria for clinically and laboratory confirmed MS, according to Poser. The results show the difference in mean DMFT (decayed, missing, filled teeth) between MS and the control group. The number of decayed and missing teeth was higher, but the number of filled teeth was significantly lower in MS group. Eighty-two per cent of the subjects with MS had a least one symptom of dysfunction compared with 24% of the subjects in the healthy control group. In the present study, pain, the pain during mouth opening, the difficulty with mouth opening and temporomandibular joint (TMJ) sounds were more commonly reported in the MS group than in the control group. This study shows a statistically significant excess of dental caries and temporomandibular disorders among MS patients compared with the control group. These results suggest that MS is a possible etiological factor in temporomandibular disorders.     

Detection of human herpesviruses and polyomaviruses DNA in a group of patients with relapsing-remitting multiple sclerosis

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system whose pathological features consist of white matter plaques of primary demyelinization and loss of oligodendrocytes. Various risk factors have been associated with MS susceptibility. We have focused this study on different viruses. In particular in the present study we used PCR to search for the genomic DNA of HHV-1, HHV-2, HHV-8, BKV and JCV in urine and peripheral blood mononuclear cells (PBMC) samples from 44 relapsing-remitting MS (RRMS) patients. No viral DNA was found in any urine sample, whereas 29.5% of RRMS PBMC samples were positive. It is suggestive that Human herpesviruses (HHV-1 and HHV-8) were constantly present in all positive samples, indicating that viral agents could contribute to create the demyelination plaques and cause MS.     

Glatiramer in the treatment of multiple sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system with both an inflammatory and degenerative component. The disease primarily affects young adults and results in significant physical and cognitive disability. Several disease-modifying agents are currently used in the management of multiple sclerosis. Glatiramer acetate (GA, Copaxone, co-polymer 1) is a disease-modifying agent approved for the treatment of relapsing remitting multiple sclerosis. Apart from its unique mode of action, there is evidence pointing toward a possible neuroprotective role. This review will critically discuss GA's potential mechanisms of action, the results of clinical trials, safety profile, and future directions of treatment.     

Effect of interferon-beta and atorvastatin on Th1/Th2 cytokines in multiple sclerosis

Beneficial effects by both interferon-beta and statin treatment in patients with multiple sclerosis (MS) may be linked to interference with the Th1/Th2 cytokine balance. We determined patterns of Th1/Th2 cytokines (interleukin (IL)-1beta, IL-2, IL-6, IL-12p70, tumor-necrosis factor (TNF)-alpha and interferon-gamma, and IL-4, IL-5 and IL-10, respectively) in the serum of patients with relapsing-remitting MS treated with 250microg interferon-beta 1b or with interferon-beta plus 40mg atorvastatin. In treatment na?ve patients with MS, a trend for lower TNF-alpha serum levels compared to controls was detected (P=0.08). Interferon-beta treatment increased TNF-alpha levels, while a trend for lowering of IL-5 serum levels was found (P=0.07). Addition of atorvastatin raised IL-12p70 serum levels (P<0.05). Mean levels of two Th2 cytokines (IL-4, IL-10) showed a non-significant increase after addition of atorvastatin. We conclude that interferon-beta and atorvastatin exert divergent action on Th1/Th2 serum cytokines levels in MS. Supplemental atorvastatin might promote a Th1-type response by raising IL-12p70. Further studies are required to support a Th2 cytokine shift by atorvastatin in patients with MS.     

Magnetic resonance spectroscopy of normal appearing white matter in early relapsing-remitting multiple sclerosis: correlations between disability and spectroscopy

Background  

What currently appears to be irreversible axonal loss in normal appearing white matter, measured by proton magnetic resonance spectroscopy is of great interest in the study of Multiple Sclerosis. Our aim is to determine the axonal damage in normal appearing white matter measured by magnetic resonance spectroscopy and to correlate this with the functional disability measured by Multiple Sclerosis Functional Composite scale, Neurological Rating Scale, Ambulation Index scale, and Expanded Disability Scale Score.     

Apoptosis in multiple sclerosis

Several recent studies have provided evidence that apoptosis is an important feature in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. Apoptosis presumably plays a role in the immunoregulation via activation-induced T-cell death (AICD) and in local processes of tissue damage. In this review the dual role of apoptosis in the MS pathogenesis and its relevance regarding therapeutic concepts is discussed.     

Polyunsaturated fatty acids in treatment of acute remitting multiple sclerosis.

One hundred and sixteen patients with acute remitting multiple sclerosis (MS) took part in a double-blind controlled trial of treatment with polyunsaturated fatty acids and were randomly allocated to one of four groups. Two groups received linoleic acid, one alone as a spread and one with gamma-linolenic acid in capsules (Naudicelle); and two control groups received oleic acid, one as a spread and one in capsules. Rates of clinical deterioration and frequencies of attacks were not significantly different between treated and control groups. Exacerbations were shorter and less severe in patients receiving a high dose of linoleic acid than in controls, but those receiving a lower dose--that is, Naudicelle--showed no such difference. Thus supplementing the diet with 20 g linoleic acid marginally affected the duration and severity of relapses of MS but had no effect on overall disability. The dose of Naudicelle used provided insufficient supplementation.