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Previous studies showed that depleting Liver Kinase-B1 (LKB1) from astrocytes increased inflammatory factors lipocalin-2 (LCN2) and osteopontin (OPN) in EAE. A single nucleotide polymorphism (SNP) in STK11 (encoding LKB1) is a risk factor for MS, suggesting increased LCN2 or OPN contributes to risk. Serum LCN2 and OPN levels in African American female MS patients were higher than healthy controls, and while levels increased with disease duration in cases without the SNP, levels decreased with duration in cases with the SNP. Increased MS risk associated with the STK11 SNP may be due to higher LCN2 or OPN levels at early times.

The aim of this study was to evaluate the therapeutic effect of PEGlated nanoliposome of pistachio unsaturated oils (PEGNLPUOs) and their efficacy to attenuate inflammation in multiple sclerosis (MS). This study was a randomized, double-blind, placebo-controlled clinical trial phase I. The level of docosahexaenoic and eicosapentaenoic acid was significantly increased and the level of matrix metallopeptidase-9 was significantly decreased in MS patients treated with PEGNLPUOs. The level of cytokine showed a Th2-biased response with attenuation of inflammation after treatment with PEGNLPUOs. The number of relapses, disability scores, and T2 lesions was significantly decreased after treatment with PEGNLPUOs.

Cladribine is an effective immunomodulatory treatment used for relapsing forms of multiple sclerosis (MS).To describe the clinical outcomes and rates of no evidence of disease activity (NEDA) in patients with highly-active disease treated with 2 years cumulative dose of cladribine, for years 3 and 4.We used the Sheba Multiple Sclerosis computerized data registry to retrospectively evaluate year-3 and year-4 clinical outcomes and NEDA-2 rates in highly active RRMS patients who completed the 2-dose 2-year cladribine treatment protocol (3.5 mg/kg cumulative dose over 2 years). The first week of treatment in year 1 was considered as baseline. Data analyses were performed using Python (version 3.0) and SAS® (version 9.4 SAS Institute, Cary, NC).Among 128 patients with highly-active MS that received cladribine treatment, 61 patients, 43 females, were studied for year-3 clinical outcomes, and 35 patients, 23 females, also for year-4. At the initiation of cladribine treatment, the mean ± SD age was 39.6 ± 10.74 years (45.9% of the patients were between 18 and 40 years), disease duration 12.7 ± 9.08 years, Expanded Disability Status Scale (EDSS) 3.7 ± 1.86 (54% had EDSS score 3.0), and the annual relapse rate was 1.6 ± 0.9. The annual relapse rate decreased to 0.36 in year-3 and was 0.17 in year-4; 68.9% (42/61) of the patients were relapse-free in year-3, and 82.9% (29/35) were relapse-free in year-4. Disability at year-3 was 3.1 ± 2.07; 83.6% (51/61) of the patients remained neurologically stable (33, 54.1%) or improved (18, 29.5%). In year-4, EDSS was 3.2 ± 1.91, and 85.7% (30/35) of the patients remained stable (20, 57.1%) or improved (10, 28.6%). NEDA-2 was achieved for 59.0% (36/61) of patients in year-3, and for 74.3% (26/35) in year-4 of cladribine treatment.In the real-world cladribine proved to be clinically effective in year-3 and year-4 of treatment in the majority of highly active RRMS patients.

Fingolimod, used to treat relapsing-remitting multiple sclerosis (RRMS), reduces motor deficits in mice with established experimental autoimmune encephalomyelitis (EAE). To better characterize the therapeutic effects of fingolimod, kinematic gait analysis was employed to precisely measure movements of a hindleg while EAE mice walked on a treadmill. Relative to the vehicle group, oral dosing with fingolimod, beginning after disease onset (1 mg/kg/day), increased hip heights and knee joint movements, and reduced spinal cord demyelination. These findings suggest that fingolimod preserves gait in RRMS patients by protecting motor circuits in the spinal cord.

Multiple Sclerosis (MS) is thought to be an autoimmune disease of the central nervous system (CNS), in which the immune system becomes activated, cross the blood-brain barrier (BBB), and cause neuroinflammation and neurodegeneration. Fingolimod is considered a disease-modifying therapy (DMT), possessing immunomodulatory effects on the immune system, especially autoreactive T cells being licensed in lymph nodes. Although the fidelity of the drug is undeniable in the management of disease course, various adverse effects have been reported in some patients taking this medication. In this study, 420 MS patients, consisted of 210 patients receiving interferon-beta (IFN-beta) and 210 patients receiving fingolimod therapies. As a control group, 210 age- and sex-matched healthy individuals were recruited in our study. The levels of anti-VZV IgG and IgM were determined using enzyme-linked immunosorbent assay (ELISA). The presence of VZV DNA in peripheral blood mononuclear cells (PBMCs) was also investigated using the PCR method. The percentage of seropositivity for anti-VZV IgG and anti-VZV IgM in MS patients was 94.8% and 0%, respectively in those taking fingolimod therapy. In patients receiving IFN-beta, the rate of seropositivity for anti-VZV IgG and anti-VZV IgM was 93.8% and 0%, respectively. In healthy individuals, the rate of seropositivity for anti-VZV IgG and anti-VZV IgM was 84.3% and 0%, respectively. The PCR results showed that 7.6% of patients receiving fingolimod were positive for VZV DNA, while none of the healthy subjects nor MS patients taking IFN-beta were positive for DNA of VZV. The statistical analysis indicated that the frequency of VZV DNA in patients receiving fingolimod was significantly (p = .00) higher than MS patients taking IFN-beta and healthy subjects. It seems that the use of fingolimod should be carefully prescribed as the occurrence of VZV infection/reactivation is increased in comparison to other MS patients who receive different therapy.

Demyelination, axonal loss and failure of tissue repair characterize MS lesions. Bone morphogenetic proteins (BMPs) signaling is associated with remyelination failure. Coco is one of the BMP antagonists. We found reduced Coco serum levels in relapsing-remitting MS (RR-MS) and primary progressive MS (PP-MS) patients compared to matched healthy controls (HC) and patients with rheumatoid arthritis. Exposure of P19 cells, in the presence of retinoic acid, BMP-2, or BMP-4 to Coco, at average sera level of MS patients failed to induce neuronal phenotype, in contrast to the average sera level of HC. Coco may be a player in the BMP dysregulation and the tissue repair failure in MS.

Most of the multiple sclerosis (MS) patients are initially diagnosed with relapsing remitting multiple sclerosis (RRMS). Th17 cells and macrophages have been shown to play critical roles in pathogenesis of MS and initiation of CNS tissue damage. MiR-301a have recently been exposed as an activator of STAT3 in Th17 cells as well as an activator of NF-κB in macrophages by targeting PIAS3 and NKRF correspondingly. However, the possible role of miR-301a in RRMS has not yet been elucidated. Herewith, for the first time, we have studied the expression of miR-301a, NKRF and PIAS3 by quantitative real-time PCR and western blotting method in peripheral blood mononuclear cells (PBMCs) of 71 RRMS patients, including two groups of patients in relapse phase (n = 44) and a group of remitting phase patients (n = 28) in comparison to healthy volunteers (n = 28). In this work, we demonstrate a significant upregulation of miR-301a in relapse phase of MS patients compared to healthy controls and remitting phase patients (P .05). Our findings also showed a striking decrease of NKRF and PIAS3 expression in relapse phase patients, in contrast to miR-301a and, NF-κB and STAT3 downstream genes (SKA2 and RORc) (P .05). Subsequently, using luciferase reporter system we confirmed that miR-301a directly targets the mRNA encoding PIAS3 and NKRF proteins. We also showed that miR-301a increasing expression is correlated with down-regulation of PIAS3 and NKRF expression in RRMS patients. Our findings suggest that miR-301a, PIAS3 and NKRF play crucial roles in RRMS and could be considered as promising therapeutic targets.

Multiple sclerosis (MS) is an autoimmune, neurological disease. We investigated genome-wide DNA methylation profiles of CD4+ and CD8+ T cells from MS patients and healthy controls at baseline and a follow-up visit. Patients were all treatment-naïve at baseline, and either on treatment or remained untreated at the follow-up visit. MS patients show more changes in their T cell DNA methylation profiles as compared to healthy controls over time, with the most pronounced differences observed in the untreated MS patients. These findings underline the potential of DNA methylation as biomarkers in MS.

Case report describing a patient infected with COVID-19 after initiation of Cladribine, with a favorable disease course and positive seroconversion.

NK/T-cell ratios predict disease activity in relapsing remitting multiple sclerosis (RRMS). We investigated in 50 RRMS patients whether interleukin-2 receptor alpha-chain (IL-2Rα) expression and shedding associates with NK/T-cell balance, as suggested by daclizumab-trials in RRMS. A subsample (N = 31) was genotyped for IL2RA-associated MS risk SNPs. CD56bright NK-cell/IL-17A+CD4+ T-cell ratios correlated negatively with plasma and PBMC-culture supernatant sIL-2Rα-levels [R = -0.209; p = 0.038 and R = -0.254; p = 0.012, resp.], and with CD4+ T-cell CD25 MFI [R = -0.341; p = 0.001]. Carriers of the rs3118470 risk-allele showed higher sIL-2Rα-levels (P = 0.031) and a lower CD56bright NK-cell/IL-17A+CD4+ T-cell ratio (P = 0.038). Therefore, IL-2Rα may be involved in the interplay between NK-cells and T-cells.

The combination of genetic and epigenetic influences alters the development of complex diseases. Aberrant patterns of DNA methylation are associated with inflammation and clinical activity in MS. We evaluated the differences between global DNA methylation in lymphocytes and monocytes of patients with MS compared to healthy controls. Thirty-three patients with RRMS (PwRMS) and five healthy individuals were included. DNA was isolated from PBMCs by a phenol-chloroform method, and global methylation was analyzed by Imprint® Methylated DNA Quantification Kit. We observed a cell-type-specific DNA methylation pattern and showed that monocyte global DNA methylation was significantly affected by IFNβ treatment.

Interferon-β (IFN-β) is among the first drugs used for reducing the symptoms of multiple sclerosis (MS). Many studies show that the genetic predisposition of patients might modulate their response to IFN-β treatment. In this study GAPVD1 gene expression and the genotyping of rs2291858 variant were analysed in 100 responder and 100 non-responder patients with MS treated using IFN-β. Moreover, rs2291858 genotyping was performed for 200 patients with MS and 200 healthy controls. GAPVD1 expression was significantly increased in the responder patients than in non-responders and the distribution of rs2291858 polymorphism was significantly different between them. The GAPVD1 expression level in AA genotype of the responder group was higher than that in other genotypes of these two groups. The results show that the GAPVD1 expression level and rs2291858 genotype probably affect the response to IFN- β in patients with MS.

Multiple Sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS) in which immune system plays a crucial role in progression of the disease. An enormous amount of research has been shown that immune mediators such as cytokines and chemokines are the culprits of MS propagation suggesting that modulation of such molecules may pave the path to hinder the disease development. It has been shown that both CD21 and CD83 contribute to the resolution of inflammation occurred in MS. CD21 and CD83 have also been ascribed to Epstein Barr virus (EBV) infection (the prime suspect of MS causality) and the levels of vitamin D, respectively. Hence, in this study, we measured the serum concentrations of soluble forms of CD21 and CD83 in 255 patients with MS divided into two groups who were receiving interferon-beta (185 MS patients) and fingolimod (70 MS patients) in comparison to 384 healthy individuals. The levels of EBV titers including anti-VCA IgM, anti-VCA IgG and anti-EBNA-1 IgG were also measured. The results showed that the concentration of soluble CD21 (sCD21) was markedly decreased in serum samples of MS patients with respect of controls. Contrarily, the level of soluble CD83 (sCD83) was elevated in MS patients compared to healthy individuals. In addition, the levels of sCD21 and sCD83 were correlated with the titers of EBV. The data showed the significant association between the expanded disability status scale (EDSS) and the levels of both sCD21 and sCD83. It seems that both sCD21 and sCD83 might be good candidate for disease monitoring and can be considered potential biomarkers for the disease activity.

Multiple sclerosis (MS) is a demyelinating neurological disease with unknown causes. In this study, we comprehensively studied blood cell counts in the early phase of MS and compared their values with eventual prognostic variables. We found that the blood monocyte count in the early phase of MS was robustly associated with the clinical severity of MS (rho = 0.64; p = 0.0002) but that the counts of the other blood cells were not associated with severity. This correlation between monocyte count and severity was not observed in neuromyelitis optica. In conclusion, blood monocytes could be a candidate for the prognostic prediction of MS.

This study aimed to examine the expression of TYK2, CBLB and LMP7 genes at both mRNA and protein levels in relapsing-remitting MS (RRMS) patients in compare with healthy controls. Seventy-eight RRMS patients treated with IFNβ-1a and 79 age- and ethnic-matched healthy subjects were studied. The mRNA expression levels of TYK2, CBLB and LMP7 in PBMCs were quantified by real-time PCR and plasma concentrations of three molecules were measured by ELISA. Results were compared between patients and controls, IFNβ-responders and non-responders. Forty-nine of 78 patients were classified as IFNβ-responders and 29 cases were non-responders. Significantly down-regulated expression of TYK2, CBLB and LMP7 genes was found in the patients group versus controls (P0.001). Decreased plasma levels of three molecules were observed in patients compared to controls (P0.001). IFNβ-responders had significantly higher expressions for CBLB (P=0.001) and LMP7 (P=0.02) than non-responders. Also, we observed increased expressions of LMP7 (P=0.39) and CBLB (P=0.02) genes in patients under 30y and increased expression of TYK2 in patients40years (P=0.002). Our results suggest that expression analysis of TYK2, CBLB and LMP7 genes could be useful for evaluation of T cells immunity and clinical response to IFNβ-therapy in RRMS patients.

Eosinophilia is common during natalizumab treatment for multiple sclerosis but risk factors are unknown. We aimed to identify demographic, clinical and laboratory characteristics predicting eosinophilia. Sustained eosinophilia occurred in 16.8%. Risk factors for sustained eosinophilia included baseline pre-treatment eosinophilia, medical conditions potentially associated with eosinophilia including allergies, and suboptimal compliance. One temporal profile was associated with the highest and most rapidly developing eosinophilia, and was less likely to resolve: in one such case, eosinophilia was symptomatic. Changes in eosinophil and lymphocyte counts were only weakly correlated, suggesting factors other than Very Late Antigen-4 (VLA-4) inhibition drive eosinophilia.

We aimed to determine whether Alemtuzumab-induced immune reconstitution affects immunoglobulin and complement levels in the serum of Relapsing-Remitting Multiple Sclerosis (RRMS) patients. IgG4-levels were increased 24-months after treatment initiation compared to baseline levels in twenty-nine patients. Alemtuzumab-treated patients with the highest IgG4-levels were more prone to thyroid-related autoimmune manifestations and specific autoimmune adverse events such as Crohn's disease, Graves' disease, and hemolytic anemia. Compared to baseline, total IgG-levels showed a trend towards reduced levels following two-courses of Alemtuzumab, but no significant change of C3 and/or C4-levels was observed. In conclusion, monitoring of IgG4-levels can serve as a marker for secondary autoimmunity risk in multiple sclerosis patients treated with Alemtuzumab.

CCL20 is a potentially important component in the pathogenesis of multiple sclerosis (MS). SIRT1 exhibits a negative regulatory effect on a variety of inflammatory cytokines and can relieve experimental autoimmune encephalomyelitis. The association between the level of CCL20 and SIRT1 activity in MS patients has not been investigated. In the present study, blood samples were collected from 38 RRMS patients and 40 healthy controls. The serum CCL20 levels were measured by ELISA. SIRT1 activity was evaluated by fluorometric assay. We revealed elevated serum CCL20 concentrations in MS, and discovered an inverse correlation between CCL20 and SIRT1 activity in MS patients.

While complement-dependent cytotoxicity (CDC) is a known effector mechanism in aquaporin-4-immunoglobulin (Ig)G-positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD), the role of CDC in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is less clear. We determined complement C3 and C4 plasma concentrations in patients with clinically stable AQP4-IgG+ NMOSD (n = 16), MOGAD (n = 15), early multiple sclerosis (MS, n = 19) and in healthy controls (HC, n = 18). C4 was lower in AQP4-IgG+ NMOSD than in MOGAD, MS and HC (p 0.05, pairwise comparisons). C3 was lower in AQP4-IgG+ NMOSD than in MS (p = 0.034). These findings suggest subtle complement consumption in clinically stable AQP4-IgG+ NMOSD, but not in MOGAD.

B cell depletion therapy has been shown to be beneficial in multiple sclerosis (MS). However, the mechanism by which B cell depletion mediates its beneficial effects in MS is still unclear. To better understand how B cell depletion may benefit patients with a disease previously thought to be primarily mediated by CD4 T cells, immune profiles were monitored in 48 patients in a phase II trial of ublituximab, a glycoengineered CD20 monoclonal antibody, at 18 time points over a year. As we previously described there was a significant shift in the percentages of T cells, NK cells, and myeloid cells following the initial dose of ublituximab, but this shift normalized within a week and these populations remained stable for the duration of the study. However, T cell subsets changed with an increase in the percentage of naive CD4 and CD8 T cells and a decline in memory T cells. Importantly, the percentage of Th1 and CD4+GM-CSF+ T cells decreased, while the percentage of Tregs continued to increase over the year. Ublituximab not only depleted CD20+ B cells, but also CD20+ T cells. The favorable changes in the T cell subsets may contribute to the beneficial effects of B cell depletion therapy.

Long noncoding RNAs (lncRNAs) as potential disease biomarkers might be related to severe course of multiple sclerosis (MS). We evaluated expression levels of NF-κB-associated lncRNAs including HOTAIR, THRIL, H19, NKILA, and ANRIL; as well as expression of IL-6, TNF-α and MMP9, in peripheral blood mononuclear cells (PBMCs) from 60 relapse-remitting MS (RRMS) patients. At relapse phase of RRMS, up-regulation of ANRIL and H19 was positively correlated with the overexpression of IL-6; high levels of THRIL and HOTAIR was positively correlated with increased levels of TNF-α and MMP9, respectively; however, the NKILA expression was negatively correlated with the expression of TNF-α.

Blockage of bone morphogenetic protein (BMP) signaling is required for differentiation of neurons and oligodendrocytes from neural stem cells (NSCs). Sera of untreated relapsing-remitting multiple sclerosis (RR-MS) patients expressed significantly higher levels of BMP-2 compared to sera of healthy controls. BMP-2 levels correlated with BMP-4 and -5 levels only in sera of untreated MS patients. Furthermore, sera of untreated patients inhibited the neuronal differentiation of RA-treated P19 cells, which was associated with induction of phospho-SMAD signaling pathway. These results suggest that BMP-2 sera levels may play a role in the failure of remyelination and neuro-regeneration in RR-MS.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), where inflammation, demyelination together with the axonopathy are the cardinal features on pathologic ground, with a combined genetic and environmental background. The associations of PD-1 single nucleotide polymorphisms (SNPs): PD-1.3 (in intron 4), PD-1.5 and PD-1.9 (both in exon 5) with clinical manifestation of MS in 479 south Polish individuals including 203 MS patients were analyzed. Presence of PD-1.5 T allele was linked with the first manifestations of disease: diplopia and pyramidal signs - favored pyramidal signs but protected against of diplopia development. Farther, PD -1.3G/ PD -1.5C/ PD -1.9C haplotype significantly favored whereas GTC protected against diplopia. Besides, GTT haplotype strongly favored non-severe RRMS outcome and ATC haplotype was specific only for these MS patients. Our population-based case-control study, investigating selected three PD-1 SNPs: PD-1.3, PD-1.5 and PD-1.9, revealed that polymorphic variation may be rather disease-modifying than MS risk factor.

Previously, we identified anti-Talin-1 antibodies in the serum of MS. In this case, we measured the serum soluble Talin-1 (sTalin-1) levels by enzyme-linked immunosorbent assay. The serum sTalin-1 levels were significantly higher in 40 patients with MS than in 43 normal controls and in the acute phase of disease than in the remission phase. Interestingly, serum sTalin-1 levels were associated with a sustained increase in disability after MS attack but not with serum anti-Talin-1 antibody levels. sTalin-1 may be a biomarker for the acute phase of MS and may be used for the short-term prognosis of MS.

Magnetic resonance imaging (MRI) has led to the identification of widespread brain abnormalities in multiple sclerosis (MS) that extend far beyond the classic white matter lesion. These findings have generated the idea that MS should be understood as a disease of the whole brain, not just the white matter. While it is no doubt the case that many different pathways are ultimately involved in the destruction of brain tissue that occurs in MS, the implications of the accumulated evidence for understanding disease pathophysiology – and hence the overall significance of these imaging findings – are doubtful. Here, I argue that the principled use of imaging can, in fact, address questions about the genesis of these whole-brain abnormalities, rather than simply describe them.

Fingolimod is used to treat patients with relapsing-remitting multiple sclerosis; it crosses the blood-brain barrier and modulates sphingosine-1-phosphate receptors (S1PRs). Oligodendrocytes, astrocytes, microglia, and neuronal cells express S1PRs, and fingolimod could potentially improve remyelination and be neuroprotective. We used the cuprizone animal model, histo-, immunohistochemistry, and quantitative proteomics to study the effect of fingolimod on remyelination and axonal damage. Fingolimod was functionally active during remyelination by downregulating S1PR1 brain levels, and fingolimod-treated mice had more oligodendrocytes in the secondary motor cortex after three weeks of remyelination. However, there were no differences in remyelination or axonal damage compared to placebo. Thus, fingolimod does not seem to directly promote remyelination or protect against axonal injury or loss when given after cuprizone-induced demyelination.

Acquired Factor VIII inhibitor is a rare acquired clotting disorder which has been seen in the setting of particular medications, autoimmune disease, and malignancy. Reports of this disorder in patients receiving immunomodulatory therapies for multiple sclerosis are rare. We present a case of a 48 year-old woman with likely development of acquired Factor VIII inhibitor in the setting of interferon beta monotherapy for multiple sclerosis, and discuss the pathogenesis of this disorder which involves shifts in helper T cell populations and increased production of immunoglobulins.

Leptin (LEP) may contribute to the pathogenesis of multiple sclerosis (MS) by its immunomodulatory, proinflammatory and prooxidant effects. Therefore, plasma LEP levels and mRNA expression of five genes related to the LEP signaling pathway (LEP, LEP receptor (LEPR), peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1A), superoxide dismutase 2, tumor necrosis factor-alpha) were investigated in relapsing-remitting MS. In patients (N = 64), compared to healthy subjects (N = 62), relative LEP mRNA levels were significantly increased (p = 0,01), while LEPR and PGC1A mRNA levels were decreased (p = 0,001 and p = 0,04, respectively). Significant positive correlation was observed between LEPR mRNA levels and clinical parameters of MS progression (EDSS, MSSS).

Our work consists of a pilot study to characterize circulating Th/c1, Th/c2, Th/c17, Treg and Tfh-like populations and IL-17 serum levels of relapsing-remitting (RR) MS patients treated with IFN-β, compared with healthy controls. In remission RRMS patients, we observe increased Th/c17 cells frequency committed to a Th1 profile and increased soluble IL-17 levels. Moreover, a shift toward Th/c2 with reduction of Tc1 cells and decrease in effector/terminal differentiated compartment of Th1 cells were also observed. Despite RRMS patients being an inactive disease phase, IL-17 and Th/c17 cells seemed to contribute to perpetuating chronic inflammation, besides the altered ratio Th1/Th2.

The aim of the current study is to evaluate IL-17 production and RORγT, and IL-23R expression by iNKT, Th17 and γδ T cells in the peripheral blood of relapsing-remitting multiple sclerosis patients. Samples of peripheral blood from 21 relapse patients and 12 remission patients, and 15 healthy volunteers were stained with monoclonal antibodies for flow cytometry analysis. No significant differences in iNKT, γδ T and Th17 percentages were noted. The significant overexpression of RORγT was observed in all three subpopulations – therefore, iNKT, γδ T and Th cells may be an important source of IL-17 shortly prior to the relapse.

Increasing systemic prolactin levels improves remyelination and neuronal survival in animal models of Multiple Sclerosis (MS), but it has been suggested that this therapeutic strategy may also increase inflammatory responses, and potentially harm patients. We analyzed serum prolactin and cytokine, chemokine and growth factor levels in sera from MS patients enrolled in two clinical trials who were treated with domperidone, a generic drug that increases systemic prolactin levels. In patients treated with domperidone, molecule levels changed little during follow up, while prolactin levels increased several-fold. We found no significant association between prolactin levels and radiological or clinical outcome.

Interleukins (ILs)-22, 32α and 34 were monitored in the sera of relapsing-remitting multiple sclerosis (RRMS) patients at different time intervals with or without interferon β-1b, interferon β-1a and fingolimod treatments. The results showed that sera of untreated RRMS patients were statistically higher in concentration of IL-22 (P .001), but not IL-32α and IL-34, than those of healthy individuals. Interestingly, interferon β-1b, interferon β-1a and fingolimod treatments led to a significant decrease of serum concentrations of ILs-22 and 32α, but not 34, at 6 and 12 months of treatment, compared to their initial concentrations before initiating therapy. The correlation analysis revealed that the changes of serum IL-22 (r = 0.814) and, to a lesser extent, IL-32α (r = 0.381) concentrations were positively correlated with those of expanded disability status score. In conclusion, serum IL-22 concentration may be a potential marker for MS disease severity and efficacy of treatment.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, thought to be mediated by myelin-specific CD4+ T cells. However, B cell depletion has proven to be an effective therapy for MS, but the mechanism is not well understood. This study was designed to determine how B cell depletion changes lymphocyte profiles. During a phase IIa clinical trial with ublituximab, a novel CD20 antibody, blood was collected from 48 MS patients at 11 time points over 24 weeks and the lymphocyte profiles were analyzed by flow cytometry. The percentage of naive CD4+ and CD8+ T cells increased, while the percentage of both effector and central memory T cells declined. CD4+ Th1 effector cells decreased, while there was a significant increase in CD4+ regulatory T cells. The depletion of B cells had a favorable shift in the lymphocyte landscape, reducing the number of naive T cells becoming activated and transitioning to memory T cells. The ratio of Th1 cells to CD4+ regulatory T cells declined, suggesting that immune regulation was being restored. These data suggest that loss of B cells as antigen presenting cells is a major mechanism of action for the beneficial effects of CD20 antibody therapy in MS.

IL-17 has been implicated in the pathogenesis of multiple sclerosis (MS). Here, we show that blockade of IL-17A, but not IL-17F, attenuated experimental autoimmune encephalomyelitis (EAE). We further show that IL-17A levels were elevated in the CSF of relapsing-remitting MS (RRMS) patients and that they correlated with the CSF/serum albumin quotient (Qalb), a measure of blood-brain barrier (BBB) dysfunction. We then demonstrated that the combination of IL-17A and IL-6 reduced the expression of tight junction (TJ)-associated genes and disrupted monolayer integrity in the BBB cell line hCMEC/D3. However, unlike IL-17A, IL-6 in the CSF from RRMS patients did not correlate with Qalb. These data highlight the potential importance of targeting IL-17A in preserving BBB integrity in RRMS.

OBJECTIVE To describe frequency of natalizumab related eosinophilia and clinical symptoms of eosinophilic disease in our monocentric cohort. METHODS Comparison of clinical characteristics of 115 natalizumab treated and 116 untreated RRMS patients and review of literature. RESULTS 38% of natalizumab treated patients had eosinophilia, which occurred significantly more frequently compared to untreated MS patients (3%, p-value

Multiple sclerosis (MS) is an autoinflammatory, chronic central nervous system disease. In the pathogenesis of the disease increased nitric oxide (NO) levels play an important role. Nitric oxide (NO) has neuroprotective effects in physiological conditions, however, it is thought that excessive NO formation in MS may lead to demyelination and axonal damage. Derivatives of methylarginine including asymmetric dimethyl arginine (ADMA), L-N monomethyl arginine (L-NMMA), symmetric dimethyl arginine (SDMA) directly or indirectly reduce NO production. Our aim was to measure the levels of methylarginine derivatives and citrulline, ornithine, arginine, homoarginine levels, which are metabolites associated with NO metabolism, in MS subgroups.

Twenty-seven treatment-naive patients with relapsing-remitting multiple sclerosis (MS) and 13 with neuromyelitis optica spectrum disorder (NMOSD) were enrolled during a time of acute flare-up. Common cerebrospinal fluid (CSF) features were increased CD29- and/or CD45RO-positive helper T cells capable of propagating inflammation in the central nervous system (CNS). B cell activation in the CSF was unique to MS, while an increase in CD4+CD192 (CCR2)+ cells in blood and breakdown of the blood-brain barrier (BBB) characterized NMOSD. Intravenous corticosteroid therapy suppressed neuroinflammation via modulation of cellular immunity in MS, as opposed to restoration of the BBB in NMOSD.

Daclizumab (DAC), a humanized monoclonal antibody that binds to the interleukin (IL)-2-receptor alpha chain, was approved in May 2016 for treatment of relapsing-remitting multiple sclerosis (RRMS). Approval was suspended in March 2018 after occurrence of severe liver failure and fatal meningoencephalitis in several patients treated with DAC. We report the clinical, laboratory and neuroimaging findings of 2 patients, who developed hypophysitis about 4 months after cessation of therapy with DAC. This report identifies delayed onset hypophysitis as a previously unrecognized severe side effect of DAC, highlighting the importance of continuous pharmacovigilance and patient monitoring even after cessation of DAC therapy.

Multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection, and the antibody response to EBV is reported to be increased in MS. EBV contains multiple antigens, and only a few have been investigated. Our hypothesis is that MS patients will have an increased antibody response to only selected EBV antigens. We used immunoprecipitation and quantitative mass spectrometry to identify candidate EBV antigens. We then measured the antibody response to 10 individual EBV proteins with quantitative ELISA. We found that the antibody response was increased in MS to three of the EBV proteins, but not to the other seven.

Galectin-9 is produced by activated astrocytes, induces a pro-inflammatory response in microglia and may be important to the pathogenesis of secondary progressive MS. In this study, Galectin-9 concentrations in CSF samples from healthy controls and two independent patient cohorts of MS patients were determined by ELISA. Patients from one of the cohorts underwent MRI as well. Galectin-9 concentrations in CSF were higher in SPMS patients than healthy controls and RRMS patients in both cohorts. Galectin-9 concentrations correlated with the number of lesions on T1-weighted images, but not with gadolinium enhancing lesions, IgG index or CSF cell count.

Objectives To investigate the relationship between TNFA-308G > A, IL10–1082A > G, IL18-607C > A, and cognitive functioning in relapsing-remitting multiple sclerosis (RRMS). Results In the patients' group: AG genotype of TNFA-308G > A was associated with higher serum tumor necrosis factor-alpha (TNF-alpha) than GG genotype, and higher TNF-alpha levels correlated with poorer results on Symbol Digit Modalities Test; CC genotype of IL18-607C > A was related to lower score on Isaacs test, compared to AC variant; AA genotype of IL10–1082A > G was associated with abnormally low results on Paced Auditory Series Addition Test. Conclusions TNFA-308G > A, IL10–1082A > G and IL18-607C > A gene variants may be associated with impaired cognitive functions in RRMS patients.

Relapsing remitting multiple sclerosis (RRMS) is the most prevalent MS subtype. Years after disease onset, most of RRMS patients show transition into secondary progressive form (SPMS). Currently, no biomarkers are available for tracking disease progression. Here, we observed marked elevation of Rho-associated protein kinase 2 (ROCK2) along with significant downregulation of miRNAs 300 and 450b-5p expressions in the serum of 39 RRMS and 35 SPMS Egyptian patients compared to healthy controls. More pronounced alterations were found in SPMS versus RRMS patients. Our findings also suggest relations between elevated ROCK2 and reduced expression of both miRNAs with the degree of disability and disease progression. Notably, these biomarkers effectively discriminated RRMS from SPMS patients with miR-450b-5p showing the highest prognostic power.

This study aims to compare NK cells obtained from multiple sclerosis (MS) patients receiving interferon-β1 and fingolimod therapies. Fingolimod reduced the CD56bright NK cell subset. The remaining CD56dim NK cells displayed NKG2D, NKp46, CD107a, and IFN-γ levels similar to those from the patients under interferon-β1 therapy. Alternatively, comparative transcriptomics and pathway analyses revealed significant distinctions between two therapy modalities. Molecular signature of the CD56dim NK cells from fingolimod-treated MS patients was closely associated to those from healthy subjects. The basic assets of NK cells were modestly influenced by interferon-β1 and fingolimod, however transcriptomics showed profound alterations in NK responses.

Objective This study aimed to quantitatively review and summarize the effectiveness and safety of rituximab (RTX) treatment for patients with relapsing-remitting multiple sclerosis (RRMS). Methods PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov databases were searched, and studies were screened based on inclusion and exclusion criteria. Meta-analysis was conducted with Stata. Primary outcomes included annualized relapse rate (ARR) change from baseline and relapse-free rate (RFR) at week 24, 48, 72, and 96. Secondary outcomes included Expanded Disability Status Scale (EDSS) change from baseline, the proportion of patients with infusion-related events (IRE) after treatment, and the proportion of patients with infections after treatment. Study quality assessment was performed using the Newcastle-Ottawa Scale and Cochrane Collaboration's tool. Results A total of 20 studies were included in this article and 13 of them were under quantitative synthesis. The 20 studies included 2020 patients suffering from RRMS. The overall absolute reduction in ARR of rituximab treatment in RRMS patients was 1.00 (95% confidence interval (CI) 0.83–1.17). And the overall RFRs at week 24, 48, 72, and 96 were 90.4%, 88.5%, 86.4% and 86.2%, respectively. The estimated reduction in EDSS score was 0.62 (95% CI 0.20–1.04). The overall proportion of IRE and infections were 31% and 33%, respectively. Conclusion Rituximab can improve relapse and disability conditions in patients with RRMS and has the potential for RRMS treatment. Additional evaluations on the safety of RTX is required.

Dimethyl Fumarate (DMF), known for its mechanism of action targeting Nrf2 and related redox homeostasis, is an approved immunotherapy for patients with Multiple Sclerosis (PwMS) in the relapsing form. We assessed how DMF modulates immune cell functions, namely the cytokine profile of co-cultured B and T cells, and the chemokine-mediated migration of immune cells. Following DMF therapy, LTα+, TNFα+ and IFNγ+ B cells were reduced while TGFβ and IL10 expression elevated. B cells from DMF-treated patients increased TGFβ and LTα expression on T cells, while DMF directly reduced TNFα+ and IFNγ+ T cells. CXCL12/CXCL13-mediated migration of B cells, Monocytes, CD4 and CD8 T cells was reduced, with altered CXCR5 and CXCR4 expression. Induction of regulatory B and T cells and reduced migration of immune cells may be part of the beneficial mechanism of DMF in PwMS.

To assess if markers of complement activation are associated with disease activity, C1q, C3, C3a and sC5b-9 levels in plasma and cerebrospinal fluid (CSF) were determined in 41 patients with clinically isolated syndrome (CIS) or remitting multiple sclerosis (RRMS), in a prospective longitudinal four-year cohort study. C1q in CSF (CSF-C1q) was significantly higher in patients than in controls. Baseline CSF-C1q and CSF-C3a correlated with several neuroinflammatory markers and neurofilament light chain levels. Baseline CSF-C3a correlated with the number of T2 lesions at baseline and new T2 lesions during follow-up. Baseline CSF-C3a was also significantly higher in patients with (n = 21) than in patients without (n = 20) signs of disease activity according to the NEDA-3 concept during one year of follow-up (p ≤ .01) Study results support that complement activation is involved in MS pathophysiology and that CSF-C3a carries prognostic information.

In patients with multiple sclerosis (MS) and healthy controls (HC) we studied circulating MAIT cells and MAIT cell subtypes expressing CXCR3 and CCR6 by flow cytometry. Absolute numbers of MAIT cells and specifically Tc17-like MAIT cells were lower in patients with primary progressive MS (PPMS) than in controls. Low numbers of Tc17-like MAIT cells were associated with smoking and high concentrations of myelin basic protein in the cerebrospinal fluid. Treatment with alemtuzumab and dimethyl fumarate decreased MAIT cell frequencies. Altogether, we have identified specific MAIT cell subtypes related to PPMS, smoking and demyelination, and MAIT cell effects of MS therapies.