Disease Activity In Multiple Sclerosis Patients Research Articles

The CXCL13 Index as a Predictive Biomarker for Activity in Clinically Isolated Syndrome.

Multiple sclerosis (MS) is a clinically heterogenous disease. Currently, we cannot identify patients with more active disease who may potentially benefit from earlier interventions. Previous data from our lab identified the CXCL13 index (ICXCL13), a measure of intrathecal production of CXCL13, as a potential biomarker to predict future disease activity in MS patients two years after diagnosis. Patients with clinically isolated syndrome (CIS) or radiologically isolated syndrome (RIS) underwent a lumbar puncture and blood draw, and the ICXCL13 was determined. They were then followed for at least 5 years for MS activity. Patients with high ICXCL13 were more likely to convert to clinically definite MS (82.4%) compared to those with low ICXCL13 (10.0%). The data presented below demonstrate that this predictive ability holds true in CIS and RIS patients, and for at least five years compared to our initial two-year follow-up study. These data support the concept that ICXCL13 has the potential to be used to guide immunomodulatory therapy in MS.

Targeting T Cell Metabolism as a Novel Approach for Treatment of MS: With a Focus on PFKFB3 Inhibitors.

Multiple sclerosis (MS) is one of the organ-specific autoimmune diseases in which immune cells invade the neurons in the central nervous system (CNS) due to loss of tolerance to self-antigens. Consequently, inflammation and demyelination occur in the central nervous system. The pathogenesis of MS is not completely understood. However, it seems that T cells, especially Th17 cells, have an important role in disease development. In recent years, studies on the manipulation of metabolic pathways with therapeutic targets have received increasing attention and have had promising results in some diseases, such as cancers. Glycolysis is a central metabolic pathway and plays an important role in the differentiation of T CD4+ cells to their subsets, especially Th17 cells. This suggests that manipulation of glycolysis, for example, using appropriate safe inhibitors of this pathway can represent a means to affect the differentiation of T CD4+, thus reducing inflammation and disease activity in MS patients. Hence, in this study, we aimed to discuss evidence showing that using inhibitors of 6-phosphofructo-2- kinase/fructose-2,6-biphosphatase 3(PFKFB3) as the main regulator of glycolysis may exert beneficial therapeutic effects on MS patients.

Dual Role of B Cells in Multiple Sclerosis.

B cells have emerged as an important immune cell type that can be targeted for therapy in multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies is effective in treating MS. Yet, atacicept treatment, which blocks B-cell Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL), two cytokines important for B cell development and function, paradoxically increases disease activity in MS patients. The reason behind the failure of atacicept is not well understood. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and anti-inflammatory functions in MS. In this review, we summarize the importance of B cells in MS and discuss the different B cell subsets that perform inflammatory and anti-inflammatory functions and how therapies modulate B cell functions in MS patients. Additionally, we discuss the potential anti-inflammatory functions of BAFF and APRIL on MS disease.

Current and Future Biomarkers in Multiple Sclerosis.

Multiple sclerosis (MS) is a debilitating autoimmune disorder. Currently, there is a lack of effective treatment for the progressive form of MS, partly due to insensitive readout for neurodegeneration. The recent development of sensitive assays for neurofilament light chain (NfL) has made it a potential new biomarker in predicting MS disease activity and progression, providing an additional readout in clinical trials. However, NfL is elevated in other neurodegenerative disorders besides MS, and, furthermore, it is also confounded by age, body mass index (BMI), and blood volume. Additionally, there is considerable overlap in the range of serum NfL (sNfL) levels compared to healthy controls. These confounders demonstrate the limitations of using solely NfL as a marker to monitor disease activity in MS patients. Other blood and cerebrospinal fluid (CSF) biomarkers of axonal damage, neuronal damage, glial dysfunction, demyelination, and inflammation have been studied as actionable biomarkers for MS and have provided insight into the pathology underlying the disease process of MS. However, these other biomarkers may be plagued with similar issues as NfL. Using biomarkers of a bioinformatic approach that includes cellular studies, micro-RNAs (miRNAs), extracellular vesicles (EVs), metabolomics, metabolites and the microbiome may prove to be useful in developing a more comprehensive panel that addresses the limitations of using a single biomarker. Therefore, more research with recent technological and statistical approaches is needed to identify novel and useful diagnostic and prognostic biomarker tools in MS.

Clinically Deployed Computational Assessment of Multiple Sclerosis Lesions.

Multiple Sclerosis (MS) is a demyelinating disease of the central nervous system that affects nearly 1 million adults in the United States. Magnetic Resonance Imaging (MRI) plays a vital role in diagnosis and treatment monitoring in MS patients. In particular, follow-up MRI with T2-FLAIR images of the brain, depicting white matter lesions, is the mainstay for monitoring disease activity and making treatment decisions. In this article, we present a computational approach that has been deployed and integrated into a real-world routine clinical workflow, focusing on two tasks: (a) detecting new disease activity in MS patients, and (b) determining the necessity for injecting Gadolinium Based Contract Agents (GBCAs). This computer-aided detection (CAD) software has been utilized for the former task on more than 19, 000 patients over the course of 10 years, while its added function of identifying patients who need GBCA injection, has been operative for the past 3 years, with > 85% sensitivity. The benefits of this approach are summarized in: (1) offering a reproducible and accurate clinical assessment of MS lesion patients, (2) reducing the adverse effects of GBCAs (and the deposition of GBCAs to the patient's brain) by identifying the patients who may benefit from injection, and (3) reducing healthcare costs, patients' discomfort, and caregivers' workload.

Neurophysiological outcomes following mesenchymal stem cell therapy in multiple sclerosis

ObjectiveTo report on neurophysiological outcomes derived from transcranial magnetic stimulation (TMS) following autologous mesenchymal stem cells (aMSCs) therapy in patients with multiple sclerosis (MS). Methods20 adults with confirmed MS were recruited to participate in a phase II randomized control trial to assess the safety and potential benefits of aMSCs infusion. At Week 0, patients were randomly assigned to receive either aMSCs (n = 9) or a placebo infusion (n = 11). At Week 24, the placebo group received the aMSCs infusion. Blind assessments were performed at Weeks 0, 24 and 48. Outcomes consisted of TMS measures of corticomotor excitability and motor conduction along with measures of motor impairments and disability. ResultsPost-infusion, no change was detected in measures of corticomotor excitability or measures of intra- or interhemispheric inhibition. The latency of motor evoked potentials and central motor conduction time were significantly prolonged. These changes in motor conduction were associated with declines in hand dexterity post-infusion. ConclusionClinical and neurophysiological measures showed no improvement following aMSCs therapy in this cohort of MS patients. SignificanceAlthough promising, stem cell therapy remains elusive regarding its benefits in influencing disease activity in MS patients.

The effect of aerobic exercise on Neurofilament light chain and glial Fibrillary acidic protein level in patients with relapsing remitting type multiple sclerosis

Background Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system in which disease activity can be monitored with some biomarkers. The aim of our study was to investigate serum Glial Fibrillary Acidic Protein (GFAP) and Neurofilament Light Chain (NFL) in relapsing-remitting MS (RRMS) patients after the aerobic exercise.Methods A total of 38 participants with RRMS (Expanded Disability Status Scale: 1.0 – 4.5) were randomized to a study group (3 × /week for 8 weeks at 60 – 70 % of maximal aerobic capacity (VO2max) + home exercises) and a control group (were given home exercises programme 3 times a week for 8 week). Serum NFL and GFAP levels were analyzed using enzyme-linked immunosorbent analysis method before and at the end of 8 weeks.Results: NFL and GFAP levels were statistically lower in the study group at the end of the study than before the study. In the control group, no significant changes were observed in serum NFL and GFAP levels. ΔNFL levels were significantly higher in the study group than control group.Conclusion It was shown, for the first time that serum GFAP and NFL levels (%10 and % 32, respectively) in RRMS patients decreased after aerobic exercise. Our study is important in terms of investigating the effects of aerobic exercise in individuals with RRMS and elucidating the underlying measurable biomarkers. The significant reduction of NFL and GFAP, which have an important role in the pathology associated with nervous system damage in MS, with aerobic exercise may be promising in understanding the regulation of disease activity in MS patients.

Redox Imbalance in CD4+ T Cells of Relapsing-Remitting Multiple Sclerosis Patients

As a prevalent autoimmune disease of the central nervous system in young adults, multiple sclerosis (MS) is mediated by T cells, particularly CD4+ subsets. Given the evidence that the perturbation in reactive oxygen species (ROS) production has a pivotal role in the onset and progression of MS, its regulation through the antioxidant molecules is too important. Here, we investigated the level of the redox system components in lymphocytes and CD4+ T cells of MS patients. The study was performed on relapsing-remitting MS (RRMS) patients (n = 29) and age- and sex-matched healthy controls (n = 15). Peripheral blood mononuclear cells (PBMCs) were cultured and stimulated by anti-CD3/CD28. The level of ROS, anion superoxide (O2−), and L-𝛾-glutamyl-Lcysteinylglycine (GSH) was measured by flow cytometry in lymphocytes/CD4+ T cells. The gene expression level of gp91phox, catalase, superoxide dismutase 1/2 (SOD), and nuclear factor-E2-related factor (Nrf2) was also measured by real-time PCR. We found that lymphocytes/CD4+ T cells of RRMS patients at the relapse phase significantly produced higher levels of ROS and O2− compared to patients at the remission phase (P value < 0.001) and healthy controls (P value < 0.001 and P value < 0.05, respectively). Interestingly, the gene expression level of gp91phox, known as the catalytic subunit of the NADPH oxidase, significantly increased in MS patients at the relapse phase (P value < 0.05). Furthermore, the catalase expression augmented in patients at the acute phase (P value < 0.05), while an increased expression of SOD1 and Nrf2 was found in RRMS patients at relapse and remission phases (P value < 0.05). The increased production of ROS in CD4+ T cells of RRMS patients highlights the importance of amplifying antioxidant components as an efficient approach to ameliorate disease activity in MS patients.

Intrathecally produced CXCL13: A predictive biomarker in multiple sclerosis.

BackgroundClinicians caring for patients with Multiple Sclerosis (MS) need improved biomarkers to aid them in disease management.ObjectiveWe assessed the predictive value of the candidate biomarker CXCL13 index in comparison to oligoclonal bands (OCBs) and CSF neurofilament light (NfL) concentration, examining the ability of each biomarker to predict future disease activity in clinically and radiologically isolated syndromes, relapsing-remitting MS, and progressive MS.MethodsMatched serum and CSF samples were obtained from 67 non-inflammatory neurologic disease patients and 67 MS patients. CSF and serum CXCL13 and CSF NfL were analyzed by Luminex and ELISA, respectively. CXCL13 data were also analyzed as CSF/serum ratios and indices. Electronic medical records were accessed to determine diagnosis, CSF profiles, and disease activity after the lumbar puncture.ResultsAmong CXCL13 measures, CXCL13 index was the best predictor of future disease activity in MS patients (AUC = 0.82; CI = 0.69–0.95; p = 0.0002). CXCL13 index values were significantly elevated in activity-positive MS patients compared to activity-negative patients (p < 0.0001). As a single predictor, CXCL13 index outperformed both OCBs and CSF NfL in sensitivity, specificity, and positive and negative predictive value, for future disease activity in MS patients. Moreover, combining CXCL13 index and CSF NfL status improved sensitivity and predictive values for disease activity in MS patients.ConclusionsThe CXCL13 index is an excellent candidate prognostic biomarker for disease activity in patients with MS.

Magnetic resonance spectroscopy of the normal appearing grey matter in the posterior cingulate gyrus in the prognosis and monitoring of disease activity in MS patients treated with interferon-β in a 3-year follow-up

Several predictors of non-response to interferon-β (IFN-β) treatment have been proposed. The aim of the study was to identify metabolite changes in the normal-appearing cortex of the posterior cingulate gyrus (PCG) using MRS (magnetic resonance spectroscopy) and to investigate their usefulness in prognosis of NEDA (no evidence of disease activity) in the 3-year follow-up and in monitoring treatment effects during IFN-β therapy in the parallel period of time in multiple sclerosis (MS) patients.Forty-one relapsing-remitting MS patients and 41 sex- and age-matched healthy subjects underwent routine MRI protocol with MRS sequence with the use of a 1.5 T magnet. A single voxel size of 2x2x2cm was inserted in the cortex of PCG region. Associations between baseline metabolic ratios, conventional MRI findings, demographic and clinical factors, and NEDA status were evaluated using logistic, Cox, and multinomial logistic regression models.MS patients in the initial scan showed a statistically significant decline in NAA/Cr ratio (p < 0.0001) and an increase in Cho/Cr ratio (p = 0.016) compared to the control group. None of the MRS parameters predicted NEDA maintenance or the time to loss of NEDA. In treatment monitoring only an improvement in the combination of NAA/Cr + Cho/Cr ratio between the 1st and 2nd year of treatment was connected with a 6.27-fold chance (p = 0.025) of having simultaneous NEDA maintenance.To conclude, metabolite alterations in the PCG region did not predict NEDA maintenance, but they seem to be useful in treatment monitoring.

B Cell Maturation Antigen deficiency increases inflammatory B-cell functions in multiple sclerosis

Abstract B cells have emerged as a therapeutic target for multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies are effective in treating MS. Yet, TACI-Ig treatment, which blocks BAFF and APRIL (two cytokines important for B cell development and function), paradoxically increased disease activity in MS patients. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and regulatory effects in MS. B cell Maturation Antigen (BCMA), a receptor that binds BAFF and APRIL, plays a prominent role in B cell function. The role BCMA plays in MS remains enigmatic and therefore we explored the impact BCMA deficiency has on the development and progression of the experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Here, we identified that the expression of BCMA is dysregulated in B cells from MS patients and is important in inhibiting inflammatory B cell responses in EAE. We discovered that BCMA expression is decreased on transitional B cells in MS. In mice we found that EAE induced with MOG35–55 was severe in BCMA−/− mice compared to BCMA+/+. The increased disease was associated with increased CNS inflammation, significantly reduced transitional B cells and a skewing of B-cells toward a mature/inflammatory phenotype. Bone marrow chimeric and in vitro experiments demonstrated that BCMA directly inhibits memory B cell expansion and anti-inflammatory cytokine production by B cells. Strikingly, BCMA impacts the efficacy of B cell depleting therapies, as anti-CD20 antibody treatment attenuated EAE in BCMA-deficient mice but not BCMA-sufficient mice. These data provide novel insights into B-cell dysregulation in MS.

Long-term use of interferon-\u03b2 in multiple sclerosis increases V\u03b41\u2212V\u03b42\u2212V\u03b39\u2212 \u03b3\u03b4 T cells that are associated with a better outcome

BackgroundWe previously reported that Vδ2+Vγ9+ γδ T cells were significantly decreased in multiple sclerosis (MS) patients without disease-modifying therapies (untreated MS) and were negatively correlated with Expanded Disability Status Scale (EDSS) scores, suggesting protective roles of Vδ2+Vγ9+ γδ T cells. Interferon-β (IFN-β) is one of the first-line disease-modifying drugs for MS. However, no previous studies have reported changes in γδ T cell subsets under IFN-β treatment. Therefore, we aimed to clarify the effects of the long-term usage of IFN-β on γδ T cell subsets in MS patients.MethodsComprehensive flow cytometric immunophenotyping was performed in 35 untreated MS and 21 MS patients on IFN-β for more than 2 years (IFN-β-treated MS) including eight super-responders fulfilling no evidence of disease activity criteria, and 44 healthy controls (HCs).ResultsThe percentages of Vδ2+Vγ9+ cells in γδ T cells were significantly lower in untreated and IFN-β-treated MS patients than in HCs. By contrast, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were markedly higher in IFN-β-treated MS patients than in HCs and untreated MS patients (both p < 0.001). A significant negative correlation between the percentages of Vδ2+Vγ9+ cells in γδ T cells and EDSS scores was confirmed in untreated MS but not evident in IFN-β-treated MS. Moreover, class-switched memory B cells were decreased in IFN-β-treated MS compared with HCs (p < 0.001) and untreated MS patients (p = 0.006). Interestingly, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were negatively correlated with class-switched memory B cell percentages in all MS patients (r = − 0.369, p = 0.005), and the percentages of Vδ1−Vδ2−Vγ9− cells in Vδ1−Vδ2− γδ T cells were negatively correlated with EDSS scores only in IFN-β super-responders (r = − 0.976, p < 0.001).ConclusionsThe present study suggests that long-term usage of IFN-β increases Vδ1−Vδ2−Vγ9− γδ T cells, which are associated with a better outcome, especially in IFN-β super-responders. Thus, increased Vδ1−Vδ2−Vγ9− cells together with decreased class-switched memory B cells may contribute to the suppression of disease activity in MS patients under IFN-β treatment.

Efficacies of anti-CD20 antibody and Atacicept are differentially impacted by B Cell Maturation Antigen in neuro-autoimmunity

Abstract B cells have emerged as a therapeutic target for multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies are effective in treating MS. Yet, TACI-Ig treatment, which blocks BAFF and APRIL (two cytokines important for B cell development and function), paradoxically increased disease activity in MS patients. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and regulatory effects in MS. B cell Maturation Antigen (BCMA), a receptor that binds BAFF and APRIL, plays a prominent role in B cell function. The role BCMA plays in MS remains enigmatic and therefore we explored the impact BCMA deficiency has on the development and progression of the experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. We found that EAE induced with MOG35–55 was severe in BCMA−/− mice compared to BCMA+/+ mice. The increased disease was associated with increased CNS inflammation and a skewing of B-cells toward a mature/inflammatory phenotype. Also, for the first time, we observed that BCMA deficiency directly affects the infiltration of inflammatory myeloid cells during EAE. We found that anti-CD20 treatment significantly reduced EAE in BCMA−/− mice but had no effect on BCMA+/+ mice. Conversely, we found that TACI-Ig treatment had no effect on BCMA−/− mice but did reduce EAE in BCMA+/+ mice. Our study demonstrates that BAFF and APRIL constrain the development and function of inflammatory B-cells through BCMA. We further demonstrate that BCMA inhibits inflammatory B cell responses, yet promotes inflammatory responses in macrophages. Finally, our data provide clues into the paradoxical results of clinical trials with anti-CD20 and TACI-Ig in MS patients.

B Cell Maturation Antigen impacts the efficacy of B-cell targeting therapies in neuro-inflammation.

Abstract B cells have emerged as a therapeutic target for multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies are effective in treating MS. Yet, blockade of BAFF and APRIL, two cytokines important for B cell development and function, paradoxically increased disease activity in MS patients. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and regulatory effects in MS. B cell Maturation Antigen (BCMA), a receptor that binds both BAFF and APRIL, plays a prominent role in B cell function. The role BCMA plays in MS remains enigmatic and therefore we designed this study to explore the impact BCMA deficiency has on the development and progression of experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. We found that EAE induced with MOG35–55 was more severe in BCMA−/− mice compared to BCMA+/+ mice. The increased disease was associated with increased CNS inflammation and a skewing of B-cells toward a mature/inflammatory phenotype. Using bone marrow chimera strategies, we found that BCMA deficiency in B-cells was responsible for the increase in disease severity. Next, we found that anti-CD20 treatment significantly reduced EAE in BCMA−/− mice but had no effects on BCMA+/+ mice. Conversely, we found that TACI-Ig treatment had no effect on BCMA−/− mice but did reduce EAE in BCMA+/+ mice. Our data demonstrate that BAFF and APRIL constrains the development and function of inflammatory B-cells through BCMA. Furthermore, our data provide clues into the paradoxical results of clinical trials with anti-CD20 and TACI-Ig in MS.

Neutralizing Antibodies Against Interferon-Beta in Korean Patients with Multiple Sclerosis

Background and PurposePatients treated with interferon-beta (IFN-β) can develop neutralizing antibodies (NAbs) against IFN-β that can negatively affect the therapeutic response. This study assessed the prevalence of NAbs and the impact of NAb positivity on the therapeutic response to IFN-β in Korean patients with multiple sclerosis (MS).MethodsThis was a multicenter study involving 150 MS patients from 9 Korean medical centers who were treated with IFN-β for at least 6 months. Sera that had not been influenced by acute treatment were assessed for NAbs using a luciferase reporter gene assay. To evaluate the association between persistent positivity for NAbs and disease activity, NAbs were tested at 2 different time points in 75 of the 150 patients. Disease activity was defined as the presence of clinical exacerbations and/or active MRI lesions during a 1-year follow-up after NAb positivity was confirmed.ResultsNAbs were found in 39 of the 150 (26%) MS patients: 30 of the 85 (35%) who were treated with subcutaneous IFN-β-1b, 9 of the 60 (15%) who were treated with subcutaneous IFN-β-1a, and 0 of the 5 (0%) who were treated with intramuscular IFN-β-1a. Thirty of the 39 patients exhibiting NAb positivity were tested at different time points, and 20 of them exhibited persistent NAb positivity. Disease activity was observed more frequently in patients with persistent NAb positivity than in those with transient positivity or persistent negativity [16/20 (80%) vs. 4/55 (7%), respectively; p<0.001]. When disease activity was compared between patients with persistent and transient NAb positivity, the difference was unchanged and remained statistically significant [16/20 (80%) vs. 2/10 (20%), p=0.004].ConclusionsThese results further support that persistent NAb positivity is associated with disease activity in MS patients treated with IFN-β.

Switching natalizumab to fingolimod within 6 weeks reduces recurrence of disease activity in MS patients

Background: Natalizumab is an effective treatment in relapsing-remitting multiple sclerosis (MS). Mainly because of the risk of progressive multifocal leukoencephalopathy (PML), a substantial proportion of John Cunningham (JC) virus–positive patients switch to fingolimod. Previous reports show a clear benefit when the duration of a washout (WO) period of natalizumab is 0–3 months in comparison to longer WO periods. However, there is no consensus regarding the optimal duration of a WO period under 3 months. Objective: We compared MS disease activity after different WO periods. In addition, we investigated several factors that possibly influence recurrence of disease activity, including serum natalizumab concentration and lymphocyte counts. Methods: From a prospective observational cohort study of natalizumab-treated patients, we selected 52 patients who switched to fingolimod. We divided the patients in three groups (<6 weeks, 6–8 weeks, >8 weeks WO). Serum natalizumab concentration and lymphocyte count were assessed during and after natalizumab treatment. Results: Patients with a WO period of >8 weeks had a significant higher recurrence of disease activity (odds ratio, 6.8; 95% confidence interval, 1.4–32.8) compared to patients with a WO period of <6 weeks. Serum natalizumab concentration and lymphocyte count did not predict recurrence of disease activity. Interpretation: A short WO period decreases the risk of recurrence of disease activity. The possible impact of a short WO period on the risk of carry-over PML in JC virus–positive patients remains uncertain.

Seasonal variations of 25-OH vitamin D serum levels are associated with clinical disease activity in multiple sclerosis patients

Low 25-hydroxy vitamin D (25-[OH]-D) serum concentrations have been associated with higher disease activity in multiple sclerosis (MS) patients. In a large cross-sectional study we assessed the vitamin D status in MS patients in relation to seasonality and relapse rate. 415 MS-patients (355 relapsing-remitting MS and 60 secondary-progressive, 282 female, mean age 39.1years) of whom 25-(OH)-D serum concentrations were determined at visits between 2010 and 2013 were included in the study. All clinical data including relapse at visit and expanded disability status scale were recorded in a standardized manner by an experienced neurologist. Seasonal variations of 25-(OH)-D serum concentrations were modelled by sinusoidal regression and seasonal variability in the prevalence of relapse by cubic regression. The mean 25-(OH)-D serum concentration was 24.8ng/ml (range 8.3–140ng/ml) with peak levels of 32.2ng/ml in July/August and nadir in January/February (17.2ng/ml). The lowest modelled prevalence of relapse was in September/October (28%) and the highest modelled prevalence in March/April (47%). The nadir of 25-(OH)-D serum concentrations preceded the peak in prevalence of relapses by two months. In summary, seasonal variation of 25-(OH)-D serum levels were inversely associated with clinical disease activity in MS patients. Future studies should investigate whether vitamin D supplementation in MS patients may decrease the seasonal risk for MS relapses.

Natural killer cell subpopulations are associated with MRI activity in a relapsing-remitting multiple sclerosis patient cohort from Australia

Background: The importance of the innate immune system in multiple sclerosis (MS) is increasingly recognized and the role of natural killer (NK) cells in controlling autoimmunity may be an important modulator of disease activity. Objective: To examine NK subsets in MS patients on different treatments and to evaluate the role of NK subsets as indicators for disease activity. Methods: We measured NK subset levels in blood obtained from 110 relapsing-remitting MS patients. Patients were either off treatment or on treatment with natalizumab, fingolimod, glatiramer acetate or beta-interferon. Disease activity was defined according to ‘No Evidence of Disease Activity’ (NEDA) criteria within an observation period of up to 2.4 years. The mean NK subset levels were compared among treatment groups using multivariate analysis of variance (ANOVA) and association analysis with disease activity performed using multi-factor logistic regression. Results: Our analysis revealed differences in NK cells and subsets on treatment compared to off treatment (p < 0.0005). A high proportion of bright NK cells were significantly associated with stable magnetic resonance imaging (MRI) imaging after adjusting for treatment effects (p < 0.05). Conclusion: The independent association of NK subsets with MRI stability needs to be confirmed in prospective studies to test their usefulness in predicting disease activity in MS patients.

Autoreactive CD19+CD20- Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis.

The contribution of autoantibody-producing plasma cells in multiple sclerosis (MS) remains unclear. Anti-CD20 B cell depletion effectively reduces disease activity in MS patients, but it has a minimal effect on circulating autoantibodies and oligoclonal bands in the cerebrospinal fluid. Recently we reported that MEDI551, an anti-CD19 mAb, therapeutically ameliorates experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. MEDI551 potently inhibits pathogenic adaptive immune responses, including depleting autoantibody-producing plasma cells. In the present study, we demonstrated that CD19 mAb treatment ameliorates EAE more effectively than does CD20 mAb. Myelin oligodendrocyte glycoprotein-specific Abs and short-lived and long-lived autoantibody-secreting cells were nearly undetectable in the CD19 mAb-treated mice, but they remained detectable in the CD20 mAb-treated mice. Interestingly, residual disease severity in the CD20 mAb-treated animals positively correlated with the frequency of treatment-resistant plasma cells in the bone marrow. Of note, treatment-resistant plasma cells contained a substantial proportion of CD19(+)CD20(-) plasma cells, which would have otherwise been targeted by CD19 mAb. These data suggested that CD19(+)CD20(-) plasma cells spared by anti-CD20 therapy likely contribute to residual EAE severity by producing autoreactive Abs. In patients with MS, we also identified a population of CD19(+)CD20(-) B cells in the cerebrospinal fluid that would be resistant to CD20 mAb treatment.

Axonal Regeneration-related Molecules as Biomarkers for Multiple Sclerosis

Abnormalities in both the nervous and immune systems are thought to be relevant to the pathogenesis of multiple sclerosis (MS). Several functional molecules closely related to axonal regeneration play an important role in not only the nervous system, but also the immune system. Many recent studies revealed that these molecules are associated with the neurological and immunological aspects of the pathogenesis of MS. Therefore, we focused on these molecules as promising biomarkers for MS. Nogo protein and its receptor (Nogo receptor-1; NgR1) are well known representative molecules that prevent axonal regeneration, and we identified lateral olfactory tract usher substance (LOTUS) as an endogenous antagonist of NgR1. We found that LOTUS expression was decreased in the spinal cord in an experimental autoimmune encephalomyelitis mouse model and that variations in LOTUS concentration in the cerebrospinal fluid correlated well with disease activity in MS patients. On the other hand, previous studies have shown that repulsive guidance molecule-a and semaphorins, known to be involved in axonal guidance and regeneration, play a role in MS pathogenesis. We review the association of these molecules with the neurological and immunological aspects of MS pathogenesis, and we show that they are promising, clinically-relevant biomarkers for MS.