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Introduction Vitamin D has long been known for its immune-modulating effects, next to its function in calcium metabolism. As a consequence, poor vitamin D status has been associated with many diseases including multiple sclerosis (MS). Epidemiological studies suggest an association between a poor vitamin D status and development of MS and a poor vitamin D status is associated with more relapses and faster progression after patients are diagnosed with MS. Area’s covered The aim of the authors was to review the role of vitamin D supplementation in the treatment of MS. Pubmed was used to review literature with a focus of vitamin D supplementation trials and meta-analyses in MS. Expert opinion There is no solid evidence to support the application of vitamin D therapy, based on current available supplementation trials, although there are some promising results in the clinically isolated syndrome (CIS) patients and young MS patients early after initial diagnosis. The authors recommend further larger clinical trials with selected patient groups, preferable CIS patients and young patients at the time of diagnosis, using vitamin D3 supplements to reach a 100 nmol/l level, to further investigate effects of vitamin D supplementation in MS.

BACKGROUND/OBJECTIVE: Data from animal models of MS suggest that GM-CSF(+)CD4(+)T cells are pathogenic cells. Therefore, GM-CSF production by CD4(+)T cells of MS patients and their susceptibility to regulatory mechanisms were investigated. METHODS: Intracellular flowcytometry was performed to determine the GM-CSF(+)CD4(+)T cell fraction in PBMC and CSF of MS patients and controls. The effect of regulatory T cells (Tregs) on GM-CSF production by CD4(+)T cells was studied in MS patients using a proliferation-suppression assay. Finally, GM-CSF(+)CD4(+)T cell fraction and GM-CSF protein levels in supernatant were assessed in anti-CD3-stimulated CD4(+)T cell cultures derived from healthy controls and MS patients, in the presence or absence of the active vitamin D metabolite calcitriol. RESULTS: The GM-CSF(+)CD4(+)T cell fraction in the peripheral blood did not differ between controls and MS patients. This T cell population could also be detected in the CSF of both subjects with MS as well as subjects with another diagnosis. In the CSF, it comprised a significant fraction of the T cell population. Upon in vitro stimulation of PBMC with anti-CD3 antibody, no differences were observed in GM-CSF(+)CD4(+)T cell frequencies. GM-CSF secretion was susceptible to regulation by Treg and vitamin D. Suppression of GM-CSF secretion by vitamin D was reduced in MS patients. CONCLUSIONS: Our study showed no elevation in GM-CSF(+)CD4(+)T cell fractions in MS patients compared to controls. Furthermore, GM-CSF secretion was prone to regulation by Treg and vitamin D, the latter being less effective in MS patients.

SUMMARY This review discusses the evidence on the role of vitamin D in multiple sclerosis (MS) and whether vitamin D supplementation is effective for the management of MS. People with MS are at high risk of vitamin D deficiency, osteoporosis and fractures. Observational data suggest that higher vitamin D levels are associated with lower relapse risk and there is promising evidence on its effect on MRI measures, disability progression, mental health and fatigue. However, there is currently insufficient randomized controlled trial evidence to recommend vitamin D supplementation with the aim to improve those outcomes. There is sufficient evidence to justify assessing and correcting vitamin D and calcium levels to optimize bone health in people with MS at high absolute risk of fracture.

In this study, we assessed B cell subsets, including Bregs, during stable and active disease in relapsing remitting multiple sclerosis (RRMS) patients and related B cell subsets to vitamin D status. We report that RRMS patients have a decreased percentage of both memory B cells and Bregs compared to healthy controls. During a relapse, the reduction in Bregs involved in particular naive Bregs. We found no correlation between vitamin D status and B cell subsets. An effect of vitamin D on Bregs cannot be ruled out, since it might be the function that is interfered with instead of relative numbers.

Epidemiological studies have shown that a poor vitamin D status is associated with an increased risk of several diseases, including autoimmune diseases. The immune regulatory function of vitamin D is thought to have an important role in these associations. Cells of the adaptive immune system have shown to be direct targets of the vitamin D metabolites. Besides being direct targets, cells of the adaptive immune system express the enzymes involved in the metabolism of vitamin D. enabling them to locally convert 25(OH)D into its active metabolite 1,25(OH)(2)D. In this review, the effects of vitamin D on cells of the adaptive immune system are described. Experimental data in vitro show that vitamin D skews cells of the adaptive immune system toward a more tolerogenic status which might be exploited in the treatment of autoimmune diseases. However, it should be noticed that in vivo effects may differ from in vitro effects due to the cross-talk between different vitamin D sensitive cells, but data support the view that vitamin D is positively involved in maintaining or restoring immune homeostasis. Upcoming vitamin D supplementation trials will further elucidate the in vivo effects of vitamin D on the immune system and its potency to serve as an immune regulating agent in autoimmune diseases.

An impaired vitamin D (vit-D) processing by immune cells of relapsing remitting multiple sclerosis (RRMS) patients may increase their vulnerability for a poor vit-D status. We assessed with qPCR the expression of vit-D related genes in PBMC and CD4(+) T-cells. Gene expression profiles of vit-D receptor (VDR), CYP27B1 and CYP24A1 did not differ between RRMS patients and healthy controls. Interestingly, more VDR expression in PBMC correlated with less circulating IFN-gamma(+) CD4(+) T-cells. Our results suggest that vit-D processing by immune cells is not impaired in RRMS, and is potentially relevant for the composition of the peripheral CD4(+) T-cell compartment. (C) 2011 Elsevier B.V. All rights reserved.

Knippenberg S, Bol Y, Damoiseaux J, Hupperts R, Smolders J. Vitamin D status in patients with MS is negatively correlated with depression, but not with fatigue. Acta Neurol Scand: 2011: 124: 171–175. © 2010 John Wiley & Sons A/S. Background – Depressive symptoms and fatigue are frequent and disabling symptoms of multiple sclerosis (MS). Depression and fatigue have been associated with a poor vitamin D status, and a poor vitamin D status is often found in MS. Aim – Assess whether vitamin D status contributes to depressive symptoms and fatigue in MS. Methods – Patients with MS that participated in previous studies in which depression and fatigue were assessed and of whom serum 25-hydroxyvitamin D (25(OH)D) levels were available within a timeframe of less than one half-life of 25(OH)D were included. Depression and fatigue were assessed with the Hospital Anxiety and Depression Scale and the Multidimensional Fatigue Inventory. Results – Fifty-nine patients were included. Mean scores of fatigue and depression were 14.6 (SD 4.2) and 6.2 (SD 4.4), respectively. The mean vitamin D status was 62.3 nm (SD 27.8). Vitamin D status correlated negatively with depression (r = −0.326, P = 0.006). No significant correlation was found between vitamin D status and fatigue. In a multiple regression model, vitamin D status was not a significant contributor to depression, after controlling for age Expanded Disability Status Scale score and fatigue (P = 0.078). Alternatively, depression and fatigue did not contribute to vitamin D status. Discussion – This study shows a negative correlation between vitamin D status and depressive symptoms in patients with MS. Although multiple confounders exist, we observed an indication that vitamin D status might contribute to the presence of depressive symptoms in MS. Therefore, further studies on vitamin D in MS should include depressive symptoms as outcome measures to confirm these findings.

BACKGROUND: The amount of myocardium at risk (MaR) during acute coronary occlusion and the duration of occlusion are important determinants of final infarct size. The main goal of early reperfusion therapy is to salvage ischemic myocardium, thereby preserving left ventricular function. The aims of the present study were to test the feasibility of developing polar plot representations of MaR, for perfusion single photon emission computed tomography (SPECT), regional wall thickening by magnetic resonance imaging (MRI), and distribution of ST-segment changes. A second aim was to test the hypothesis that these different modalities display similar localization of the MaR in patients with reperfused first-time myocardial infarction. METHODS: Eleven patients with first-time myocardial infarction with ST-elevation received (99m)Tc tetrofosmin before primary percutaneous coronary intervention, SPECT imaging within 3 hours, and cardiac MRI of the left ventricle within 24 hours. The results for SPECT, MRI, and electrocardiogram (ECG) were developed into polar plots, and two expert observers designated the culprit coronary artery as assessed by angiography. RESULTS: The perfusion SPECT, MRI wall thickening, and ST changes are presented in side-by-side polar plots. In total, the culprit artery, based on the location of the MaR, was correctly designated in 91%, 82%, and 91% of cases by SPECT, MRI, and ECG, respectively. CONCLUSIONS: Polar representation for localization of the MaR by SPECT perfusion, MRI wall thickening, and ECG ST-segment deviation is feasible. All 3 modalities have the potential to be used for indirect visual designation of the culprit artery in patients with first-time acute coronary occlusion. (Less)

The NLRP3 inflammasome is a macromolecular complex importantly involved in IL-1beta processing. A role for this has been described in multiple sclerosis (MS). One mechanism by which IL-1beta might be involved in MS is by inducing pathogenic Th17 cells, i.e. GM-CSF+ Th17 cells. In the present study, we show that expression of the inflammasome related genes, NLRP3, caspase-1, IL-1beta and the IL-1beta/IL-1Ra ratio, was increased in PBMC from MS patients compared to healthy controls (HC). However, in an in vitro inflammasome activity assay with PBMC, IL-1beta protein secretion and the IL-1beta/IL-1Ra protein ratio were similar in MS patients and HC. Th cells cultured in the presence of supernatant derived from LPS/ATP inflammasome activated PBMC showed increased Th17 and GM-CSF+ Th17 cell frequencies in HC and MS patients and decreased anti-inflammatory IL-10+Th cell frequency in HC compared to Th cells cultured in the presence of control supernatant. Moreover, addition of the immune modulator calcitriol to the former condition resulted in reduced frequencies of Th17 and GM-CSF+Th17 cells, and also of IL-10+ Th cells. Evidently, our data indicate that inflammasome activity can skew the Th cell population toward a more pro-inflammatory composition, an effect that might be inhibited by vitamin D, and that might be importantly involved in inflammation within the central nervous system.

OBJECTIVES: B cells have immunoregulatory function acting as antigen-presenting cells. A separate subset of interleukin (IL)-10 producing B cells (Breg) regulating T cell mediated immunity has been identified. In the present study, we investigated the role of Breg in antineutrophil cytoplasmic antibodies-associated vasculitis (AAV). METHODS: 17 healthy controls (HCs) and 41 patients with AAV were enrolled. 30 patients with AAV were in remission. Furthermore, 11 patients with AAV with active disease were studied. Breg were defined as IL-10(+)CD19(+) B cells upon culture with cytosine-phosphate-guanosine oligodeoxynucleotide (CpG ODN) 2006. Next to Breg, CD4(+)CD127(low)CD25(hi)CD39(neg)/CD39(+) regulatory T-cells (Treg), interferon (IFN)gamma(+), IL-4(+) and Il-17A(+)T helper cell subsets were determined via flow cytometry. RESULTS: Patients with active or quiescent disease showed a diminished fraction of Breg as compared with HCs. The frequency of IFNgamma(+) T helper cells was negatively associated with Breg in untreated AAV in remission but not in active vasculitis or in HCs. Interestingly, the total Treg population and the CD39(+) Treg subpopulation correlated positively with Breg in inactive patients with AAV. CONCLUSIONS: IL-10 producing B cells are diminished in AAV. Furthermore, Breg might regulate Th1 cells and are associated with Treg in quiescent AAV. Suppression of Th1 cells by Breg may be insufficient in active AAV.

Objective: Insufficient sun exposure and vitamin D deficiency have both been associated with increased risk of multiple sclerosis (MS). Depressi on, anxiety, fatigue and cognitive impairment are prevalent and disabling symptoms in MS. Our objective was to examine the associations between personal sun exposure and serum 25-hydroxyvitamin D (25(OH)D), and depression, anxiety, fatigue and cognition. Methods: A total of 198 participants with multiple sclerosis were followed prospectively for an average of 2.3 years. Assessments of serum 25(OH)D, sun exposure, depression, anxiety and fatigue were carried out biannually; cognition was assessed annually. Results: Personal reported sun exposure was inversely associated with depression scores ( β −0.26 (95%CI −0.40, −0.12); P ≤ 0.001) and fatigue scores ( β −0.65 (95%CI −1.23, −0.07); P = 0.028). Only high levels of 25(OH)D (>80 n m ) were inversely associated depression scores ( β −0.64 (95%CI −1.15, −0.13); P = 0.015), but this was not significant after adjustment for reported sun exposure. No associations were seen between reported sun exposure or serum 25(OH)D levels and anxiety or cognition scores. Conclusion: We found that higher levels reported sun exposure, rather than 25(OH)D levels, were associated with less depressive symptoms and levels of fatigue. The role of UV or light therapy will need to be evaluated in randomized controlled trials to confirm an effect on these symptoms in MS.

Background: Vitamin D has been proposed as a promoter of immune homeostasis in multiple sclerosis (MS). During the past decade, the focus of the effects of vitamin D has been on dendritic cells and on T cells. Since there is an increasing interest in the role of B cells in the pathophysiology of MS, we studied the role of vitamin D on B cells in vivo in patients with MS. Objective: We explored the effects of 12 weeks high-dose vitamin D3 supplementation on peripheral B cell differentiation, immunoglobulin production and levels of B cell activating factor (BAFF) in 15 patients with MS. Methods: Circulating B cell subsets were characterized by flow cytometry. Plasma immunoglobulin levels were assessed by nephelometry. Plasma BAFF levels were assessed by enzyme-linked immunosorbent assay (ELISA). Results: Although a significant increase serum 25-hydroxyvitamin D was induced, we found no significant shift in B cell differentiation, isotype switching, or plasma BAFF levels. Conclusion: In patients with MS, supplementation of high doses vitamin D3 does not have substantial effects on phenotypic markers of B cell differentiation in circulating B cells. Future studies may unravel more subtle changes in the B cell compartment, either in the circulation or in the central nervous system.

In the present study, circulating proportions of CD8+ T (Tc) cell subsets, including IL-17 (Tc17) and IL-10 (Tc10) producing cells, were assessed in relapsing–remitting MS (RRMS) patients and a possible effect of beta interferon (IFN-β), glatiramer acetate (GA), and vitamin D (VitD) on these cell subsets was investigated. We show that both Tc17 and Tc10 cell fractions are elevated in the circulation of RRMS patients in remission compared to healthy subjects and that these Tc subsets remain unaffected by current immune modulating regimens.

In this study, percentages of CD39(+) Treg and Th17 cells were compared between relapsing-remitting MS patients and controls and were related to the vitamin D status. The Th17 cell population was expanded in about 40% of the MS patients. In MS patients in remission, but not during relapse, a positive association was found between Th17 cell and CD39(+) Treg percentages (r=0.468, p=0.007). Since CD39(+) Tregs have been shown to have Th17 suppressive capacities, we propose that a dysregulated Th17/CD39(+) Treg balance might contribute to disease exacerbation. A clear role for vitamin D in this regulation could not be established.