- Department of Neurology
Erasmus University Medical Center
Dr. Molewaterplein 40
3015 GD Rotterdam
Joost Smolders
Erasmus University Rotterdam, Neurology, Faculty Member
- Neurologist/ associate professor, working at MS center ErasMS, departments of Neurology and Immunology, Erasmus Unive... moreNeurologist/ associate professor, working at MS center ErasMS, departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam (The Netherlands), and at the Neuroimmunology Researchgroup of Netherlands Institute for Neuroscience, Amsterdam (The Netherlands).edit
Vitamin D exposure has gained interest as a potential disease modifying treatment in multiple sclerosis. First trials show a positive effect of vitamin D supplementation on several important MS related outcomes. Nevertheless, several... more
Vitamin D exposure has gained interest as a potential disease modifying treatment in multiple sclerosis. First trials show a positive effect of vitamin D supplementation on several important MS related outcomes. Nevertheless, several issues need to be solved, centering around the questions why (which disease outcomes should be targeted), who (which patients at which stage in their disease or even healthy individuals prior to clinical disease onset) and how (which therapeutic strategies). In this chapter, we elaborate in detail on these issues. We conclude that there is consistent evidence for a beneficial effect of vitamin D supplements on selected disease outcomes in RRMS and CIS. The way forward for vitamin D in MS is the design of further supplementation trials to better understand and analyze the precise benefit of vitamin D supplements for our MS patients, and possibly also for subjects prior to clinical MS onset.
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Multiple sclerosis (MS) is the most common disabling neurological disease of young adults. More than 2.3 million people are affected by MS worldwide. Symptoms can vary widely, depending on the localization and amount of the damage induced... more
Multiple sclerosis (MS) is the most common disabling neurological disease of young adults. More than 2.3 million people are affected by MS worldwide. Symptoms can vary widely, depending on the localization and amount of the damage induced by combined inflammatory, demyelinating, and neurodegenerative processes. Although a cure for MS does not currently exist, therapies can help treat MS attacks, attenuate disease activity, reduce progress of the disease, and manage symptoms.
Translational Neuroimmunology in Multiple Sclerosis provides an overview of recent findings and knowledge of the neuroimmunology of multiple sclerosis, from experimental models and the human disease to the translation of this research to immunotherapeutic strategies. Chapters describe genetic and environmental factors underlying the disease pathogenesis of MS as a basis for development of immunotherapies, immunological markers of disease activity, pharmacogenetics, and responses to therapy. Immunomodulatory therapies currently in practice and future therapeutic strategies on the horizon—such as neuroprotective strategies, stem cells, and repair promotion—are discussed. Contributed by renowned leaders in the field, this cross-disciplinary volume is a great resource for basic scientists and clinical practitioners in neuroscience, neurology, immunology, pharmacology, and in-drug development.
Translational Neuroimmunology in Multiple Sclerosis provides an overview of recent findings and knowledge of the neuroimmunology of multiple sclerosis, from experimental models and the human disease to the translation of this research to immunotherapeutic strategies. Chapters describe genetic and environmental factors underlying the disease pathogenesis of MS as a basis for development of immunotherapies, immunological markers of disease activity, pharmacogenetics, and responses to therapy. Immunomodulatory therapies currently in practice and future therapeutic strategies on the horizon—such as neuroprotective strategies, stem cells, and repair promotion—are discussed. Contributed by renowned leaders in the field, this cross-disciplinary volume is a great resource for basic scientists and clinical practitioners in neuroscience, neurology, immunology, pharmacology, and in-drug development.
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Multiple sclerosis (MS) is a inflammatory, demyelinating disease of the central nervous system, characterized by an auto-reactive T cell response. High serum 25-hydroxyvitamin D (25(OH)D) levels have been associated with decreased risk of... more
Multiple sclerosis (MS) is a inflammatory, demyelinating disease of the central nervous system, characterized by an auto-reactive T cell response. High serum 25-hydroxyvitamin D (25(OH)D) levels have been associated with decreased risk of developing MS and less severe disease. It is hypothesized that the underlying mechanism behind this association is the immune modulating effect of vitamin D on the adaptive immune response. In vitro studies and in vivo studies in the experimental autoimmune encephalomyelitis (EAE) animal model have shown consistently that immune cells are functional targets of vitamin D. However, in vivo studies in humans are limited. In this chapter, studies on the relation between vitamin D and immunological parameters in healthy individuals and patients with different auto immune disease, including MS, are evaluated. Correlation studies and supplementation studies performed thus far are heterogeneous in many aspects and studied a diverse repertoire of immunological outcome measures. Overall, there seems to be a trend towards an anti-inflammatory role of vitamin D, but this impression is not substantiated by conclusive data. Well-powered and controlled studies assessing disease-specific relevant immunological outcomes are warranted before conclusions can be drawn. Clinical trials on vitamin D supplementation in MS and other diseases may provide excellent frameworks for such studies.
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Vitamin D is a potent immune modulator, keeping the T-cell compartment in a more tolerogenic state. Multiple sclerosis (MS), a disease in which an autoreactive T-cell response contributes to inflammation in the central nervous system, has... more
Vitamin D is a potent immune modulator, keeping the T-cell compartment in a more tolerogenic state. Multiple sclerosis (MS), a disease in which an autoreactive T-cell response contributes to inflammation in the central nervous system, has been associated with vitamin D deficiency. The effects of vitamin D on the immune system are believed to be an important driver of this association. In this chapter, we elaborate on vitamin D as a modulator of the T-cell response. This discussion will be placed in the perspective of MS as a T-cell-mediated disease and in the perspective of the numerous association studies on vitamin D deficiency and multiple health outcomes. We conclude that there is a firm experimental and epidemiological basis supporting the model of vitamin D as a physiological immune modulator, on which intervention studies assessing clinical and immunological outcome measures should be designed.
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Background In high-income countries, four anti-CD20 monoclonal antibodies (mAbs) are used or in the pipeline for relapsing MS: ocrelizumab, ofatumumab (both registered), ublituximab (awaiting registration) and rituximab (off-label). List... more
Background In high-income countries, four anti-CD20 monoclonal antibodies (mAbs) are used or in the pipeline for relapsing MS: ocrelizumab, ofatumumab (both registered), ublituximab (awaiting registration) and rituximab (off-label). List prices differ significantly between registered and off-label drugs. Objective Comparing differences in benefits between anti-CD20 mAbs from a health-economic and societal perspective. Methods To reflect lifetime use of DMTs, we used a treatment-sequence model to compare ocrelizumab/ofatumumab and eight other drug classes in terms of health (lifetime relapses, time to Expanded Disability Status Scale [EDSS] 6, lifetime quality-adjusted life years) and cost-effectiveness (net health benefit). To become cost-effective compared to ocrelizumab, we modelled the list price of ublituximab and desired effect on EDSS progression of rituximab. Results Although drug sequences with ocrelizumab in first- and second-line were more cost-effective than ofatumumab, our probabilistic analysis suggests this outcome was very uncertain. To be more cost-effective than ocrelizumab, ublituximab needs to be about 25% cheaper whilst rituximab needs to equal the effect on disability progression seen with first-line treatments. Conclusions Our model showed no clear difference in cost-effectiveness between ocrelizumab and ofatumumab. Hence, prescribing the least costly anti-CD20 mAb can democratise MS care without a loss in health benefits.
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ObjectiveChanges in the normal‐appearing white matter (NAWM) in multiple sclerosis (MS) may contribute to disease progression. Here, we systematically quantified ultrastructural and subcellular characteristics of the axon–myelin unit in... more
ObjectiveChanges in the normal‐appearing white matter (NAWM) in multiple sclerosis (MS) may contribute to disease progression. Here, we systematically quantified ultrastructural and subcellular characteristics of the axon–myelin unit in MS NAWM and determined how this correlates with low‐grade inflammation.MethodsHuman brain tissue obtained with short postmortem delay and fixation at autopsy enables systematic quantification of ultrastructural characteristics. In this study, we performed high‐resolution immunohis tochemistry and quantitative transmission electron microscopy to study inflammation and ultrastructural characteristics of the axon–myelin unit in MS NAWM (n = 8) and control white matter (WM) in the optic nerve.ResultsIn the MS NAWM, there were more activated and phagocytic microglia cells (HLA+P2RY12− and Iba1+CD68+) and more T cells (CD3+) compared to control WM, mainly located in the perivascular space. In MS NAWM compared to control WM, there were, as expected, longer paranodes and juxtaparanodes and larger overlap between paranodes and juxtaparanodes. There was less compact myelin wrapping, a lower g‐ratio, and a higher frequency of axonal mitochondria. Changes in myelin and axonal mitochondrial frequency correlated positively with the number of active and phagocytic microglia and lymphocytes in the optic nerve.InterpretationThese data suggest that in MS NAWM myelin detachment and uncompact myelin wrapping occurs, potassium channels are unmasked at the nodes of Ranvier, and axonal energy demand is increased, or mitochondrial transport is stagnated, accompanied by increased presence of activated and phagocytic microglia and T cells. These subclinical alterations to the axon–myelin unit in MS NAWM may contribute to disease progression. ANN NEUROL 2023;93:856–870
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Clusters of ramified HLA-DR+cells, known as microglia nodules, are associated with brain pathology. Here we investigated if microglia nodules in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) are different from... more
Clusters of ramified HLA-DR+cells, known as microglia nodules, are associated with brain pathology. Here we investigated if microglia nodules in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) are different from microglia nodules in white matter (WM) in stroke and whether they may relate to the start of demyelinating MS lesions. We studied the relation between microglia nodules and pathological severity in an MS autopsy cohort (n=167), and we compared frequency, size, and gene expression of microglia nodules in MS (n=7) and stroke (n=7). MS donors with microglia nodules (64%) had a higher lesion load and a higher proportion of active lesions compared to donors without microglia nodules (36%). We found altered expression of genes in microglia nodules in MS compared to stroke, including genes previously shown to be upregulated in MS lesions. Genes associated with lipid metabolism, presence and proliferation of T and B cells, production of and response to immunoglobulins and cytokines (specifically TNF and IFN), activation of the complement cascade, and metabolic stress were upregulated. Using immunohistochemistry, we confirmed that in MS, more than in stroke, microglia nodules are associated with membrane attack complexes, have phagocytosed oxidized phospholipids, and have a tubular mitochondrial network reflecting increased metabolic activity. Furthermore, in MS, some nodules encapsulated partially demyelinated axons. Taken together, we propose that activation of some microglia nodules in MS by pro-inflammatory cytokines and immunoglobulins in combination with phagocytosis of oxidized phospholipids may lead to a volatile phenotype prone to form MS lesions.
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Background and purpose: Despite the 2017 revisions to the McDonald criteria, diagnosing primary progressive multiple sclerosis (PPMS) remains challenging. To improve clinical practice, the aim was to identify frequent diagnostic... more
Background and purpose: Despite the 2017 revisions to the McDonald criteria, diagnosing primary progressive multiple sclerosis (PPMS) remains challenging. To improve clinical practice, the aim was to identify frequent diagnostic challenges in a real-world setting and associate these with the performance of the 2010 and 2017 PPMS diagnostic McDonald criteria. Methods: Clinical, radiological and laboratory characteristics at the time of diagnosis were retrospectively recorded from designated PPMS patient files. Possible complicating factors were recorded such as confounding comorbidity, signs indicative of alternative diagnoses, possible earlier relapses and/or incomplete diagnostic work-up (no cerebrospinal fluid examination and/or magnetic resonance imaging brain and spinal cord). The percentages of patients fulfilling the 2010 and 2017 McDonald criteria were calculated after censoring patients with these complicating factors. Results: A total of 322 designated PPMS patients were included. Of all participants, it was found that n = 28/322 had confounding comorbidity and/or signs indicative of alternative diagnoses, n = 103/294 had possible initial relapsing and/or uncertainly progressive phenotypes and n = 73/191 received an incomplete diagnostic work-up. When applying the 2010 and 2017 diagnostic PPMS McDonald criteria on n = 118 cases with a full diagnostic work-up and a primary progressive disease course without a better alternative explanation, these were met by 104/118 (88.1%) and 98/118 remaining patients (83.1%), respectively (p = 0.15). Conclusion: Accurate interpretation of the initial clinical course, consideration of alternative diagnoses and a full diagnostic work-up are the cornerstones of a PPMS diagnosis. When these conditions are met, the 2010 and 2017 McDonald criteria for PPMS perform similarly, emphasizing the importance of their appropriate application in clinical practice.
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Abstract A poor circulating vitamin D status has been associated with an increased risk of developing multiple sclerosis (MS) and with a more severe disease course of MS as reflected by clinical and radiological outcomes. As underlying... more
Abstract A poor circulating vitamin D status has been associated with an increased risk of developing multiple sclerosis (MS) and with a more severe disease course of MS as reflected by clinical and radiological outcomes. As underlying mechanism, immune-modulating effects of vitamin D in the neurological periphery as well as within the borders of the central nervous system (CNS) have been proposed. The present chapter discusses studies in vitro, in experimental autoimmune encephalomyelitis, and in MS assessing the interaction of vitamin D metabolites with leukocytes and resident CNS cells. We conclude that an effect of vitamin D status, whether or not obtained by vitamin D supplementation in MS patients, on the behavior of these cells in secondary lymphoid organs and the CNS is plausible, but not yet proven. Upcoming clinical trials will provide biological material to assess this hypothesis.
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Research Interests: Multiple sclerosis, Biology, Transcriptome, Microglia, iScience, and 3 moreOsteopontin, CD, and White matter
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The role of vitamin D in calcium homeostasis is well known. More recently vitamin D has become a topic of interest in immune regulation and multiple sclerosis. The main reason for this is the observed geographical distribution of multiple... more
The role of vitamin D in calcium homeostasis is well known. More recently vitamin D has become a topic of interest in immune regulation and multiple sclerosis. The main reason for this is the observed geographical distribution of multiple sclerosis. Areas with high sunlight exposure, the principal inducer of vitamin D synthesis, have a relatively low prevalence of multiple sclerosis and vice versa. Furthermore, low levels of the principal vitamin D metabolite (25-hydroxy vitamin D) in the circulation are associated with a high incidence of multiple sclerosis. Other epidemiological evidence also supports the view that vitamin D metabolites have an immune and disease modulating effect in multiple sclerosis. Experimental research in vitro and in animal models has further clarified the interaction of vitamin D metabolites with the immune system. The evidence obtained from these studies strongly supports a model in which vitamin D mediates a shift to a more anti-inflammatory immune response, and in particular to enhanced regulatory T cell functionality. In the current review we link the basic knowledge on vitamin D and immune regulation with the vitamin D related observations in multiple sclerosis. We conclude that there is a sound basis on which to initiate double-blind placebo-controlled trials that not only address the effect of vitamin D on the clinical outcome of multiple sclerosis, but also on the regulatory T cell compartment.
Research Interests: Immunology, Immune response, Multiple sclerosis, Inflammation, Disease susceptibility, and 15 moreExperimental Research, Neuroimmunology, Humans, Female, Animals, Male, Immune regulation, Bone Density, Animal Model, Incidence, Immune modulation, Calcium Homeostasis, Immune system, Geographic distribution, and Clinical Trials as Topic
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In early multiple sclerosis (MS), an IFN-γhighGM-CSFhighIL-17low CD4+ T-cell subset termed T helper 17.1 (Th17.1) reveals enhanced capacity to infiltrate the central nervous system. Th17.1 cells express high levels of multidrug resistance... more
In early multiple sclerosis (MS), an IFN-γhighGM-CSFhighIL-17low CD4+ T-cell subset termed T helper 17.1 (Th17.1) reveals enhanced capacity to infiltrate the central nervous system. Th17.1 cells express high levels of multidrug resistance protein 1 (MDR1), which contributes to their poor glucocorticoid responsiveness. In this study, we explored whether glucocorticoid sensitivity of Th17.1 cells can generically be improved through synergy between steroid hormones, including calcitriol (1,25(OH)2D3), estradiol (E2) and progesterone (P4). We showed that human blood Th17.1 cells were less sensitive to 1,25(OH)2D3 than Th17 cells, as reflected by lower vitamin D receptor (VDR) levels and reduced modulation of MDR1, IFN-γ and GM-CSF expression after 1,25(OH)2D3 exposure. Upon T-cell activation, VDR levels were increased, but still lower in Th17.1 versus Th17 cells, which was accompanied by a 1,25(OH)2D3-mediated decline in MDR1 surface expression as well as secretion of IFN-γ and GM-CSF. ...
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Patients with multiple sclerosis (MS) have altered T cell function and composition. Common genetic risk variants for MS affect proteins that function in the immune system. It is currently unclear to what extent T cell composition is... more
Patients with multiple sclerosis (MS) have altered T cell function and composition. Common genetic risk variants for MS affect proteins that function in the immune system. It is currently unclear to what extent T cell composition is affected by genetic risk factors for MS, and how this may precede a possible disease onset. Here, we aim to assess whether an MS polygenic risk score (PRS) is associated with an altered T cell composition in a large cohort of children from the general population.
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Objective: The SOLAR study (NCT01285401) investigated the effects of vitamin D 3 (cholecalciferol) as add-on to scIFN β-1a. Background: The role of vitamin D supplementation in MS disease progression remains uncertain. Design/Methods: A... more
Objective: The SOLAR study (NCT01285401) investigated the effects of vitamin D 3 (cholecalciferol) as add-on to scIFN β-1a. Background: The role of vitamin D supplementation in MS disease progression remains uncertain. Design/Methods: A prospective, randomized, double-blind, multicenter, 48-week study. Patients with RRMS and 25-hydroxyvitamin D serum concentration ≤150 nmol/L were randomized to 44 μg scIFNβ-1a tiw plus either cholecalciferol (14,007 IU [350 μg]) or placebo. Primary endpoint: % subjects disease activity free (DAF) at Week 48, defined as the absence of relapses, EDSS progression or new combined unique active (CUA) lesions. Due to recruitment delays, the original primary endpoint was changed, allowing study duration and sample size to be reduced. Secondary endpoints at Week 48: mean ARR, % subjects free from any EDSS progression and mean number of new CUA lesions/subject/scan. Results: 229 patients were randomized to cholecalciferol or placebo. The ITT population (81.2...
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B-cells contribute to MS pathogenesis. The association of circulating B-cell phenotypes with combined unique active lesions (CUA) on MRI at 48 weeks follow-up was investigated in 50 interferon beta-treated MS patients. Transitional B-cell... more
B-cells contribute to MS pathogenesis. The association of circulating B-cell phenotypes with combined unique active lesions (CUA) on MRI at 48 weeks follow-up was investigated in 50 interferon beta-treated MS patients. Transitional B-cell proportions were lower in participants with CUA at week 0 and 48 [p = 0.004, p = 0.002]. A decrease in circulating anti-EBNA-1 IgG levels between week 0 and 48 associated with absence of CUA [p = 0.047], but not with B-cell profiles. In a multi-factor model for CUA-risk, transitional B-cell proportions contributed independent from NK/T-cell ratio, change in anti-EBNA-1 IgG, and vitamin D supplementation. Transitional B-cells may predict treatment response in MS.
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ObjectiveTo study whether glucocorticoid (GC) resistance delineates disease-relevant T helper (Th) subsets that home to the CNS of patients with early MS.MethodsThe expression of key determinants of GC sensitivity, multidrug resistance... more
ObjectiveTo study whether glucocorticoid (GC) resistance delineates disease-relevant T helper (Th) subsets that home to the CNS of patients with early MS.MethodsThe expression of key determinants of GC sensitivity, multidrug resistance protein 1 (MDR1/ABCB1) and glucocorticoid receptor (GR/NR3C1), was investigated in proinflammatory Th subsets and compared between natalizumab-treated patients with MS and healthy individuals. Blood, CSF, and brain compartments from patients with MS were assessed for the recruitment of GC-resistant Th subsets using fluorescence-activated cell sorting (FACS), quantitative polymerase chain reaction (qPCR), immunohistochemistry, and immunofluorescence.ResultsAn MS-associated Th subset termed Th17.1 showed a distinct GC-resistant phenotype as reflected by high MDR1 and low GR expression. This expression ratio was further elevated in Th17.1 cells that accumulated in the blood of patients with MS treated with natalizumab, a drug that prevents their entry in...
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BackgroundAlthough distinct brain-homing B cells have been identified in multiple sclerosis (MS), it is unknown how these further evolve to contribute to local pathology. In this study, we explored B-cell maturation in the central nervous... more
BackgroundAlthough distinct brain-homing B cells have been identified in multiple sclerosis (MS), it is unknown how these further evolve to contribute to local pathology. In this study, we explored B-cell maturation in the central nervous system (CNS) of MS and control brain donors and determined their association with immunoglobulin (Ig) production, T-cell presence and lesion formation. MethodsEx vivo multicolor flow cytometry was performed on postmortem blood, cerebrospinal fluid (CSF), meninges and white matter from 28 MS and 10 non-demented control donors. MS brain tissue sections were analyzed with immunostainings and laser-capture microdissection to obtain paired lesional rims and perilesional areas. IgG index and CSF oligoclonal bands were measured with nephelometry, isoelectric focusing and immunoblotting. Blood-derived B cells from MS patients and healthy controls were cocultured under T follicular helper-like conditions to evaluate their ASC-differentiating capacity in vit...
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Background and ObjectivesTo investigate whether white matter lesion activity, acute axonal damage, and axonal density in MS associate with CSF neurofilament light chain (NfL) levels.MethodsOf 101 brain donors with MS (n = 92 progressive... more
Background and ObjectivesTo investigate whether white matter lesion activity, acute axonal damage, and axonal density in MS associate with CSF neurofilament light chain (NfL) levels.MethodsOf 101 brain donors with MS (n = 92 progressive MS, n = 9 relapsing-remitting MS), ventricular CSF was collected, and NfL levels were measured. White matter lesions were classified as active, mixed, inactive, or remyelinated, and microglia/macrophage morphology in active and mixed lesions was classified as ramified, ameboid, or foamy. In addition, axonal density and acute axonal damage were assessed using Bielschowsky and amyloid precursor protein (APP) (immune)histochemistry.ResultsCSF NfL measurements of donors with recent (<1 year) or clinically silent stroke were excluded. CSF NfL levels correlated negatively with disease duration (p = 6.9e-3, r = 0.31). In donors without atrophy, CSF NfL levels correlated positively with the proportion of active and mixed lesions containing foamy microglia...
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Additional file one contains all supplemental information mentioned in this manuscript: supplemental table 1, supplemental figures 1-8, and the detailed microglia isolation protocol description. (PDF 320Â kb)
The Stein et al. conclusion that high-dose ineffective vs. low-dose vitamin D2 supplementation in relapsing-remitting multiple sclerosis (RRMS) is not supported by data enabling level 1 evidence...
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Vitamin D3 upregulates IL-2 receptor alpha (IL2RA, CD25)-expression on CD4(+) T cells in vitro. We investigated effects of 48-weeks vitamin D3 supplements on CD25-expression by CD4(+) T cells of patients with multiple sclerosis (MS).... more
Vitamin D3 upregulates IL-2 receptor alpha (IL2RA, CD25)-expression on CD4(+) T cells in vitro. We investigated effects of 48-weeks vitamin D3 supplements on CD25-expression by CD4(+) T cells of patients with multiple sclerosis (MS). There was no significant difference between the vitamin D3 (n=30) and placebo group (n=23) in IL2RA mRNA-expression by PBMC. Likewise, CD25 cell surface-expression by conventional or regulatory T cells (Treg) did not differ between groups, although Treg CD25-expression and circulating soluble-CD25 levels decreased significantly in the placebo but not vitamin D3-group. We speculate that vitamin D3 may promote the maintenance of CD25-related immune homeostasis in MS.
Research Interests: Endocrinology, Immunology, Multiple sclerosis, Biology, Vitamin D, and 15 moreMedicine, Neuroimmunology, Internal Medicine, Regulatory T cells, Proliferation, T Cell, Dietary Supplements, CD, Vitamin, IL, Immune system, Randomized Controlled Trial, Immune Responses, Neurosciences, and Regulatory T cell
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Research Interests: Immunology, Multiple sclerosis, Medicine, Neuroimmunology, Humans, and 15 moreInternal Medicine, Placebo, Female, Male, Immune regulation, Dietary Supplements, Vitamin, Middle Aged, Cytokine, Immune system, Adult, Lymphocytes, Neurosciences, Regulatory T cell, and relapsing remitting multiple sclerosis
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Sex steroids, corticosteroids and vitamin D3-derived molecules have all been subject to experimental studies and clinical trials in a plethora of autoimmune diseases. These molecules are all derived from cholesterol metabolites and are... more
Sex steroids, corticosteroids and vitamin D3-derived molecules have all been subject to experimental studies and clinical trials in a plethora of autoimmune diseases. These molecules are all derived from cholesterol metabolites and are ligands for nuclear receptors. Ligation of these receptors results in direct regulation of multiple gene transcription involved in general homeostatic and adaptation networks, including the immune system. Indeed, the distinct ligands affect the function of both myeloid and lymphoid cells, eventually resulting in a less pro-inflammatory immune response which is considered beneficial in autoimmune diseases. Next to the immune system, also the central nervous system is prone to regulation by these nuclear receptor ligands. Understanding of the intricate interactions between sex-steroids, corticosteroids and vitamin D3 metabolites, on the one hand, and the immune and central nervous system, on the other hand, may reveal novel approaches to utilize these n...
Research Interests: Immunology, Multiple sclerosis, Biology, Evolution, Medicine, and 15 moreNuclear Receptor, Cortisol, Progesterone, Humans, Animals, Estrogen, HPA axis, Central Nervous System, Immune system, Receptor, Corticosteroids, Experimental Autoimmune Encephalomyelitis, Ligands, Glucocorticoids, and Adrenal cortex hormones
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Research Interests: Multiple sclerosis, Gastroenterology, Biomarkers, Medicine, Disability, and 15 moreHumans, Internal Medicine, Female, Male, Risk factors, Middle Aged, Longitudinal Studies, Adult, Retrospective Studies, Prognosis, Disease Progression, Risk Factors, Biochemistry and cell biology, hydroxyvitamin D, and relapsing remitting multiple sclerosis
A 58-year-old man presented with a balance disorder, followed by progressive memory disturbance, urinary incontinence and vomiting. MRI of the brain revealed multiple cavernous malformations, with recent haemorrhage from one of them, in... more
A 58-year-old man presented with a balance disorder, followed by progressive memory disturbance, urinary incontinence and vomiting. MRI of the brain revealed multiple cavernous malformations, with recent haemorrhage from one of them, in the brainstem, causing a hydrocephalus. After treatment for the hydrocephalus, the symptoms resolved quickly. Cerebral cavernomas may cause epileptic seizures, haemorrhaging and progressive neurological deficits. Diagnosis is on the basis of the typical MRI pattern of a hyperintense core, surrounded by a hypointense rim of old blood. Treatment consists of surgery if the lesion is easily accessible and can be completely removed. Other options are gamma-knife surgery, stereotactic radiotherapy and conservative treatment.
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Vitamin D is a potent immune modulator, keeping the T-cell compartment in a more tolerogenic state. Multiple sclerosis (MS), a disease in which an autoreactive T-cell response contributes to inflammation in the central nervous system, has... more
Vitamin D is a potent immune modulator, keeping the T-cell compartment in a more tolerogenic state. Multiple sclerosis (MS), a disease in which an autoreactive T-cell response contributes to inflammation in the central nervous system, has been associated with vitamin D deficiency. The effects of vitamin D on the immune system are believed to be an important driver of this association. In this chapter, we elaborate on vitamin D as a modulator of the T-cell response. This discussion will be placed in the perspective of MS as a T-cell-mediated disease and in the perspective of the numerous association studies on vitamin D deficiency and multiple health outcomes. We conclude that there is a firm experimental and epidemiological basis supporting the model of vitamin D as a physiological immune modulator, on which intervention studies assessing clinical and immunological outcome measures should be designed.
Research Interests: Immunology, Multiple sclerosis, Inflammation, Medicine, Association study, and 15 moreHumans, Autoimmune Disease, Animals, Disease, Immune regulation, Immunomodulation, Central Nervous System, Dendritic cell, Immune modulation, Clinical Sciences, Immune system, Intervention study, Health Outcome, Outcome measure, and Pharmacology and pharmaceutical sciences
We read with great interest the recently published article by Salzer et al. in Multiple Sclerosis Journal that aimed to investigate the relation between circulating antibody levels against the Epstein-Barr virus (EBV), vitamin D and the... more
We read with great interest the recently published article by Salzer et al. in Multiple Sclerosis Journal that aimed to investigate the relation between circulating antibody levels against the Epstein-Barr virus (EBV), vitamin D and the risk of multiple sclerosis (MS).1 In particular, the authors have further strengthened the known positive association between antibodies against the EBV antigen EBNA1 and the risk of developing MS later in life.1,2 Interestingly, the association was especially evident in younger individuals, in which an inverse correlation between anti-EBNA1 antibody and 25-hydroxyvitamin D levels was also found.1 Studies have shown that a poor vitamin D status is itself associated with an increased risk of MS later in life.3,4 We believe the findings of Salzer et al. are of great importance since they suggest the presence of a link between vitamin D deficiency and EBV infection in the aetiology of this complex disease. We collected serum samples from 15 relapsing– remitting MS (RRMS) patients who were supplemented with 20,000 IU/day vitamin D3 for 12 weeks.5 We measured their circulating antibody levels against EBNA1 using the Liaison® quantitative chemiluminescent assay.6 We found that the initial antibody levels (mean=77.98, SD=37.16) were significantly reduced after vitamin D supplementation (mean=62.27, SD=28.05) (mean difference=15.72; 95% confidence interval (CI)=3.37–28.07; paired T test p=0.016). The effect of vitamin D was particularly strong in those patients with the higher antibody levels, and a positive correlation was present between pre-supplementation antibody levels and their decrease following supplementation (Pearson’s rho=0.66, p=0.007) (Figure). It is important to note that this observation appears to be specific for anti-EBNA1 and/or for other specific antibodies, since we could not find any change in total immunoglobulin (Ig)-load and B cell differentiation profile after vitamin D supplementation in these patients.7 This study has several limitations. The inverse correlation between vitamin D status and EBV antibody titres observed by Salzer et al. was seen in individuals aged less than 26 years and with physiological vitamin D status. The 15 RRMS patients we studied were older (median=35.15, range=25.47–49.36), treated with beta interferon and reached supra-physiological levels of vitamin D. Despite these differences, our findings suggest that the negative correlation between vitamin D status and circulating antibody levels against EBV observed by Salzer et al. may not be a chance finding and that the link between these two factors could be causal. Notably, vitamin D has well-described antibacterial and antiviral roles and is able to modulate antibody production by plasma cells.8–10 Individuals with high serum vitamin D levels are also less likely to have EBV shedding in saliva.11 Furthermore, latitude is a major determinant of vitamin D status, and we have previously shown that EBV seroprevalence positively correlates with latitude in the MS as well as the general population.12 Finally, in relation to the potential therapeutic use of vitamin D in MS, we hypothesise that a stratification of MS patients based on baseline anti-EBNA1 antibody status may highlight differences in the immunological and perhaps also clinical response to vitamin D supplementation. We believe future studies are needed to understand how vitamin D influences the production of antibodies against EBV, the immune response against this virus and whether this mechanism is specific to EBV or shared with other viruses such as cytomegalovirus and varicella zoster virus. These studies will elucidate how these two environmental factors are linked in the causal cascade leading to MS and how we can program future effective strategies of disease prevention. 494494 MSJ191210.1177/1352458513494494Multiple Sclerosis JournalDisanto et al. 2013
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There is increasing awareness that vitamin D might be beneficial in autoimmune diseases, like multiple sclerosis (MS), and that the effects are mediated via the immune system. In line with this theory Allan et al. recently performed a... more
There is increasing awareness that vitamin D might be beneficial in autoimmune diseases, like multiple sclerosis (MS), and that the effects are mediated via the immune system. In line with this theory Allan et al. recently performed a small vitamin D3 supplementation study to further support the potentially ameliorating immune modulating effects of vitamin D in MS.1 They report an increase in IL-10 production by peripheral blood mononuclear cells (PBMC), probably caused mainly by non T cells, and a decreased Thelper (Th)17 response. This study, however, included only four healthy controls, two males and two females. Obviously, these results might be used for identifying study endpoints and concomitant power calculations, both essential in the design of trials, but statistically this approach will be error prone. Interestingly, in recent years several small and uncontrolled vitamin D supplementation studies, which took into account state of the art immunological parameters, have been performed in MS.2–4 All of these studies are supplementation studies administering 10,000–20,000 IU vitamin D3 per day for 12 to 52 weeks. In agreement with Allan et al.1, Mosayebi et al.3 also reported an increase in IL-10 production by PBMC, while Smolders et al.4 even demonstrated higher percentages of IL-10 producing CD4+ T cells. Kimball et al.2 could not detect differences in IL-10 production after in vivo vitamin D supplementation in sera nor in supernatant after additional in vitro T cell activation. Th17 responses have only been investigated by Smolders et al. and here no effect on the proportion of IL-17+ CD4+ T cells could be shown. A second point of concern, which is shared by some of the previously mentioned vitamin D supplementation studies in MS, is the relatively short duration of the supplementation. Although a steady state in the vitamin D metabolism might be reached within 12 to 15 weeks,1,4 there is no evidence that a new equilibrium in immune homeostasis has been established by then. Currently at least two well powered placebo-controlled supplementation trials in MS patients are ongoing.5,6 Both trials share a long-term duration of supplementation of at least 18 months and have multiple clinical but also immunological outcome parameters. These studies will give us more reliable data with respect to the effects of vitamin D on the immune system. Furthermore, they will give us more information with regard to safety concerns of high dose vitamin D3 supplementation in autoimmune disease.
Research Interests:
Patients with multiple sclerosis (MS) are more frequently born in spring when compared to autumn. Fluctuation of UV-light has been hypothesized to drive this phenomenon. To assess the correlation between fluctuation of sunlight and birth... more
Patients with multiple sclerosis (MS) are more frequently born in spring when compared to autumn. Fluctuation of UV-light has been hypothesized to drive this phenomenon. To assess the correlation between fluctuation of sunlight and birth season in persons with MS. For this record-linkage study, we collected from the international MSBase and the Italian MS iMed-web databases the dates of birth of 11,415 patients with MS from 36 centres from 15 countries worldwide and compared these to dates of live-births from national registries. From all participating sites, we collected data on UV-light fluctuation and assessed its correlation with seasonal fluctuation in MS births. Compared with the reference cohort, an increased proportion of persons with MS were born in spring and a decreased proportion in autumn (odds ratio (OR) to be born in spring versus autumn = 1.158, χ² = 36.347, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001). There was no significantly increased fluctuation of MS births with increased quartile of ambient UV-light fluctuation (Ptrend = 0.086). Seasonal fluctuation of MS births as found in this worldwide cohort of patients with MS did not correlate with variation in seasonal fluctuation of UV-light. Most likely, it results from a complex interplay between fluctuation of sunlight, behavioural factors, other environmental factors and (epi)genetic factors.