open access

Vol 53, No 2 (2019)
Review articles
Published online: 2019-03-27
Submitted: 2019-01-22
Accepted: 2019-01-22
Get Citation

Vitamin D as an immune modulator in multiple sclerosis

Halina Bartosik-Psujek, Marek Psujek
DOI: 10.5603/PJNNS.a2019.0015
·
Pubmed: 30916776
·
Neurol Neurochir Pol 2019;53(2):113-122.

open access

Vol 53, No 2 (2019)
Review articles
Published online: 2019-03-27
Submitted: 2019-01-22
Accepted: 2019-01-22

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of the central nervous system. The disease is characterised by inflammation with extensive immune infiltration, demyelination, axonal loss and damage of oligodendrocytes, presumably auto-immune in nature. The influence of environmental factors on the development and activity of MS has been known for a long time. Vitamin D and sun exposure are among the most important ones. Both serum vitamin D level and sun exposure independent of vitamin D production are correlated with epidemiological and clinical parameters of MS, and the impact of vitamin D on immune parameters has been clearly confirmed in experimental studies. Nevertheless, the impact on clinical aspects is inconclusive, especially when the influence of supplementation is assessed. In this work we review the state of knowledge regarding the effect of vitamin D on immune cells subsets in relation to experimental and clinical studies.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder of the central nervous system. The disease is characterised by inflammation with extensive immune infiltration, demyelination, axonal loss and damage of oligodendrocytes, presumably auto-immune in nature. The influence of environmental factors on the development and activity of MS has been known for a long time. Vitamin D and sun exposure are among the most important ones. Both serum vitamin D level and sun exposure independent of vitamin D production are correlated with epidemiological and clinical parameters of MS, and the impact of vitamin D on immune parameters has been clearly confirmed in experimental studies. Nevertheless, the impact on clinical aspects is inconclusive, especially when the influence of supplementation is assessed. In this work we review the state of knowledge regarding the effect of vitamin D on immune cells subsets in relation to experimental and clinical studies.

Get Citation

Keywords

multiple sclerosis, vitamin D, supplementation, T cells, B cells, dendritic cells, macrophages

About this article
Title

Vitamin D as an immune modulator in multiple sclerosis

Journal

Neurologia i Neurochirurgia Polska

Issue

Vol 53, No 2 (2019)

Pages

113-122

Published online

2019-03-27

DOI

10.5603/PJNNS.a2019.0015

Pubmed

30916776

Bibliographic record

Neurol Neurochir Pol 2019;53(2):113-122.

Keywords

multiple sclerosis
vitamin D
supplementation
T cells
B cells
dendritic cells
macrophages

Authors

Halina Bartosik-Psujek
Marek Psujek

References (88)
  1. Yong H, Chartier G, Quandt J. Modulating inflammation and neuroprotection in multiple sclerosis. J Neurosci Res. 2018; 96(6): 927–950.
  2. Lucas RM, Byrne SN, Correale J, et al. Ultraviolet radiation, vitamin D and multiple sclerosis. Neurodegener Dis Manag. 2015; 5(5): 413–424.
  3. Kubicka K, Pierzchała K. Concentration of 25(OH)D3 and calcium and phosphorus metabolism in patients suffering from relapsing-remitting multiple sclerosis. A pilot study. Neurologia i Neurochirurgia Polska. 2013; 47(2): 126–130.
  4. Bell TD, Demay MB, Burnett-Bowie SAM. The biology and pathology of vitamin D control in bone. J Cell Biochem. 2010; 111(1): 7–13.
  5. Kępczyńska K, Zajda M, Lewandowski Z, et al. Bone metabolism and vitamin D status in patients with multiple sclerosis. Neurol Neurochir Pol. 2016; 50(4): 251–257.
  6. Bikle D. Vitamin D Metabolism, Mechanism of Action, and Clinical Applications. Chemistry & Biology. 2014; 21(3): 319–329.
  7. Wacker M, Holick MF. Vitamin D - effects on skeletal and extraskeletal health and the need for supplementation. Nutrients. 2013; 5(1): 111–148.
  8. Lu M, Taylor BV, Körner H. Genomic Effects of the Vitamin D Receptor: Potentially the Link between Vitamin D, Immune Cells, and Multiple Sclerosis. Front Immunol. 2018; 9: 477.
  9. Veldman CM, Cantorna MT, DeLuca HF. Expression of 1,25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys. 2000; 374(2): 334–338.
  10. Tai Yu, Wang Q, Korner H, et al. Molecular Mechanisms of T Cells Activation by Dendritic Cells in Autoimmune Diseases. Front Pharmacol. 2018; 9: 642.
  11. Xie ZX, Zhang HL, Wu XJ, et al. Role of the immunogenic and tolerogenic subsets of dendritic cells in multiple sclerosis. Mediators Inflamm. 2015; 2015: 513295.
  12. Piemonti L, Monti P, Sironi M, et al. Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol. 2000; 164(9): 4443–4451.
  13. Bartosik-Psujek H, Tabarkiewicz J, Pocinska K, et al. Immunomodulatory effects of vitamin D on monocyte-derived dendritic cells in multiple sclerosis. Mult Scler. 2010; 16(12): 1513–1516.
  14. Unger WWJ, Laban S, Kleijwegt FS, et al. Induction of Treg by monocyte-derived DC modulated by vitamin D3 or dexamethasone: differential role for PD-L1. Eur J Immunol. 2009; 39(11): 3147–3159.
  15. van Halteren AGS, Tysma OM, van Etten E, et al. 1alpha,25-dihydroxyvitamin D3 or analogue treated dendritic cells modulate human autoreactive T cells via the selective induction of apoptosis. J Autoimmun. 2004; 23(3): 233–239.
  16. Dankers W, Colin EM, van Hamburg JP, et al. Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential. Front Immunol. 2016; 7: 697.
  17. Farias AS, Spagnol GS, Bordeaux-Rego P, et al. Vitamin D3 induces IDO+ tolerogenic DCs and enhances Treg, reducing the severity of EAE. CNS Neurosci Ther. 2013; 19(4): 269–277.
  18. Chiuso-Minicucci F, Ishikawa LL, Mimura LA, et al. Treatment with Vitamin D/MOG Association Suppresses Experimental Autoimmune Encephalomyelitis. PLoS One. 2015; 10(5): e0125836.
  19. Mansilla MJ, Sellès-Moreno C, Fàbregas-Puig S, et al. Beneficial effect of tolerogenic dendritic cells pulsed with MOG autoantigen in experimental autoimmune encephalomyelitis. CNS Neurosci Ther. 2015; 21(3): 222–230.
  20. Mansilla MJ, Contreras-Cardone R, Navarro-Barriuso J, et al. Cryopreserved vitamin D3-tolerogenic dendritic cells pulsed with autoantigens as a potential therapy for multiple sclerosis patients. J Neuroinflammation. 2016; 13(1): 113.
  21. Zhang X, Zhou M, Guo Y, et al. 1,25-Dihydroxyvitamin D₃ Promotes High Glucose-Induced M1 Macrophage Switching to M2 via the VDR-PPARγ Signaling Pathway. Biomed Res Int. 2015; 2015: 157834.
  22. Kim EW, Teles RMB, Haile S, et al. Vitamin D status contributes to the antimicrobial activity of macrophages against Mycobacterium leprae. PLoS Negl Trop Dis. 2018; 12(7): e0006608.
  23. Fabri M, Stenger S, Shin DM, et al. Vitamin D is required for IFN-gamma-mediated antimicrobial activity of human macrophages. Sci Transl Med. 2011; 3(104): 104ra102.
  24. Korf H, Wenes M, Stijlemans B, et al. 1,25-Dihydroxyvitamin D3 curtails the inflammatory and T cell stimulatory capacity of macrophages through an IL-10-dependent mechanism. Immunobiology. 2012; 217(12): 1292–1300.
  25. Nashold FE, Miller DJ, Hayes CE. 1,25-dihydroxyvitamin D3 treatment decreases macrophage accumulation in the CNS of mice with experimental autoimmune encephalomyelitis. J Neuroimmunol. 2000; 103(2): 171–179.
  26. Cantorna MT, Snyder L, Lin YD, et al. Vitamin D and 1,25(OH)2D regulation of T cells. Nutrients. 2015; 7(4): 3011–3021.
  27. Sheikh V, Kasapoglu P, Zamani A, et al. Vitamin D3 inhibits the proliferation of T helper cells, downregulate CD4 T cell cytokines and upregulate inhibitory markers. Hum Immunol. 2018; 79(6): 439–445.
  28. Boonstra A, Barrat FJ, Crain C, et al. 1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol. 2001; 167(9): 4974–4980.
  29. Nashold FE, Hoag KA, Goverman J, et al. Rag-1-dependent cells are necessary for 1,25-dihydroxyvitamin D(3) prevention of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2001; 119(1): 16–29.
  30. Mayne CG, Spanier JA, Relland LM, et al. 1,25-Dihydroxyvitamin D3 acts directly on the T lymphocyte vitamin D receptor to inhibit experimental autoimmune encephalomyelitis. Eur J Immunol. 2011; 41(3): 822–832.
  31. Pedersen LB, Nashold FE, Spach KM, et al. 1,25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking. J Neurosci Res. 2007; 85(11): 2480–2490.
  32. Mahon BD, Gordon SA, Cruz J, et al. Cytokine profile in patients with multiple sclerosis following vitamin D supplementation. J Neuroimmunol. 2003; 134(1-2): 128–132.
  33. Burton JM, Kimball S, Vieth R, et al. A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology. 2010; 74(23): 1852–1859.
  34. O'Connell K, Sulaimani J, Basdeo SA, et al. Effects of vitamin D in clinically isolated syndrome and healthy control participants: A double-blind randomised controlled trial. Mult Scler J Exp Transl Clin. 2017; 3(3): 2055217317727296.
  35. Ashtari F, Toghianifar N, Zarkesh-Esfahani SH, et al. Short-term effect of high-dose vitamin D on the level of interleukin 10 in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial. Neuroimmunomodulation. 2015; 22(6): 400–404.
  36. McGeachy MJ, Bak-Jensen KS, Chen Yi, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007; 8(12): 1390–1397.
  37. Cheng Y, Sun Li, Xie Z, et al. Diversity of immune cell types in multiple sclerosis and its animal model: Pathological and therapeutic implications. J Neurosci Res. 2017; 95(10): 1973–1983.
  38. Babaloo Z, Aliparasti MR, Babaiea F, et al. The role of Th17 cells in patients with relapsing-remitting multiple sclerosis: interleukin-17A and interleukin-17F serum levels. Immunol Lett. 2015; 164(2): 76–80.
  39. Sintzel MB, Rametta M, Reder AT. Vitamin D and Multiple Sclerosis: A Comprehensive Review. Neurol Ther. 2018; 7(1): 59–85.
  40. Chang JH, Cha HR, Lee DS, et al. 1,25-Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H)17 cells to protect against experimental autoimmune encephalomyelitis. PLoS One. 2010; 5(9): e12925.
  41. Joshi S, Pantalena LC, Liu XK, et al. 1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A. Mol Cell Biol. 2011; 31(17): 3653–3669.
  42. Jafarzadeh A, Azizi S, Arabi Z, et al. Vitamin D down-regulates the expression of some Th17 cell-related cytokines, key inflammatory chemokines, and chemokine receptors in experimental autoimmune encephalomyelitis. Nutritional Neuroscience. 2018: 1–13.
  43. da Costa DS, Hygino J, Ferreira TB, et al. Vitamin D modulates different IL-17-secreting T cell subsets in multiple sclerosis patients. J Neuroimmunol. 2016; 299: 8–18.
  44. Bhargava P, Sotirchos E, Eckstein C, et al. High-dose vitamin D supplementation reduces IL-17-producing CD4+ Tcells and effector-memory CD4+ T-cells in multiple sclerosis patients (S38. 001). Neurology. 2015; 84(14 Supplement): S38–001.
  45. Smolders J, Thewissen M, Peelen E, et al. Vitamin D Status Is Positively Correlated with Regulatory T Cell Function in Patients with Multiple Sclerosis. PLoS ONE. 2009; 4(8): e6635.
  46. Smolders J, Peelen E, Thewissen M, et al. Safety and T cell modulating effects of high dose vitamin D3 supplementation in multiple sclerosis. PLoS One. 2010; 5(12): e15235.
  47. Toghianifar N, Ashtari F, Zarkesh-Esfahani SH, et al. Effect of high dose vitamin D intake on interleukin-17 levels in multiple sclerosis: a randomized, double-blind, placebo-controlled clinical trial. J Neuroimmunol. 2015; 285: 125–128.
  48. Muris AH, Smolders J, Rolf L, et al. SOLARIUM study group. Immune regulatory effects of high dose vitamin D supplementation in a randomized controlled trial in relapsing remitting multiple sclerosis patients receiving IFNβ; the SOLARIUM study. J Neuroimmunol. 2016; 300: 47–56.
  49. Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune tolerance. Cell. 2008; 133(5): 775–787.
  50. Viglietta V, Baecher-Allan C, Weiner HL, et al. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004; 199(7): 971–979.
  51. Huan J, Culbertson N, Spencer L, et al. Decreased FOXP3 levels in multiple sclerosis patients. J Neurosci Res. 2005; 81(1): 45–52.
  52. Venken K, Hellings N, Thewissen M, et al. Compromised CD4+ CD25(high) regulatory T-cell function in patients with relapsing-remitting multiple sclerosis is correlated with a reduced frequency of FOXP3-positive cells and reduced FOXP3 expression at the single-cell level. Immunology. 2008; 123(1): 79–89.
  53. Xie Z, Chen J, Zheng C, et al. 1,25-dihydroxyvitamin D -induced dendritic cells suppress experimental autoimmune encephalomyelitis by increasing proportions of the regulatory lymphocytes and reducing T helper type 1 and type 17 cells. Immunology. 2017; 152(3): 414–424.
  54. Spanier J, Nashold F, Mayne C, et al. Vitamin D and estrogen synergy in Vdr-expressing CD4+ T cells is essential to induce Helios+FoxP3+ T cells and prevent autoimmune demyelinating disease. Journal of Neuroimmunology. 2015; 286: 48–58.
  55. Sinha S, Boyden AW, Itani FR, et al. Immune regulation of multiple sclerosis by CD8+ T cells. Immunol Res. 2014; 59(1-3): 254–265.
  56. Machado-Santos J, Saji E, Tröscher AR, et al. The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells. Brain. 2018; 141(7): 2066–2082.
  57. Lysandropoulos AP, Jaquiéry E, Jilek S, et al. Vitamin D has a direct immunomodulatory effect on CD8+ T cells of patients with early multiple sclerosis and healthy control subjects. J Neuroimmunol. 2011; 233(1-2): 240–244.
  58. Disanto G, Morahan JM, Barnett MH, et al. The evidence for a role of B cells in multiple sclerosis. Neurology. 2012; 78(11): 823–832.
  59. Chen S, Sims GP, Chen XX, et al. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol. 2007; 179(3): 1634–1647.
  60. Lemire JM, Adams JS, Sakai R, et al. 1 alpha,25-dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J Clin Invest. 1984; 74(2): 657–661.
  61. Heine G, Niesner U, Chang HD, et al. 1,25-dihydroxyvitamin D(3) promotes IL-10 production in human B cells. Eur J Immunol. 2008; 38(8): 2210–2218.
  62. Rolf L, Muris AH, Hupperts R, et al. Illuminating vitamin D effects on B cells--the multiple sclerosis perspective. Immunology. 2016; 147(3): 275–284.
  63. Knippenberg S, Smolders J, Thewissen M, et al. Effect of vitamin D(3) supplementation on peripheral B cell differentiation and isotype switching in patients with multiple sclerosis. Mult Scler. 2011; 17(12): 1418–1423.
  64. Peelen E, Rijkers G, Meerveld-Eggink A, et al. Relatively high serum vitamin D levels do not impair the antibody response to encapsulated bacteria. Eur J Clin Microbiol Infect Dis. 2013; 32(1): 61–69.
  65. Knippenberg S, Peelen E, Smolders J, et al. Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naïve/memory Breg ratio during a relapse but not in remission. J Neuroimmunol. 2011; 239(1-2): 80–86.
  66. Stein MS, Liu Y, Gray OM, et al. A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis. Neurology. 2011; 77(17): 1611–1618.
  67. Kampman MT, Steffensen LH, Mellgren SI, et al. Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial. Mult Scler. 2012; 18(8): 1144–1151.
  68. Soilu-Hänninen M, Aivo J, Lindström BM, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon β-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012; 83(5): 565–571.
  69. Smolders J, Hupperts R, Vieth R, et al. High dose cholecalciferol (vitamin D3) oil as add-on therapy in subjects with relapsing-remitting multiple sclerosis receiving subcutaneous interferon b-1a. In: Presented at the European Committee for Treatment and Research in Multiple Sclerosis conference. London, England, September 14–17, 2016. Abstract S166.
  70. Camu W, Pierrot-Deseilligny C, Hautecoeur P, et al. Cholecalciferol supplementation in relapsing multiple sclerosis patients treated with subcutaneous interferon beta-1a: a randomized, controlled trial. In: Presented at the European Committee for treatment and research in multiple sclerosis conference. London. England, September 14–17, 2016.Abstract P750.
  71. Shaygannejad V, Janghorbani M, Ashtari F, et al. Effects of Adjunct Low-Dose Vitamin D on Relapsing-Remitting Multiple Sclerosis Progression: Preliminary Findings of a Randomized Placebo-Controlled Trial. Multiple Sclerosis International. 2012; 2012: 1–7.
  72. Mosayebi G, Ghazavi A, Ghasami K, et al. Therapeutic effect of vitamin D3 in multiple sclerosis patients. Immunol Invest. 2011; 40(6): 627–639.
  73. Golan D, Halhal B, Glass-Marmor L, et al. Vitamin D supplementation for patients with multiple sclerosis treated with interferon-beta: a randomized controlled trial assessing the effect on flu-like symptoms and immunomodulatory properties. BMC Neurol. 2013; 13: 60.
  74. James E, Dobson R, Kuhle J, et al. The effect of vitamin D-related interventions on multiple sclerosis relapses: a meta-analysis. Mult Scler. 2013; 19(12): 1571–1579.
  75. Zheng C, He L, Liu L, et al. The efficacy of vitamin D in multiple sclerosis: A meta-analysis. Mult Scler Relat Disord. 2018; 23: 56–61.
  76. Bhargava P, Steele SU, Waubant E, et al. Multiple sclerosis patients have a diminished serologic response to vitamin D supplementation compared to healthy controls. Mult Scler. 2016; 22(6): 753–760.
  77. Lucas RM, Ponsonby AL, Dear K, et al. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology. 2011; 76(6): 540–548.
  78. Zivadinov R, Treu CN, Weinstock-Guttman B, et al. Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013; 84(10): 1075–1081.
  79. Hart PH, Gorman S, Finlay-Jones JJ. Modulation of the immune system by UV radiation: more than just the effects of vitamin D? Nat Rev Immunol. 2011; 11(9): 584–596.
  80. Ullrich SE, Byrne SN. The immunologic revolution: photoimmunology. J Invest Dermatol. 2012; 132(3 Pt 2): 896–905.
  81. Beecham AH, Patsopoulos NA, Xifara DK, et al. International Multiple Sclerosis Genetics Consortium (IMSGC), Wellcome Trust Case Control Consortium 2 (WTCCC2), International IBD Genetics Consortium (IIBDGC). Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet. 2013; 45(11): 1353–1360.
  82. Mowry EM, Pelletier D, Gao Z, et al. Vitamin D in clinically isolated syndrome: evidence for possible neuroprotection. Eur J Neurol. 2016; 23(2): 327–332.
  83. Hancock REW, Haney EF, Gill EE. The immunology of host defence peptides: beyond antimicrobial activity. Nat Rev Immunol. 2016; 16(5): 321–334.
  84. Cela EM, Friedrich A, Paz ML, et al. Time-course study of different innate immune mediators produced by UV-irradiated skin: comparative effects of short and daily versus a single harmful UV exposure. Immunology. 2015; 145(1): 82–93.
  85. Bruhs A, Schwarz T, Schwarz A. A. Prevention and mitigation of experimental autoimmune encephalomyelitis by murine b-defensins via induction of regulatory T cells. F1000 - Post-publication peer review of the biomedical literature. 2015; 136: 173–181.
  86. Breuer J, Schwab N, Schneider-Hohendorf T, et al. Ultraviolet B light attenuates the systemic immune response in central nervous system autoimmunity. Ann Neurol. 2014; 75(5): 739–758.
  87. Kok LF, Marsh-Wakefield F, Marshall JE, et al. B cells are required for sunlight protection of mice from a CNS-targeted autoimmune attack. J Autoimmun. 2016; 73: 10–23.
  88. Breuer J, Loser K, Mykicki N, et al. Does the environment influence multiple sclerosis pathogenesis via UVB light and/or induction of vitamin D? Journal of Neuroimmunology. 2018.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk, Poland
tel.:+48 58 320 94 94, fax:+48 58 320 94 60, e-mail: viamedica@viamedica.pl