Brain Advance Access published online on March 24, 2009
Brain, doi:10.1093/brain/awp033
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Immunomodulatory effects of Vitamin D in multiple sclerosis
Department of Neurology, Institute for Neurological Research Dr. Raúl Carrea, FLENI, Buenos Aires, Argentina
Correspondence to:
Jorge Correale, MD, Raúl Carrea Institute for Neurological Research, FLENI, Montañeses 2325, (1428) Buenos Aires, Argentina E-mail: jcorreale{at}fleni.org.ar; bairesla{at}fibertel.com.ar
Although Vitamin D is best known as a modulator of calcium homeostasis, it also has immune modulating potential. A protective effect of Vitamin D on multiple sclerosis is supported by the reduced risk associated with sun exposure and use of Vitamin D supplements. Moreover, high circulating levels of Vitamin D have been associated with lower risk of multiple sclerosis. In this study, we measured 1,25 (OH)2 Vitamin D and 25 (OH) Vitamin D levels in multiple sclerosis patients separated into different clinical subgroups according to disease status. In addition, direct effects of 1,25 (OH)2 Vitamin D on ex vivo CD4+ T cells and myelin-peptide specific T cell lines were investigated to gain more insight into putative regulatory mechanisms in the disease pathogenesis. One hundred and thirty-two Hispanic patients with clinically definite multiple sclerosis were studied, 58 with relapsing remitting multiple sclerosis during remission, 34 during relapse and 40 primary progressive multiple sclerosis cases. Sixty healthy individuals matched with respect to place of residence, race/ethnicity, age and gender served as controls. Levels of 25(OH)D3 and 1,25(OH)2D3, measured by ELISA were significantly lower in relapsing–remitting patients than in controls. In addition, levels in patients suffering relapse were lower than during remissions. In contrast, primary progressive patients showed similar values to controls. Proliferation of both freshly isolated CD4+ T cells and MBP-specific T cells was significantly inhibited by 1,25(OH)2D3. Moreover, activated Vitamin D enhanced the development of IL-10 producing cells, and reduced the number of IL-6 and IL-17 secreting cells. Notably, Vitamin D receptor expression was induced by 1,25(OH)2D3 in both activated and resting cells. Interestingly, T cells were able to metabolize 25(OH)D3 into biologically active 1,25(OH)2D3, since T cells express 
1-hydroxylase constitutively. Finally, 1,25(OH)2D3 also increased the expression and biological activity of indoleamine 2,3-dioxygenase, mediating significant increase in the number of CD4+CD25+ T regulatory cells. Collectively, these data suggest that 1,25(OH)2D3 plays an important role in T cell homeostasis during the course of multiple sclerosis, thus making correction of its deficiency may be useful during treatment of the disease.
Key Words: multiple sclerosis; vitamin D; T cells; cytokines; regulatory T cells
Abbreviations: Ag, Antigen; EAE, experimental allergic encephalomyelitis; IDO, indoleamine 2,3-dioxygenase; PBMC, peripheral blood mononuclear cells
Received July 22, 2008. Revised December 29, 2008. Accepted January 22, 2009.