Immunomodulatory effects of Vitamin D in multiple sclerosis

摘要

Although Vitamin D is best known as a modulator of calcium homeostasis, it also has immune modulating potential. A pro-ntective effect of Vitamin D on multiple sclerosis is supported by the reduced risk associated with sun exposure and use ofnVitamin D supplements. Moreover, high circulating levels of Vitamin D have been associated with lower risk of multiplensclerosis. In this study, we measured 1,25 (OH)2 Vitamin D and 25 (OH) Vitamin D levels in multiple sclerosis patientsnseparated into different clinical subgroups according to disease status. In addition, direct effects of 1,25 (OH)2 Vitamin D onnex vivo CD4+ T cells and myelin-peptide specific T cell lines were investigated to gain more insight into putative regulatorynmechanisms in the disease pathogenesis. One hundred and thirty-two Hispanic patients with clinically definite multiple sclerosisnwere studied, 58 with relapsing remitting multiple sclerosis during remission, 34 during relapse and 40 primary progressivenmultiple sclerosis cases. Sixty healthy individuals matched with respect to place of residence, race/ethnicity, age and gendernserved as controls. Levels of 25(OH)D3 and 1,25(OH)2D3, measured by ELISA were significantly lower in relapsing–remittingnpatients than in controls. In addition, levels in patients suffering relapse were lower than during remissions. In contrast, primarynprogressive patients showed similar values to controls. Proliferation of both freshly isolated CD4+ T cells and MBP-specificnT cells was significantly inhibited by 1,25(OH)2D3. Moreover, activated Vitamin D enhanced the development of IL-10 pro-nducing cells, and reduced the number of IL-6 and IL-17 secreting cells. Notably, Vitamin D receptor expression was inducednby 1,25(OH)2D3 in both activated and resting cells. Interestingly, T cells were able to metabolize 25(OH)D3 into biologicallynactive 1,25(OH)2D3, since T cells express a1-hydroxylase constitutively. Finally, 1,25(OH)2D3 also increased the expressionnand biological activity of indoleamine 2,3-dioxygenase, mediating significant increase in the number of CD4+CD25+ T regu-nlatory cells. Collectively, these data suggest that 1,25(OH)2D3 plays an important role in T cell homeostasis during the coursenof multiple sclerosis, thus making correction of its deficiency may be useful during treatment of the disease.