A Brief Review of the Effects of Vitamin D on Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is characterized as an autoimmune disease affecting the central nervous system. It is one of the most common neurological disorders in young adults. Over the past decades, increasing evidence suggested that hypovitaminosis D is a contributing factor to the risk of developing MS. From different risk factors contributing to the development of MS, vitamin D status is of particular interest since it is not only a modifiable risk factor but is also associated with MS disease activity. MS patients with lower serum vitamin D concentrations were shown to have higher disease activity. However, this finding does not demonstrate causality. In this regard, prospective vitamin D supplementation studies missed statistical significance in its primary endpoints but showed promising results in secondary outcome measures or post hoc analyses. An explanation for missed primary endpoints may be underpowered trials. Besides vitamin D supplementation as a potential add-on to long-term immunotherapeutic treatment, a recent laboratory study of our group pointed toward a beneficial effect of vitamin D to improve the efficacy of glucocorticoids in relapse therapy. In the following article, we will briefly review the effects of vitamin D on MS by outlining its effects on the immune and nervous system and by reviewing the association between vitamin D and MS risk as well as MS disease activity. We will also review the effects of vitamin D supplementation on MS risk and MS disease activity.

Keywords: MS risk; calcitriol; cholecalciferol; disease activity; guidelines; innate adaptive immune system; metabolism; nervous system.

FIGURE 1

Vitamin D₃ metabolism and its effects on cells of the immune and nervous system. 80–90% of the body’s vitamin D supply is produced by the skin’s exposure to UVB radiation and 10–20% is acquired through diet (7). Fatty fish contain high amounts of vitamin D₃ (cholecalciferol) (8). In the skin, the vitamin D₃ precursor 7-dehydrocholesterol converts to previtamin D₃ after UVB exposure (10, 11). Previtamin D₃ then isomerizes to cholecalciferol (10, 11). This physiologically inactive form of vitamin D₃ is hydroxylated in the liver to 25(OH)D₃ by CYP2R1 (13). It is then hydroxylated by the enzyme CYP27B1 in the kidneys or at inflammatory sites by immune cells such as DCs and macrophages, resulting in the fully-active metabolite 1,25(OH)₂D₃ (12, 14). In target cells, 1,25(OH)₂D₃ binds to the VDR, thereafter forming a complex with the RXR-γ (15, 16). The 1,25(OH)₂D₃-VDR-RXR-γ complex binds certain DNA sequences (VDREs), thereby modulating gene transcription (–17). 1,25(OH)₂D₃ increases the production of antimicrobial peptides from macrophages, while in the DC line it inhibits (I) monocyte differentiation into DCs, (II) DC maturation, (III) production of pro-inflammatory cytokine IL-12, (IV) MHC class II expression, (V) and antigen presentation (, , –55). DCs are induced to undergo apoptosis (55). 1,25(OH)₂D₃ increases (I) T cell apoptosis, (II) anti-inflammatory cytokine production, (III) Treg cell differentiation, and (IV) the proportion of central memory CD4 + T cells (–58, 67, 77, 78). In addition, it decreases (I) pro-inflammatory cytokine production, (II) T cell proliferation, (III) Th1, Th2, and Th17 cell differentiation, (IV) the proportion of effector memory CD4 + T cells, and (V) T cell trafficking into the CNS (–57, 67, 78, 88). In B cells, 1,25(OH)₂D₃ increases apoptosis and reduces proliferation, differentiation and antibody production (, –61). 1,25(OH)₂D₃ increases regulation of calcium uptake in neurons and phagocytic activity in microglia but reduces iNOS expression in microglia (97, 98). Lastly, 1,25(OH)₂D₃ stimulates oligodendrocyte maturation and astrocyte activation (99). Abbreviations: CYP2R1, vitamin D₃ 25-hydroxylase; CYP27B1, 25(OH)D₃-1α-hydroxylase; DC, dendritic cell; iNOS, inducible nitric acid synthase; MHC, major histocompatibility complex; RXR, retinoid x receptor; UVB, ultraviolet B; VDR, vitamin D receptor; VDREs, vitamin D response elements; 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D₃; 25(OH)D₃, 25-hydroxyvitamin D₃. This figure was created using Servier Medical Art templates licensed under a Creative Commons License (https://creativecommons.org/licenses/by/3.0/).