Vitamin D Deficiency as a Risk Factor for Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune neurological disorder that affects over 2 million people worldwide. Onset of the disease is thought to occur following exposure of genetically predisposed individuals to an unknown environmental trigger that activates myelin-specific T cells. These cells cross the blood-brain barrier to trigger an inflammatory attack that demyelinates axons in the central nervous system.1, 2, 3 Polymorphisms in the vitamin D receptor are among the genetic variations that increase the risk of MS. The incidence of MS is also elevated in northern climates, where vitamin D deficiency is common. Since exposure of the skin to ultraviolet light aids in the conversion of inactive vitamin D to the active form, 1,25(OH)2VitD3 (VitD3), the short days, low UV intensity, and lack of exposed skin common to winter months, decrease the amount of active VitD3 that can be produced.1, 2 Although the correlation between VitD3 deficiency and MS is intriguing, we are only now beginning to understand the biology that may explain this connection. In both human MS and in experimental autoimmune encephalomyelitis (EAE), the mouse model of the disease, VitD3 can influence specialized populations of cells that may play a critical role in protection against the disease. VitD3 promotes the formation of tolerogenic or "semi-mature" dendritic cells (DCs).2 These DCs induce the development of CD25FoxP3+/–IL-10++ Tr1 cells, a subset of regulatory T cells (Treg), and downregulate the production of Th1 inflammatory cells.1, 2, 3 A pair of interacting co-inhibitory proteins, B7-H1 (also known as PD-L1) and PD-1, appear to be critical molecules in this process.3

VitD3 Promotes the Differentiation of Immunosuppressive Regulatory T Cells.
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VitD3 Promotes the Differentiation of Immunosuppressive Regulatory T Cells. Upon stimulation of immature DCs, the presence of active VitD3 promotes the formation of tolerogenic, semi-mature DCs (smDCs), rather than mature DCs. These smDCs secrete IL-10 and show increased surface expression of the co-inhibitory molecule, B7-H1, which interacts with PD-1 on the surface of naïve CD4+ T cells. This interaction, aided by the presence of VitD3, promotes antigen-specific Tr1 regulatory T cell differentiation. The Tr1 cells suppress Th1 cell proliferation and production of inflammatory cytokines, such as IFN-gamma and IL-23. These and other regulatory T cells modulate the activity of inflammatory antigen-specific effector T cells (such as Th1) in the central nervous system that can promote demyelination. In multiple sclerosis, balance between the anti-inflammatory and inflammatory pathways is compromised.

Available data in humans support the hypothesis that VitD3 deficiency promotes a breakdown of B7-H1/PD-1 interactions between tolerogenic DCs and Tr1 cells. VitD3 stimulates Treg development, improves IL-10 production and Treg suppressive activity, and inhibits Th1 cell proliferation and inflammatory cytokine production in vitro.4, 5, 6 In blood or cerebrospinal fluid from MS patients during an acute phase of the disease, significantly fewer B7-H1+IL-10+ DCs, and reduced PD-1 expression on myelin basic protein antigen-specific T cells were found compared to samples from individuals with a stable form of the disease.7 In another study, IL-10 suppressive activity and Tr1 function were significantly impaired in patients with MS compared to control subjects.8 Several methods have been reported for producing "semi-mature" DCs that can induce Tr1 in vitro.9, 10 Intriguingly, methods that include VitD3 treatment result in high levels of B7-H1 expression on DCs, and these DCs promote antigen-specific Tr1-mediated tolerance.9

In EAE, it is established that prior treatment with VitD3 can prevent induction of the disease, while VitD3 given after the onset of EAE induces remission.2 Although a direct connection with VitD3 has not yet been made in the mouse, deletion or down-modulation of B7-H1 or PD-1 downregulates Treg suppressive activity, accelerates the establishment of EAE, and exacerbates its severity.11, 12 A B7-H1-Ig fusion protein alone can direct naïve mouse CD4+ T cells toward a Tr1-like phenotype, enhancing secretion of IL-10 and TGF-beta, and suppressing Th1 mixed lymphocyte reactions.13 Similarly, while
B7-H1–/– DCs minimally convert naïve CD4+ cells to Treg cells, beads coated with the B7-H1 protein enhance Treg production and suppressive activity.13

Other lines of evidence linking VitD3 to immune functions are also being pursued. For example, VitD3 appears to regulate expression of the pro-inflammatory molecule osteopontin and specific HLA-DR molecules, such as the HLA-DRB1*1501 allele associated with MS susceptibility.1 The association of VitD3 with cell types and mediators that are critical to immune suppression supports the idea that VitD3 deficiency may increase the risk of autoimmune disorders, such as MS.


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  14. Francisco, L. M. et al. (2009) J. Exp. Med. 206:3015.Reference uses R&D Systems products

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