The Role of Vitamin D in the Pathogenesis of Multiple Sclerosis
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS of unknown aetiology. Although a genetic susceptibility is well known, there are still many undefined environmental risk factors that are probably involved: apart from viral infections and variations in food intake, environmental supplies of vitamin D have been proposed, for the geographical, biological and immunological evidence, as a risk factor for developing MS.
Although vitamin D is known as a molecule involved in the calcium homeostasis, it also has strong immune modulating potential. If we consider MS as an autoimmune disorder, the connection with the beneficial immune modulating effect of vitamin D is logical and it has been investigate in vitro, in experimental allergic encephalomyelitis, and in vivo, in MS patients.
Background on Vitamin D
Source and metabolism
The primary form of vitamin D, colecalciferol (vitamin D3), is available from two sources: skin exposure to UVB radiation in sunlight and diet. UVB photolyses 7-dehydrocholesterol in the skin to form pre-vitamin D3, which then isomerises to colecalciferol.
Colecalciferol (and ergocalciferol [vitamin D2]) is also available from fortified foods (milk, cereal...), dark fish (salmon and tuna) and vitamin supplements.
Both forms of vitamin D, colecalciferol and ergocalciferol, are biologically inactive and are enzymatically converted in the liver to 25-hydroxyvitamin D. The hydroxylations are performed by two P450 enzymes (25-hydroxylase and 1-alpha-hydroxylase, respectively). This molecule then undergoes a second hydroxylation in the kidney to give the active form, 1,25-dihydroxyvitamin D (also known as calcitriol if derived from vitamin D3), which binds and activates the vitamin D receptor (VDR), a transcription factor that regulates the expression of almost 500 genes. The VDR is also present in cell membranes, where it mediates some of the rapid response to 1,25-dihydroxyvitamin D. After hetero-dimerisation with nuclear receptors of the retinoic X receptor (RXR) family, the VDR and its ligand bind to VDRE.
Plasma calcium levels are regulated by PTH and 1,25-dihydroxy vitamin D, which have to be in balance to achieve a good regulation of the cellular uptake and renal retention of calcium.
Vitamin D and its metabolites are transported through the circulation in complex with the serum globulin Vitamin D- binding protein. Excessive amounts of vitamin D metabolites are catalysed by 24-hydroxylase and excreted by the kidneys in the form of calcitroic acid.
Non-calcaemic effects
Although the best-known role of vitamin D is to regulate the calcium homeostasis, it has also important effects on cell proliferation and apoptosis, brain development and function, regulation of blood pressure and insulin secretion, and on the differentiation of immune cells and modulation of immune responses.
Vitamin D and T cells
The receptor for vitamin D is present in multiple cell of immune system. The presence of the VDR in the thymus and the peripheral T cells suggests a role for 1,25dihydroxyvitamin D in function and development of T cells. 1,25dihydroxyvitamin D increases both regulatory T cells and IL-4 production by Th2 cells. Physiologically the VDR is required to maintain a balance in the response of T cell and it has been demonstrated that Th2 are diminished in absence of VDR. Because of this, it is now clear that normal cell function and the prevention of autoimmune disease require vitamin D and signaling via VDR.
Vitamin D and its role in immunology: multiple sclerosis, and inflammatory bowel disease.2006
Immunomodulatory effects of Vitamin D in multiple sclerosis.2009
Vitamin D in the CNS
It is now established that many tissues, including the brain, express vitamin D 1-alpa-hydroxylase. Moreover, vitamin D receptors (VDRs) are widely distribuited thoughout the brain. VDRE can located upstream from genes coding for Brain Derived Neurotrophic Factor (BDNF), Nerve Growth Factor (NGF) and Neurotrophin3 (NT3). As a result, vitamin D regulates the expression of NGF, NT3 and NT4 and Glial cell line-Derived Neurotrophic Factor (GDNF).
It is established that the VDR is present in both oligodendrocytes and Schwann cells.
Vitamin D is most abundant as its metabolite 25(OH)D. The 99% of the vitamin D metabolites is tightly bound to vitamin D binding protein, which is a protein synthesized in the liver. The gene of DBP is located on the same chromosome of albumin and these two proteins are structurally closely related. Therefore, the passage of DBP through the BBB is presumably limited like the one of the albumin. There are several mechanism by which circulating 25(OH)D and 1,25-dihydroxy vitamin D could theoretically access the CNS in healthy individuals. The “free hormone hypothesis” postulates that binding proteins in the circulation keep steroids in a biologically inactive state and regulate the circulating concentration of free hormones which can enter calls by diffusion. According to this hypothesis there would be only a very limited amount of vitamin D metabolites available for entering the CNS. This model seems unlikely as exclusive transport mechanism, since substantial amounts of DBP are found in the cerebral spinal fluid of healthy subjects. Because of this, an active transport of vitamin D metabolites through the BBB has been postulated. Specific transport mechanism have been described for the transportation of the vitamin D metabolite-DBP-complex is dependent on the molecules Megalin and Cubulin at the luminal side of the proximal tubuli.
Probable role in receptor-mediated transport of apolipoprotein J alone and in a complex with Alzheimer disease amyloid beta at the blood-brain and blood-cerebrospinal fluid barriers.1996
Therefore, megalin dependent transport in the choroid plexus could be important for the crossing of vit D-DBP complex through the blood-CSF barrier.
The role of vitamin D in the brain cells includes regolating proliferation and apoptosis, blood pressure and inflammation but the activation of these several pathways depends on the type of cell: in vitro studies, in fact, revealed that vitamin D has different roles if it works, for example, on dorsial root ganglia or Schwann cells.
Cholecalciferol (Vitamin D3) Improves Myelination and Recovery after Nerve Injury.2013
Although vitamin D metabolite levels seem to be low in the CNS in physiological condition, the global expression in the nervous system of VDR and CYP27B1, abundant in specific regions including sub stantia nigra and hypothalamus, suggest that it is likely that vitamin D has a biological role in the homeostasis of the healthy CNS.
It seems that vitamin D metabolism in the nervous system is responsive to inflammation: in particolare either LPS or IFNγ induces increate synthesis of 1,25(OH)2 D in the microglia. This upregulates cytochrome P24A1. Expression of the VDR is also enhanced.
Vitamin D and pathogenesis of MS
Since 25(OH)D is present (and activated) in the CNS o MS patients, and the receptors are expressed in several cells, it may exert local effects on key components of MS pathology: infammation, demyelination, axonal damage, and remyelination.
Vitamin D seems to protect form local demyelination and seems to be involved in several mechanisms that prevent axonal damage such as the induction of neuroprotective agents (like neurotrophins), expression of neurotrophic growth factor, upregulation of MAP-2 and GAP43.
Inflammation
In the CNS, antigen presentation via MHC class II molecules is reduced by vitamin D like it happens in peripheral antigen presenting cells. Exposure to vitamin D also reduces proliferation and pro-inflammatory cytokine release in CD4+ and CD8+ cells. B cells, instead, increase their production of IL10 (anti-inflammatory cytokine). So it seems that vitamin D exposure may shift the leucocytes towards and anti-inflammatory phenotype. On the microglia vitamin D has been proved to reduce TNF-α and IL-6 production.
Vitamin D in the healthy and inflamed central nervous system: access and function.2011
Vitamin D and MS risk
Strong evidence that directly supports the hypothesis that vitamin D is able to modulate disease in MS is lacking. However, a lot of clinical observations were made in MS populations that support a role for vitamin D in MS. These include associations with plasma 25(OH)D levels, the geographic
distribution of MS prevalence, the low bone mass density found in MS patients, the seasonal fluctuation of plasma 25(OH)D, MS disease parameters and MS births, the clinical remission of disease during pregnancy and the associations of various genetic polymorphisms of the VDR with MS.
Serum 25-hydroxyvitamin D
If vitamin D had any effect on MS risk we would expect MS incidence to decrease with increasing 25-hidroxyvitamin D concentrations. One study, based on 25-OH vitamin D concentrations before the onset of MS, concluded that serum concentration in healthy young adults is an important predictor of their risk of developing MS, independently from other aspects.
Serum vitamin D and multiple sclerosis risk.2005
Sun exposure
The effect of sun exposure on vitamin D synthesis depends on many factors, including some that are difficult to assess retrospectively (clothing, use of sunscreen...). Therefore, the correlation between recalled duration of sun exposure and 25-OH vitamin D is usually modest.
If sun exposure were to decrease risk, MS should be less common than expected among individuals with outdoor occupations. However, the connection between outdoor occupation and MS seems to be confounded by the heat-related fatigue and the intensity of sunlight.
Month of birth
Month of birth has been suggested as a factor that affects MS risk. In fact, it seems that prenatal exposures or exposures in the first months of life could be important in MS aetiology, but the link with vitamin D is still unclear.
However, this is not the only aspect that has to be considered about the prenatal and early life: in fact, also the maternal milk and the vitamin D intake during pregnancy has been demonstrated to be related with MS risk in the offspring.2012
Obesity
Obesity is associated with lower serum 25-hydroxyvitamin D concentrations. The difference in the .serum might be notable if it occurs during an aetiologically relevant period. The relation between BMI and MS risk has been examined in one study in which obesity at age 18 years conferred a two times higher risk of developing MS.
Genetic factors
Genes can influence circulating vit D concentration by affecting metabolism, skin colour and behavior. Genetic variations in VDR and other genes might influence the effect of vitamin D on the immune system. Therefore, genetic variations in vitaminD-related-genes might also affect the risk of developing MS. However, little is known about the role of vitamin D- related genes or genetics interactions in the onset of MS.
If vitamin D had a role in MS aetiology, functional variations in genes in the vitamin D path way would be expected to influence MS risk. The most important (and studied) gene is VDR, but the connection between its polymorphisms and MS is inconsistent, although this can be related to differences in environmental exposures.
Vitamin D and multiple sclerosis
Vitamin D and MS activity and progression
Many patients with MS have deficient of insufficient vitamin D concentrations. In addition, serum 25-hydroxyvitamin D concentrations in patients with MS are lower during MS relapses than during remissions had correlate inversely with disease severity. Even a modest systematic effect of an MS relapse on 25-kydroxyvitamin D concentrations could be sufficient to induce a spurious inverse correlation between vitamin D and disease activity. The result of some studies support an increase in MS relapses during the months when vitamin D concentrations are at their lowest.
Other studies of patients with MS or individuals presenting with a first demyelinating episode are thus needed to strengthen and refine the hypothesis in terms of the amount of vitamin D required for optimum protection and the identification of patients who are most likely to benefit from supplementation.
Conclusion
Vitamin D supplementation in healthy individuals is emerging as a promising approach for MS prevention. In uterus and early-life exposure could also be important, but there is strong evidence that vitamin D concentrations during late adolescence and young adulthood have a major effect in determining MS risk. Whereas future observational epidemiological studies, and genetic and molecular investigations, will be useful to strengthen and refine the hypothesis, evidence is approaching equipoise, at which the soundest decision might be to do a large randomized trial to establish the safety and efficacy needed to promote large-scale vitamin D supplementation.
Evidence supporting a therapeutic effect of vitamin D in modifying the course of MS is less compelling than evidence of a preventive effect. However, given the safety of high doses of vitamin D, there is sufficient evidence to support the need for large randomized trials to determine whether
vitamin D supplementation could delay the time to progress from a first demyelinating episode to MS or to MS treatment.
Furthermore, screening of serum 25-hydroxyvitamin D concentrations is likely to identify a large proportion of patients who are vitamin D deficient or insufficient, who might benefit from vitamin D supplementation for prevention of osteoporosis and other common disease.
Vitamin D as an immune modulator in multiple sclerosis.2008
