Multiple Sclerosis is a disease caused by degradation of the myelin sheath. The definite cause and mechanism of Multiple Sclerosis are unknown, but vitamin D deficiency is recognized as one of the risk factors of Multiple Sclerosis based on geographic research. The studies suggested that as the latitude increases, the amount of sunlight exposure decreases, the levels of vitamin D synthesized by sunlight are lowered, and thus the Multiple Sclerosis risk increases . Based on this idea, several studies determined that Multiple Sclerosis patients present lower serum levels of vitamin D compared to controls . Lower levels of vitamin D also increase the relapse rate of Multiple Sclerosis . Possible explanations of this association are mainly related to signaling pathways of vitamin D and expression of vitamin D involved genes [31-32]. Several pieces of research were conducted to develop vitamin D-based treatment of Multiple Sclerosis, but the statistical results of the research were not significant. Therefore, this paper provides future research directions for using vitamin D in the treatment of Multiple Sclerosis.
Multiple Sclerosis (MS) is a nervous system disease that causes demyelination, which damages the myelin sheath, a whitish insulating sheath that wraps around axons to speed up neuron impulses. Although the myelin sheath can regenerate, it is hard for MS patients to fully recover their myelin sheath since the rate of destruction is much greater than the rate of regeneration. As the myelin sheath degrades, the transmission of electrical impulses is reduced, which in turn speeds down or blocks the signals between body and brain. The blockage of signals later leads to shrinkage of the brain cortex. MS is not only a neurodegenerative disease, but also an autoimmune disease.
Multiple Sclerosis is classified into four types: Relapse-remitting MS (RRMS), Primary progressive MS (PPMS), Secondary progressive MS (SPMS), and Progressive-relapsing MS (PRMS). RRMS, the most common form, afflicts about 85 percent of MS patients. Patients with RRMS experience relapses--the period in which symptoms flare--and remissions--the periods of partial or complete recovery. Unlike RRMS, PPMS does not have relapses or remissions and is characterized by disability in legs in an early stage. SPMS is a second stage of MS after experiencing initial relapses and remissions. PRMS is the least common type of MS and the symptoms get worse as relapses proceed .
Over 2.3 million people in the world are classified as MS patients and the number of patients increases every year . Multiple Sclerosis occurs at every age, but predominantly among people between 20 and 40 years old . Generally, MS affects approximately twice as many women as men [4-7]. The reason for this gap is unknown, but one possible explanation is that female MS patients have more variation in a protein called interferon-γ, which can accelerate inflammation . Patients commonly show the following symptoms: sensory loss (paresthesias), motor spinal cord symptoms (numbness or weakness in one or more limbs), autonomic spinal cord symptoms (bladder, bowel, and sexual dysfunction), cerebellar symptoms (dysarthria, ataxia, and tremor), optic neuritis (partial or complete loss of central vision), other eye symptoms (blurred or doubled vision), trigeminal neuralgia, facial myokymia, heat intolerance, fatigue, dizziness, lack of sleep, pain, subjective cognitive difficulties, and depression .
The mechanism and definite cause of MS are still unknown and thus there is no effective cure. The concordance rate of monozygotic twins for MS is only 20-35% . This result can be interpreted as genetic factors do not significantly contribute to the outbreak of MS, but non-Mendelian and environmental factors play an important role. Different risk factors of MS other than genetic factor are Epstein-Barr virus infection, disruption of peroxisome proliferator-activated receptors, geography, smoking behavior, and vitamin D deficiency [11-14]. Among these risk factors, this paper will suggest that there is an association between the risk of MS and deficiency of vitamin D and provide the direction for further study.
The biological role of Vitamin D
Vitamin D is a lipid-soluble vitamin but acts like a hormone. The vitamin D levels in the body are represented by concentrations of molecule 25(OH)D3. 25(OH)D3 represents the concentration of vitamin D because it has the longer half-life than the most active form of vitamin D: 1,25(OH)2D3 . The deficiency level of vitamin D is 25(OH)D3 <50 nmol/L . The naturally occurring form of vitamin D, such as D2-ergocalciferol and D3-cholecalciferol, is inactive and requires hydroxylation to become activated . Human body can accumulate vitamin D from food, but the main source of vitamin D is sunlight. When vitamin D in the skin--D2-ergocalciferol and D3-cholecalciferol--exposed to ultraviolet B (UV-B) rays from the sun, it is converted to pre-vitamin D3 and then converted to vitamin D3 by isomerization, a change in atomic array based on same atomic composition .
Vitamin D primarily maintains calcium homeostasis by controlling the number of minerals in the blood. Vitamin D also regulates the production of type 1 and type 2 helper T-cell cytokines, which prevents immunological disorder by balancing between protection and immunopathology . Other than that, it plays a key role in cellular growth, proliferation, differentiation, apoptosis, DNA repair, oxidative stress, membrane transport and adhesion [18, 21-23]. Vitamin D controls gene expression through signaling pathways, with Vitamin D Receptors (VDR) playing a crucial role. As vitamin D binds to VDR, VDR becomes activated. VDR forms a heterodimer with the retinoid-X receptor (RXR) and binds to vitamin D response elements (VDRE) in a gene to express the gene. These steps allow the regulation of cellular activities of vitamin D-related genes including immune response, so it can control the outbreak of diseases .
Vitamin D and Multiple Sclerosis risk
Recent studies show the incidence of the MS is lower in the equatorial regions of the world than in the southernmost and northernmost regions . Since vitamin D is synthesized by sunlight, it is evident that decreased amount of sunlight exposure leads to reduced levels of vitamin D and thus higher MS risk. Another study suggests a correlation between season of birth and MS risk. The season when the mother was pregnant affects the mother’s amount of exposure to sunlight, vitamin D levels, and MS susceptibility . Several studies found out that MS patients have lower serum levels of vitamin D compared to control. One study found that an increase of 25(OH)D levels by 50% reduced the chance of MS by approximately 50% . Research by the Network of Pediatric Multiple Sclerosis Centers on US and Sweden population concluded that genetic risk scores showed association between low 25(OH)D levels and pediatric-onset MS . Randomized double-blind control study on 40 MS patients between 18 and 55 years provided them either a high dose (260 mcg) or low dose (20 mcg) daily for 6 months, proving vitamin D controls the immune system in MS since the higher dose of vitamin D reduced the production of key molecules of MS, interleukin (IL)-17 and effector memory CD4+ T cells . Not only that, levels of vitamin D also affect the MS relapse rate. Patients with higher levels of vitamin D showed a lower relapse rate while patients with lower levels of vitamin D showed a higher disability rate .
Several studies identified the effect of vitamin D on the signaling pathway. Human body stabilizes the low resting state of the redox and Ca(2+) signaling pathway with vitamin D. Vitamin D maintains redox and Ca(2+) signaling pathways by increasing the expression of nuclear factor-erythroid-2-related factor 2 (Nrf2) and klotho--the major regulators of those signaling . As vitamin D level decreases, the stability of regulatory signaling network declines. Therefore, deficiency of vitamin D leads to attenuation of cell signaling pathways including myelin synthesis pathway . Genetic studies found out that four MS risk-associated single-nucleotide polymorphisms (SNPs) that are located in or near genes are associated with vitamin D metabolism . The gene (CYP27B1) encoding enzyme for vitamin D gene activation is identified as the risk of MS . The presence of VDR-binding sites in the promoter region of the MS susceptibility gene, HLA-DRB1, is another evidence for an association between vitamin D and MS .
Current Vitamin D related treatment of Multiple Sclerosis
Recent studies support an association between vitamin D and risk of MS, but vitamin D does not work as an effective treatment. Randomized, double-blind and placebo-controlled studies discovered using 500 mcg vitamin D3 per week reduced the number of lesions on brain MRI but was not powerful enough for clinical parameters of disease activity [36, 37]. Another double-blind placebo-controlled study provided participants with RRMS 25 mcg capsules of vitamin D2 every day, while randomly selected participants received an additional 150 mcg capsules for 6 months . But there is no significant result that high-dose of vitamin D2 is effective than low-dose of vitamin D2 for RRMS patients. Adding 350 mcg vitamin D3 to interferon beta in 229 RRMS patients reduced the active MRI lesions by 32%, but a 30% relapse rate reduction was not statistically significant result .
Discussion and Conclusion
Knowledge of Multiple Sclerosis is extremely limited. Unlike manydiseases, MS does not have significant genetic factors; rather, the environment and non-Mendelian factors are more likely to affect its outbreak. Among these risk factors, vitamin D is the only factor that does not only affect a certain population, but the entire human population. Therefore, it is important to prove the association between vitamin D deficiency and susceptibility to MS and develop a treatment based on it.
The difference in the incidence of MS by latitude leads studies to suggest a relationship between sunlight and MS, and moreover, a relationship between the amount of vitamin D and MS. Several current pieces of research point out that vitamin D deficiency can work as the risk factor of MS. However, it is not yet known whether a lack of vitamin D is the direct cause of MS and a clear mechanism of how vitamin D work as a risk factor of MS. It is also unknown whether vitamin D control the expression of MS independently or control with various factors. Therefore, developing medicine using vitamin D is processing slowly.
In order to develop vitamin D as a medication, further study should be conducted on the following factors: how to use the function of vitamin D as an immunomodulator, how much dosage is proper to improve MS, when the patients should get the treatment, and what will be the results and side effects of using vitamin D as treatment? Fundamentally, an analysis of the overall mechanism and main cause of MS is urgent.
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