Conformational Changes of Vitamin D Receptor as a Potential Cause of Multiple Sclerosis
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2019, Vol 13, Issue 4
Abstract
Multiple sclerosis (MS) is an autoimmune inflammatory disorder of unknown etiology affecting central nervous system (CNS)characterized by demyelination and variable degrees of axonal loss [1]. The etiology of MS is still unknown; however, it is believed to be caused by combination of immune dysregulation, genetic and environmental factors [2]. Recent studies have revealed severeal genes as risk factors including MHC HLA DR15/DQ6 allele being the strongest one, alleles of interleukin-2 receptor alpha gene (IL2RA) and interleukin-7 receptor alpha gene (IL7RA) have also been identified [3]. The pathogenesis of MS includes immune attack against CNS antigens through activation of CD4+ myelin-reactive T cells and a possible contribution by B cells [4]. Furthermore, there are some environmental factors related to increased risk of developing MS like Epstein-Barr virus (EBV) infection and vitamin D deficiency [5,6,7]. Prevalence of MS is increased in geographic areas further away from the equator [8]. This could be related to reduced sun exposure leading to vitamin D deficiency as a possible contributing factor [6,7].Also, studies have shown that higher levels of vitamin D could be protective in certain patient populations [9,10]. Recently, there is a growing number of studies showing how vitmin D deficiency is related to MS development. Approximately one billion people worldwide have vitamin D deficiency or insufficiency [11]. Vitamin D is a fat-soluble vitamin existing in two forms – ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3) which is more bioactive than vitamin D2. It can be consumed in food or synthesised in skin by sun exposure [12]. The vitamin D binding protein transports vitamin D3 to the liver where it is hydroxylated, this process results in the formation of 25-hydroxyvitamin D3 (25(OH)D3), the 25(OH)D3 metabolite is also hydroxylated by renal CYP27B1 to 1,25-dihydroxyvitamin D [1,25(OH)2D; calcitriol], the most bioactive vitamin D metabolite [13-15]. When calcitriol binds to the vitamin D receptor (VDR),it forms a nuclear heterodimer with the retinoid X receptor so this complex binds to genomic vitamin D response elements and downregulates expression of a variety of genes [16]. There are many binding patterns throughout heterodimerisation or overlaps of vitamin D responsive elements (VDREs) in the DNA [17]. Furthermore, it is considered that conformational changes between retinoid X receptor (RXR) and vitamin D receptor (VDR) through their heterodimerisation can activate different signaling pathways resulting in production of a large number of proteins involved in cell function [18]. It is known that MS is more prevalent in higher latitudes, where sunlight is of lower intensity and several studies found that increased body exposure to sunlight is also associated with a decreased risk of MS, especially if the sun exposure occurred during childhood and adolescence [19-21]. Recently, it is found that the birth month is correlated with MS risk; individuals born in the fall (whose mothers were exposed to summer sunlight) have a low MS risk, whereas individuals born in the spring have a higher risk of MS [22]. This could be a possible association between sunlight exposure during pregnancy, vitamin D status and the risk of MS, but it is still unknown if provocative factor for MS is vitamin D deficiency or reduced sunlight exposure by itself.
Authors and Affiliations
Miskic B, Cosc V, Rajkovaca I
Keywords
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- EP ID EP594734
- DOI 10.26717/BJSTR.2019.13.002426
- Views 140
- Downloads 0
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