Abstract
Vitamin D3 (cholecalciferol) is a secosteroid and prohormone which is metabolized in various tissues to the biologically most active vitamin D hormone 1,25(OH)2D3 (calcitriol). 1,25(OH)2D3 has multiple pleiotropic effects, particularly within the immune system, and is increasingly utilized not only within prophylaxis, but also within therapy of various diseases. In this context, the latest research has revealed clinical benefits of high dose vitamin D3 therapy in autoimmune diseases. The necessity of high doses of vitamin D3 for treatment success can be explained by the concept of an acquired form of vitamin D resistance. Its etiology is based on the one hand on polymorphisms within genes affecting the vitamin D system, causing susceptibility towards developing low vitamin D responsiveness and autoimmune diseases; on the other hand it is based on a blockade of vitamin D receptor signaling, e.g. through pathogen infections. In this paper, we review observational and mechanistic evidence for the acquired vitamin D resistance hypothesis. We particularly focus on its clinical confirmation from our experience of treating multiple sclerosis patients with the so-called Coimbra protocol, in which daily doses up to 1000 I.U. vitamin D3 per kg body weight can be administered safely. Parathyroid hormone levels in serum thereby provide the key information for finding the right dose. We argue that acquired vitamin D resistance provides a plausible pathomechanism for the development of autoimmune diseases, which could be treated using high-dose vitamin D3 therapy.
Highlights
Vitamin D is a secosteroid and prohormone which can be obtained from food, but whose main source is endogenous production in the skin
Vitamin D3 mainly binds to vitamin-D binding protein (DBP) and gets transported to the liver where it is transformed into its storage form calcidiol (25hydroxyvitamin D3 or 25(OH)D3) through hydroxylation via the vitamin D3 25-hydroxylases CYP2R1, CYP27A1 or CYP27B1, all members of the cytochrome P450 enzyme family [3, 4]. 25(OH) D3 is the main laboratory parameter to judge an individual’s vitamin D status; concentrations
The expression of the vitamin D receptor (VDR) as a gene regulatory protein in almost all tissues of the human body suggests functional roles well beyond those classically associated with calcium metabolism
Summary
Vitamin D is a secosteroid and prohormone which can be obtained from food (as either vitamin D2 or D3), but whose main source is endogenous production in the skin. Individuals being vitamin D resistant would require very high doses of vitamin D3 supplementation to achieve an adequate physiological response, such as a reduction of PTH concentrations or the down-regulation of an activated adaptive immune system – the latter effect is important for the treatment of autoimmune diseases as discussed further below. We propose the hypothesis that an interplay between acquired blockades of the VDR and polymorphisms affecting autoimmune disease susceptibility in either the VDR or other genes of the vitamin D system are able to cause a progressively severe form of low vitamin D responsiveness, which we refer to as acquired vitamin D resistance and which mediates the development of an autoimmune disease (Figure 2). Future research on the effects of environmental toxins such as aluminum and cadmium on the vitamin D system is urgently needed
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