The Implication of Vitamin D and Autoimmunity: a Comprehensive Review

October 2013
Chen-Yen Yang, Patrick S. C. Leung, Iannis E. Adamopoulos, and M. Eric Gershwin

Abstract

Historically, vitamin D has been associated with the regulation of bone metabolism. However, increasing evidence demonstrates a strong association between vitamin D signaling and many biological processes that regulate immune responses.

The discovery of the vitamin D receptor in multiple immune cell lineages, such as monocytes, dendritic cells, and activated T cells credits vitamin D with a novel role in modulating immunological functions and its subsequent role in the development or prevention of autoimmune diseases.

In this review we, discuss five major areas in vitamin D biology of high immunological significance: (1) the metabolism of vitamin D; (2) the significance of vitamin D receptor polymorphisms in autoimmune diseases, such as multiple sclerosis, type 1 diabetes mellitus, and systemic lupus erythematosus; (3) vitamin D receptor transcriptional regulation of immune cell lineages, including Th1, Th17, Th2, regulatory T, and natural killer T cells; (4) the prevalence of vitamin D insufficiency/deficiency in patients with multiple sclerosis, type 1 diabetes mellitus, and systemic lupus erythematosus; and finally, (5) the therapeutic effects of vitamin D supplementation on disease severity and progression.

Keywords: Vitamin D, Autoimmunity, Multiple sclerosis, Type 1 diabetes mellitus, Systemic lupus erythematosus

Introduction

Vitamin D deficiency is an increasingly described phenomenon worldwide [1]. Compelling evidence from human disease associations and basic physiological studies demonstrated the significance of vitamin D deficiency in various physiological disorders including neuropathy [2], malignancy [3, 4], infertility [5], cardiovascular diseases [6, 7], kidney diseases [8], glucose metabolism [9], and immunological dysfunctions [10–13]. Vitamin D was first identified as a nutritional regimen for rickets in the early twentieth century and was broadly defined as a compound with curative effects on rickets.

Chemically, vitamin D is the derivative of a steroid, 7-dehydrocholesterol, derived from cholesterol and is found in the sebaceous glands of the skin of animals. Upon exposure to sunlight, 7-dehydrocholesterol will absorb UVB light (~280 to 315 nm) and convert to precalciferol (also called previtamin D3) in the skin. Much of the precalciferol eventually is isomerized into cholecalciferol (also called vitamin D3) through thermal conversion [14].

Since sunlight is necessary for photosynthesis of previtamin D3 in human skin, vitamin D is also commonly called “sunshine vitamin” (Fig. 1). In addition to 7-dehydrocholesterol in animals, ergosterol is another commonly occurring steroid in plants that can be activated by irradiation to produce ergocalciferol (also called vitamin D2).

Both vitamin D3 formed in the skin and vitamin D3 absorbed from the digestive tract, travel to the liver, where they are hydroxylated at carbon 25 to form clacidiol (also called 25-hydroxy vitamin D3, abbreviated as 25(OH)D) by liver 25-hydroxylase, CYP2R1 and CYP27A1. 25(OH)D is the major circulating vitamin D metabolite and a reliable indicator of vitamin D status. Following the hydroxylation in liver, calcidiol is further hydroxylated by 1-α-hydroxylase, CYP27B1, in the proximal convoluted tubule cells of kidney, forming calcitriol (also called 1,25-dihydroxy vitamin D3, abbreviated as 1,25(OH)2D) which is considered the active form of vitamin D [15] (Fig. 1).

At the cellular level, 1,25(OH)2D interacts with nuclear vitamin D3 receptor (VDR), which belongs to the superfamily of nuclear hormone receptors, to modulate gene transcription. Ligand binding initiates a conformational change that increases the receptor’s affinity to the retinoid X receptor (RXR). Once the VDR-1,25(OH)2D complex is heterodimerized with RXR, this complex will bind to vitamin D3 response elements (VDREs) and recruit a number of nuclear coactivator or corepressor proteins. The transcription of genes for specific mRNA may be ultimately either enhanced or inhibited by this ligand-activated transcription factor [16] (Fig. 2).