Autoimmune disease and interconnections with vitamin D

Abstract

Vitamin D has well-documented effects on calcium homeostasis and bone metabolism but recent studies suggest a much broader role for this secosteroid in human health. Key components of the vitamin D system, notably the vitamin D receptor (VDR) and the vitamin D-activating enzyme (1α-hydroxylase), are present in a wide array of tissues, notably macrophages, dendritic cells and T lymphocytes (T cells) from the immune system. Thus, serum 25-hydroxyvitamin D (25D) can be converted to hormonal 1,25-dihydroxyvitamin D (1,25D) within immune cells, and then interact with VDR and promote transcriptional and epigenomic responses in the same or neighbouring cells. These intracrine and paracrine effects of 1,25D have been shown to drive antibacterial or antiviral innate responses, as well as to attenuate inflammatory T cell adaptive immunity. Beyond these mechanistic observations, association studies have reported the correlation between low serum 25D levels and the risk and severity of human immune disorders including autoimmune diseases such as inflammatory bowel disease, multiple sclerosis, type 1 diabetes and rheumatoid arthritis. The proposed explanation for this is that decreased availability of 25D compromises immune cell synthesis of 1,25D leading to impaired innate immunity and over-exuberant inflammatory adaptive immunity. The aim of the current review is to explore the mechanistic basis for immunomodulatory effects of 25D and 1,25D in greater detail with specific emphasis on how vitamin D-deficiency (low serum levels of 25D) may lead to dysregulation of macrophage, dendritic cell and T cell function and increase the risk of inflammatory autoimmune disease.

Keywords: T cell; autoimmune; dendritic cell; inflammation; vitamin D.

Figure 1

Vitamin D metabolism and the ‘vitamin D metabolome’. Schematic showing the synthesis of vitamin D (vitamin D3 and vitamin D2) and different subsequent metabolic pathways: synthesis of 25-hydroxyvitamin D (25D) from vitamin D by 25-hydroxylase (25-OHase); synthesis of 17-hydroxyvitamin D (17OHD), 20S-hydroxyvitamin D (20OHD), and 22-hydroxyvitamin D (22OHD) from vitamin D by the side-chain cleavage enzyme; synthesis of 1,25-dihydroxvitamin D (1,25D) from 25D by 1α-hydroxylase (1α-OHase); synthesis of 24,25-dihydroxvitamin D (24,25D) from 25D by 24-hydroxylase (24-OHase); synthesis of 1,24,25-trihydroxvitamin D (1,24,25D) from 25D by 24-OHase; synthesis of calcitroic acid from 1,24,25D by 24-OHase. 25D (and other vitamin D metabolites) can circulate bound to vitamin D-binding protein (DBP) or unbound (free 25D). Other prominent forms of 25D found in the circulation include 3epi-25D and sulphated and glucuronide forms of 25D. Intracrine synthesis of 1,25D from 25D in tissues such as the placenta, spleen (immune system) and lungs is associated with immunomodulatory effects. Endocrine synthesis of 1,25D in the kidneys is associated with mineral homeostasis and bone health.

Figure 2

Intracrine vs paracrine effects of vitamin D on helper and regulatory T cell function. Schematic showing the metabolism of 25-hydroxyvitamin D (25D) to active 1,25-dihydroxyvitamin D (1,25D) via 1α-hydroxylase (1α-OHase) activity in antigen-presenting cells such as dendritic cells and T helper (Th)1 cells. Serum transport of 25D by vitamin D-binding protein (DBP) may suppress cellular availability of 25D. Transcriptional response to 1,25D following binding to the vitamin D receptor (VDR) modulates antigen presentation through target molecules such as CD80 and CD86 to influence the activation of quiescent T helper (Th)0 cells to Th1, Th17 , Tfh and regulatory T cells (Treg). These T cell phenotypes require specific cytokines (shown next to arrows). Production of 1,25D by antigen-presenting cells may result in paracrine effects on adjacent VDR-expressing T cells leading to the down or up-regulation of specific T cell cytokines (shown next to the T cell sub-types). Production of 1,25D by Th1 cells may also result in intracrine effects to suppress inflammatory Th1 immunity.

Figure 3

Determinants of the impact of vitamin D on immune function. Schematic showing the diverse array of mechanisms that can influence the interaction between vitamin D and the immune system. The principal marker of vitamin D function continues to be serum levels of 25-hydroxyvitamin D (25D) as determined by exposure to UV light or dietary intake of vitamin D and liver activity of the enzyme 25-hydroxylase (25-OHase). However, vitamin D is also converted to alternative metabolites by the cholesterol side-chain cleavage enzyme. 25D can also circulate as epi or conjugated forms. Transport of vitamin D metabolites, particularly 25D, involves the vitamin D binding protein (DBP) which is essential for renal conversion of 25D to 1,25-dihydroxvitamin D (1,25D) by 1α-hydroxylase (1α-OHase). By contrast, acquisition of 25D by immune cells appears to involve free (unbound) 25D and subsequent 1α-OHase activity. In immune cells, the level of 1α-OHase expression, as well as expression of the vitamin D receptor (VDR) for 1,25D may be defined by various regulators of immune cell function including bacteria, viruses, complement and other immune cells. Collectively, these factors, along with catabolic activity of enzymes such as 24-hydroxylase act to enhance or attenuate the central effects of serum 25D in driving innate and adaptive immune responses. Text boxes on each side (dashed lines) describe the different mechanisms that modify the core effects of altered serum 25D levels.