Vitamin D, Autoimmune Disease and Rheumatoid Arthritis

Abstract

Vitamin D has been reported to influence physiological systems that extend far beyond its established functions in calcium and bone homeostasis. Prominent amongst these are the potent immunomodulatory effects of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25-(OH)₂D3). The nuclear vitamin D receptor (VDR) for 1,25-(OH)₂D3 is expressed by many cells within the immune system and resulting effects include modulation of T cell phenotype to suppress pro-inflammatory Th1 and Th17 CD4+ T cells and promote tolerogenic regulatory T cells. In addition, antigen-presenting cells have been shown to express the enzyme 1α-hydroxylase that converts precursor 25-hydroxyvitamin D3 (25-OHD3) to 1,25-(OH)₂D3, so that immune microenvironments are able to both activate and respond to vitamin D. As a consequence of this local, intracrine, system, immune responses may vary according to the availability of 25-OHD3, and vitamin D deficiency has been linked to various autoimmune disorders including rheumatoid arthritis (RA). The aim of this review is to explore the immune activities of vitamin D that impact autoimmune disease, with specific reference to RA. As well as outlining the mechanisms linking vitamin D with autoimmune disease, the review will also describe the different studies that have linked vitamin D status to RA, and the current supplementation studies that have explored the potential benefits of vitamin D for prevention or treatment of RA. The overall aim of the review is to provide a fresh perspective on the potential role of vitamin D in RA pathogenesis and treatment.

Keywords: Autoimmune disease; Inflammation; Rheumatoid arthritis; T cell; Vitamin D; Vitamin D receptor.

Fig. 1

Role of vitamin D in the immune system. Schematic representation of cells from the innate and adaptive immune systems. Monocyte/macrophages from the innate immune system expression pattern recognition receptors (PRR) such as toll-like receptors (TLR), and response to pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS). PAMP–PRR responses include induction of transcription to increased expression of the vitamin D receptor (VDR) and the vitamin D-activating enzyme 1α-hydroxylase (CYP27B1) via STAT 1 or 5, AP-1, NF-κB or CEBP response elements. This increases monocyte/macrophage capacity to metabolise 25-hydroxyvitamin D3 (25-OHD3) to 1,25-dihydroxyvitamin D3 (1,25-(OH)₂D3), which then interacts with VDR to regulate gene expression via DNA vitamin D response elements (VDRE). Prominent target genes for regulation by 1,25-(OH)₂D3 include Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), hepcidin antimicrobial protein (HAMP), cathelicidin (CAMP) and β-defensin 2 (DEFB4). 1,25-(OH)₂D3 also enhances pathogen killing by inducing autophagy and reactive oxygen species (ROS), but acts to inhibit inflammation by suppressing inflammatory cytokines and expression of TLR2/4. Monocytes/macrophages may contribute to local levels of 1,25-(OH)₂D3 which may then act on non-immune cells such as local tissue fibroblasts, chondrocytes or epithelial cells. For other innate immunity cells such as dendritic cells (DC), differentiation of these cells from immature (iDC) to mature (mDC) phenotypes is associated with increased expression of CYP27B1 but decreased expression of VDR, suggesting local conversion of 25-OHD3 to 1,25-(OH)2D3, which results in a paracrine effect to generate tolerogenic DC. Synthesis of 1,25-(OH)₂D3 by mDC may also have paracrine effects on cells from the adaptive immune system such as T cells which, when activated, express VDR and respond to 1,25-(OH)₂D3 by inducing Th2 and Treg phenotypes whilst suppressing Th1 and Th17 inflammatory phenotypes. 1,25-(OH)₂D3 can also act on B cells to decrease CD40 expression and enhance class switching