Exploring the Evidence for an Immunomodulatory Role of Vitamin D in Juvenile and Adult Rheumatic Disease

Abstract

Vitamin D is synthesized in the skin following exposure to UVB radiation or is directly absorbed from the diet. Following hydroxylation in the liver and kidneys, vitamin D becomes its bioactive form, 1,25(OH)₂D, which has been described to have potent immunomodulatory capacity. This review will focus on the effect of vitamin D in modulating the dysregulated immune system of autoimmune rheumatic diseases (ARD) patients across age, in particular in arthritis (rheumatoid arthritis and juvenile idiopathic arthritis), and systemic lupus erythematosus (with adult and juvenile onset). As well as delineating the impact of vitamin D on the innate and adaptive immune functions associated with each disease pathology, this review will also summarize and evaluate studies that link vitamin D status with disease prevalence, and supplementation studies that examine the potential benefits of vitamin D on disease outcomes. Exploring this evidence reveals that better designed randomized controlled studies are required to clarify the impact of vitamin D supplementation on ARD outcomes and general health. Considering the accessibility and affordability of vitamin D as a therapeutic option, there is a major unmet need for evidence-based treatment recommendations for the use of vitamin D in this patient population.

Keywords: autoimmunity; immunomodulatory; juvenile idiopathic arthritis; rheumatoid arthritis; systemic lupus erythematosus; vitamin D.

Figure 1

Vitamin D (both D₃ and D₂) metabolic pathway and its physiological impact on immune cells. D₃ is synthesized from either 7-dehydrocholesterol from the skin via UVB activation or through the diet. D₂ is obtained from the diet. CYP2R1 enzyme converts D₃/D₂ to 25(OH)D₃/D₂ in the liver. CYP27B1 transforms 25(OH)D₃/D₂ into 1,25(OH)₂D₃/D₂ in the kidneys. 1,25(OH)₂D binds to VDR in immune cells which then bind to VDRE on genes to change gene expression. 1,25(OH)₂D can inhibit dendritic cell maturation, promote monocyte proliferation and differentiation into macrophages. It can also increase anti-inflammatory cytokines and the frequency of T_regs, as well as reduce pro-inflammatory Th1 cytokines. 1,25(OH)₂D can also reduce the ratio of CD4/CD8 and inhibit pro-inflammatory T cell differentiation and suppress antibody production by B cells.

Figure 2

Pathogenesis of RA/JIA and mechanisms of vitamin D acting on immune cells. A breakdown in tolerance in RA/JIA leads to increased Th1/Th17 cells and promotes macrophages to produce pro-inflammatory cytokines (IL-1β, IL-17, IL-6, TNF-α) which in turn stimulates fibroblast synoviocyte proliferation. Synoviocytes then activate osteoclasts and secrete MMPs which break down bone and cartilage. Vitamin D shifts the balance of Th cells from Th1/Th17 to Th2/T_reg, inhibit B cells and autoantibody production, reduces pro-inflammatory cytokines, and inhibits synoviocyte proliferation. MMP, matrix metallopeptidase.

Figure 3

SLE pathogenesis and mechanism of vitamin D on immune cells. UVB light causes apoptosis of cells that release endogenous nucleic acids. The nucleic acids bind to and trigger plasmacytoid dendritic cells to release IFN-α. Mature dendritic cells recruit T helper cells, cytotoxic T cells and B cells. Vitamin D increases protective innate immune response while dampening the over-active immune response. Vitamin D also inhibits the maturation of dendritic cells and suppresses IFN-α production from plasmacytoid dendritic cells as well as IFN-α induced gene expression.