Although increasing evidence supports the role of vitamin D in modulating the immune system, many details remain to be elucidated. While specific mechanisms have been discovered for the influence of vitamin D on innate immunity, the potential role for vitamin D in the adaptive immune system is still not clear. Several mechanisms exist by which vitamin D could potentially modulate adaptive immune responses, including modulation of antigen presentation as well as direct actions on T and B lymphocytes.
This study suggests a role for vitamin D in modulating auto-antigenic immune responses. Vitamin D deficiency was associated with an increased presence of autoantibodies in healthy controls. While vitamin D deficiency has been reported in many autoimmune diseases, this is the first observation in ANA-positive healthy individuals. This finding is interesting because patients with autoimmune disease, especially those with SLE, possess many risk factors for vitamin D deficiency whereas healthy controls do not. This provides epidemiological evidence to suggest that vitamin D deficiency in autoimmunity is not solely a consequence of lifestyle changes associated with the disease. A longitudinal study would determine if replenishing vitamin D to sufficient levels would cause a decrease in ANA titres.
We also showed evidence of a relationship between vitamin D levels in patients with SLE and the magnitude of B lymphocyte activation in PBMCs, as determined by pERK1/2 levels. This observation suggests that vitamin D deficiency could be playing a role in the B cell hyperactivity seen in patients with SLE, thus contributing to an increased production of autoantibodies. Interestingly, this same correlation was not seen in the controls, suggesting a potential gene–environment interaction between SLE susceptibility genes and vitamin D. In this manner, vitamin D deficiency would contribute to B cell hyperactivation and autoantibody production in genetically susceptible individuals. Vitamin D deficiency is probably not sufficient to cause B cell hyperactivation and autoantibody production, but rather is a contributing factor along with other genetic and environmental risks.
The hypothesis that vitamin D deficiency contributes to increased B cell activation in patients with SLE and increased production of autoantibodies, in particular those directed against nucleic acids, provides a mechanism for the association of vitamin D deficiency with increased IFNα activity (working hypothesis shown in ). Nucleic acids contained within autoantibody immune complexes can activate TLRs, thus promoting IFNα production from plasmacytoid dendritic cells (pDCs) in patients with SLE.34
Vitamin D may bind vitamin D receptors present in pDCs and influence their IFNα production, although it has been shown that 1,25(OH)2
D did not modulate IFNα production by pDCs in vitro at the concentrations used.35
Additionally, it has been shown that vitamin D suppresses the expression of the IFN signature in myeloid-derived dendritic cells (MDDCs). This was accomplished using MDDCs from patients with SLE as well as MDDCs generated from controls which had been incubated with plasma from patients with SLE.24,25
Figure 4 Potential mechanism for the role of vitamin D in B cell hyperactivity, autoantibody production and interferon α (IFNα) activity. Together with genetic susceptibility and other environmental factors, vitamin D deficiency could contribute (more ...)
Experimental studies have also shown that 1,25(OH)2
D is able to skew the T cell compartment into a more anti-inflammatory and regulated state, with inhibitory actions on Th1 and Th17 cells and promoting the development of CD4 CD25 Foxp3+
regulatory T cells (Treg).17
Vitamin D has been shown to induce tolerogenic dendritic cells, which promote Treg cell development and enhance recruitment of Treg cells to inflammatory sites.17
Thus, there are several different possible pathways by which vitamin D can influence the pathogenesis of SLE, B cell activity and autoantibody production.
The fact that both ANA-positive healthy individuals and patients with SLE have decreased vitamin D suggests that the mechanism operates early in the steps to SLE development, before the appearance of clinical findings. Beyond considering the molecular mechanisms by which vitamin D deficiency would predispose to autoimmunity, the extraordinarily high prevalence of vitamin D deficiency in ANA-positive healthy individuals and patients with SLE strongly suggests that repletion with vitamin D should be considered. A recent study sought to examine the effects of oral vitamin D supplementation on disease activity in SLE; however, more than 70% of the patients in the study still had insufficient levels of vitamin D after 2 years of treatment.36
While this study did not report any improvements in SLE disease activity after oral administration of vitamin D, interpretation of the results is limited by the small percentage of patients with SLE who achieved adequate 25(OH)D levels. Although no definitive study has been published demonstrating a beneficial effect of vitamin D supplementation on SLE disease severity, current knowledge supports vitamin D replacement for calcium homeostasis, bone health and potential immune system benefits.