The Impact of Vitamin D on Dendritic Cell Function in Patients with Systemic Lupus Erythematosus

Excessive activity of dendritic cells (DCs) is postulated as a central disease mechanism in Systemic Lupus Erythematosus (SLE). Vitamin D is known to reduce responsiveness of healthy donor DCs to the stimulatory effects of Type I IFN. As vitamin D deficiency is reportedly common in SLE, we hypothesized that vitamin D might play a regulatory role in the IFNalpha amplification loop in SLE. Our goals were to investigate the relationship between vitamin D levels and disease activity in SLE patients and to investigate the effects of vitamin D on DC activation and expression of IFNalpha-regulated genes in vitro.In this study, 25-OH vitamin D (25-D) levels were measured in 198 consecutively recruited SLE patients. Respectively, 29.3% and 11.8% of African American and Hispanic SLE patient had 25-D levels <10 ng/ml. The degree of vitamin D deficiency correlated inversely with disease activity; R = -.234, p = .002. In 19 SLE patients stratified by 25-D levels, there were no differences between circulating DC number and phenotype. Monocyte-derived DCs (MDDCs) of SLE patients were normally responsive to the regulatory effects of vitamin D in vitro as evidenced by decreased activation in response to LPS stimulation in the presence of 1,25-D. Additionally, vitamin D conditioning reduced expression of IFNalpha-regulated genes by healthy donor and SLE MDDCs in response to factors in activating SLE plasma.We report on severe 25-D deficiency in a substantial percentage of SLE patients tested and demonstrate an inverse correlation with disease activity. Our results suggest that vitamin D supplementation will contribute to restoring immune homeostasis in SLE patients through its inhibitory effects on DC maturation and activation. We are encouraged to support the importance of adequate vitamin D supplementation and the need for a clinical trial to assess whether vitamin D supplementation affects IFNalpha activity in vivo and, most importantly, improves clinical outcome

Assessment of 25-D levels in patients with SLE.

<p>The distribution and median blood level for 25-D (+/− 1 SD) is shown for each ethnic group (A). Severe vitamin D deficiency (defined as a blood level of 25-D less than 10 ng/ml) is most prevalent among African American and Hispanic patients (B). Disease activity scores (SLEDAI) exhibited an inverse correlation with 25-D levels (C).</p

Vitamin D inhibits the induction of an IFN signature in MDDCs exposed to activating SLE plasma.

<p>Relative expression of three IFN inducible genes, compared to the housekeeping gene HPRT1, is shown in MDDC from 2 healthy donors cultured in the presence or absence of 1, 25-D at a concentration of 10 nM followed by exposure to activating SLE plasma or healthy donor plasma (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009193#pone-0009193-g003" target="_blank">Figure 3A</a>). MDDC from 2 SLE subjects were subjected to an identical sequence of events (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0009193#pone-0009193-g003" target="_blank">Figure 3B</a>). One of these patients was an African American female with active renal disease, a SLEDAI of 10 and a serum 25-D level of 24. The other was a Hispanic female with SLEDAI score of 0 and a serum 25-D level of 19. Although expression of the 3 IFNα targeted genes appears to differ between healthy MDDC and SLE MDDC, overall expression is reduced with the addition of physiologic levels of Vitamin D during MDDC culture.</p

Demographic and clinical characteristics of the patients.

<p>Except where indicated otherwise, values are the mean (range). MMC  =  Montefiore Medical Center, NIH  =  National Institutes of Health.</p><p>MUSC  =  Medical University of South Carolina; SLEDAI  =  Systemic Lupus Erythematosus Disease Activity Index.</p><p>dsDNA  =  anti-double-stranded DNA.</p