Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus

Abstract

Objectives: Vitamin D deficiency is widespread and has been associated with many chronic diseases, including autoimmune disorders. A study was undertaken to explore the impact of low vitamin D levels on autoantibody production in healthy individuals, as well as B cell hyperactivity and interferon α (IFNα) activity in patients with systemic lupus erythematosus (SLE).

Methods: Serum samples from 32 European American female patients with SLE and 32 matched controls were tested for 25-hydroxyvitamin D (25(OH)D) levels, lupus-associated autoantibodies and serum IFNα activity. Isolated peripheral blood mononuclear cells were tested for intracellular phospho-ERK 1/2 as a measure of B cell activation status.

Results: Vitamin D deficiency (25(OH)D <20 ng/ml) was significantly more frequent among patients with SLE (n=32, 69%) and antinuclear antibody (ANA)-positive controls (n=14, 71%) compared with ANA-negative controls (n=18, 22%) (OR 7.7, 95% CI 2.0 to 29.4, p=0.003 and OR 8.8, 95% CI 1.8 to 43.6, p=0.011, respectively). Patients with high B cell activation had lower mean (SD) 25(OH)D levels than patients with low B cell activation (17.2 (5.1) vs 24.2 (3.9) ng/ml; p=0.009). Patients with vitamin D deficiency also had higher mean (SD) serum IFNα activity than patients without vitamin D deficiency (3.5 (6.6) vs 0.3 (0.3); p=0.02).

Conclusions: The observation that ANA-positive healthy controls are significantly more likely to be deficient in vitamin D than ANA-negative healthy controls, together with the finding that vitamin D deficiency is associated with certain immune abnormalities in SLE, suggests that vitamin D plays an important role in autoantibody production and SLE pathogenesis.

Figure 1

Antinuclear antibody (ANA)-positive healthy individuals and patients with systemic lupus erythematosus (SLE) are more likely to be deficient in vitamin D. (A) Median (IQR) 25-hydroxyvitamin D levels were 17.3 (11.9–21.2) ng/ml in patients with SLE (n=32), 17.4 (14.5–25.8) ng/ml in ANA-positive controls (n=14) and 29.4 (19.0–36.3) ng/ml in ANA-negative controls (n=18). Bars indicate IQR. **p<0.01, Kruskal–Wallis test with Dunn’s multiple comparison. (B) Patients with SLE and ANA-positive controls were more likely to be vitamin D deficient (69% and 71%, respectively) than ANA-negative controls (22%). **p=0.003, *p=0.011 (Fisher exact test).

Figure 2

Lower 25-hydroxyvitamin D (25(OH)D) levels are associated with increased B cell activation in patients with systemic lupus erythematosus (SLE). (A) Increased B cell activation (as measured by phospho-ERK (pERK1/2)) was correlated with decreased 25(OH)D levels in patients with SLE (r=−0.40, p=0.03). (B) Patients with SLE with 25(OH)D levels <20 ng/ml had higher B cell activation (as measured by pERK1/2) than patients with 25(OH)D levels >20 ng/ml; *p=0.045 (unpaired t test with Welch’s correction of log-transformed data). Error bars indicate SEM.

Figure 3

Increased serum interferon α (IFNα) activity is associated with vitamin D deficiency and increased number of autoantibody specificities. (A) Patients with systemic lupus erythematosus (SLE) with 25-hydroxyvitamin D (25(OH)D) <20 ng/ml had mean (SD) serum IFNα activity of 3.53 (6.56) compared with 0.34 (0.33) in patients with 25(OH)D >20 ng/ml. *p=0.02 (unpaired t test with Welch’s correction of log-transformed data). (B) Patients with SLE with low IFNα activity (IFNα activity <1 SD above the mean of healthy controls) had fewer mean number of autoantibody specificities than patients with high IFNα activity (IFNα activity >1 SD above the mean of healthy controls): 0.9 vs 2.1. **p=0.002 (unpaired t test). Errors bars indicate SEM.

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 to increased B cell activation and autoantibody production. This increase in autoantibody production, specifically of antibodies directed against self-nucleic acids, could lead to an increase in IFNα production by plasmacytoid dendritic cells via Toll-like receptor (TLR) signalling mediated by immune complexes. Vitamin D deficiency could also contribute to an increased IFN signature in myeloid dendritic cells.