Abstract and Introduction
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.
Introduction
Vitamin D deficiency has been associated with several autoimmune diseases including multiple sclerosis (MS), rheumatoid arthritis (RA), type 1 diabetes mellitus, inflammatory bowel disease (IBD), mixed connective tissue disease, autoimmune thyroid disease, scleroderma and systemic lupus erythematosus (SLE). Vitamin D levels are lower in individuals with undifferentiated connective tissue disease than in controls, and lower in patients who progressed to well-established connective tissue diseases than in those whose did not progress.
Vitamin D supplementation has been shown to improve disease in murine models of MS, RA, type 1 diabetes mellitus, IBD and SLE. Addition of vitamin D and its synthetic analogues to murine models of SLE have resulted in improved dermatological disease, reduced proteinuria and increased survival. SLE is a complex heterogeneous autoimmune disorder arising from genetic predisposition and environmental risks. Vitamin D deficiency has been found in approximately two-thirds of patients with SLE, with approximately one-fifth of patients having severe deficiency (<10 ng/ml). Additionally, serum vitamin D levels have been shown to correlate inversely with disease activity.
Vitamin D has modulatory effects on B lymphocytes and Ig production. Many immune cells contain vitamin D receptors—including monocytes, macrophages, dendritic cells and activated T and B cells—and these immune cells possess the enzymatic machinery (1α-hydroxylase, CYP27B1) necessary to convert vitamin D into its active form. Isolated peripheral blood mononuclear cells (PBMCs) from patients with SLE incubated with 1,25(OH)2D or its synthetic analogues significantly reduced cellular proliferation, as well as polyclonal and anti-dsDNA Ig production. 1,25(OH)2D has also been shown to induce apoptosis in activated B cells and to inhibit the generation of plasma cells and postswitch memory B cells, as well as induce regulatory T cells. The importance of vitamin D in innate immunity has been highlighted by studies demonstrating that monocyte/macrophage responses to bacterial infections via Toll-like receptors (TLRs) are potentially stimulated by 25-hydroxyvitamin D (25(OH)D) following localised induction of both vitamin D receptor (VDR) and 1α-hydroxylase.
Interferon α (IFNα) has been shown to be a key cytokine in the pathogenesis of SLE. Numerous studies have confirmed the association between raised IFNα levels and increased disease activity in SLE. Strong evidence for the pathogenic role of IFNα in SLE comes from clinical studies showing treatment with recombinant IFNα for malignancies or hepatitis causes de novo SLE, with resolution after discontinuation of treatment. Induction of IFNα from stimulation of TLRs by nucleic acid-containing immune complexes is thought to be one of the mechanisms by which patients with SLE have increased IFNα activity. Supporting this hypothesis is evidence that activation of the IFNα pathway is associated with the presence of autoantibodies directed against DNA and RNA binding proteins.
While in vitro studies have demonstrated a suppressive action of vitamin D on Ig production and the IFN signature, an association between vitamin D status in patients with SLE and these disease features has not been previously reported. We examined the prevalence of vitamin D deficiency in antinuclear antibody (ANA)-positive healthy individuals in comparison with ANA-negative healthy individuals and patients with SLE. The relationship between vitamin D status and the interrelated pathways involving B cell activation, autoantibody production and IFNα activity in SLE and healthy individuals was also evaluated.