Further emergent evidence for the vitamin D endocrine system involvement in autoimmune rheumatic disease risk and prognosis.

VITAMIN D: A TRUE ENDOGENOUS IMMUNOMODULATOR Recently, vitamin D has received increased worldwide attention for its involvement in reducing risk for several chronic diseases including many cancers, infectious diseases, type 1 diabetes and notably autoimmune rheumatic diseases. The final active metabolite of vitamin D (1,25(OH)D3) is considered a steroid hormone for its origin from cholesterol (D-hormone), and like glucocorticoids exerts immunomodulatory activities (figure 1). 3 Pathophysiological investigations confirm that severe hypovitaminosis D, in genetically predisposed subjects, can impair self tolerance and immune responses by compromising the regulation of dendritic cells, regulatory T-lymphocytes (Tregs), Th1 cells and B cell function. Cross-sectional studies have shown that deficient serum levels of vitamin D (25(OH)D) (<20 ng/ml) are present in a significant percentage, not only in patients with autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes, systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), but also in healthy subjects. 5 In addition, the presence of severe 25(OH)D deficiency (<10 ng/ml) is also involved in the generation of symptoms that characterise patients with rheumatic diseases (ie, musculoskeletal pain in RA), and supplementation seems to induce improvements. 7 VITAMIN D DEFICIENCY, AUTOANTIBODY INDUCTION AND IDIOPATHIC INFLAMMATORY MYOPATHIES Azali et al report significant vitamin D deficiency in patients with idiopathic inflammatory myopathies (IIM)—polymyositis, dermatomyositis (DM), inclusion body myositis—compared to a gender matched control population and based on samples collected during the same months of the year. The IIM patients with shorter disease duration showed lower levels of serum 25 (OH)D than those with established treated disease, supporting the hypothesis that low levels of vitamin D could be at least one of several risk factors in development of IIM, as already assessed in MS, RA and SLE. The suggested role for low serum 25 (OH)D as a risk factor in autoimmunity seems strongly reinforced by some recent investigations showing that even antinuclear antibodies (ANA)-positive healthy controls are significantly more likely to be deficient in vitamin D serum levels than ANA-negative healthy controls. Conversely, in a recent survey, vitamin D supplementation (140 000 IU at baseline and after 4 weeks) was found to be associated with significant increases of Tregs frequency (%Tregs) in apparently healthy individuals. Interestingly, a significantly higher frequency of autoantibodies (anti-Jo-1) was also found by Azali et al in IIM patients who had significantly lower median serum 25(OH)D levels compared to controls. In addition to the finding that vitamin D deficiency is associated in SLE patients with certain immune abnormalities and significantly correlates in a negative manner with clinical SLE activity and anti-dsDNA titre, it is strongly suggested that vitamin D deficiency plays an important role in enhancing autoantibody production. 11 Interestingly, in an interventional study evaluating the immunological effects of vitamin D supplementation in 20 SLE patients with hypovitaminosis D, a decrease of memory B cells and anti-DNA antibodies together with a preferential increase of naive CD4 Tcells, an increase of regulatory T cells and a decrease of effector Th1 and Th17 cells were observed. Furthermore, a very recent study showed that reduced serum 25(OH)D levels are associated with the presence of autoimmune response in tuberculosis patients, by reporting a significant negative correlation between the titres of the ANA and the serum levels of 25(OH)D. A new and intriguing study links low serum 25(OH)D and elevated immunoreactivity against Epstein–Barr virus (EBV) in 25 individuals who had donated blood prior to the first clinical MS manifestation (clinically isolated syndrome). In fact, a novel role for low vitamin D as risk factor and/or modifier of autoimmune response is introduced. It is proposed that deprivation of solar light or low serum 25(OH) D at higher latitudes, facilitates the development of autoimmune diseases by aggravating the CD8 T-cell deficiency, thereby further impairing control of EBV and permitting clonal expansion of autoreactive B cells infected with EBV.