Over the last three decades it has become clear that the role of vitamin D goes beyond the regulation of calcium homeostasis and bone health. An important extra-skeletal effect of vitamin D is the modulation of the immune system. In the context of autoimmune diseases, this is illustrated by correlations of vitamin D status and genetic polymorphisms in the vitamin D receptor with the incidence and severity of the disease. These correlations warrant investigation into the potential use of vitamin D in the treatment of patients with autoimmune diseases. In recent years several clinical trials have been performed to investigate the therapeutic value of vitamin D in multiple sclerosis, rheumatoid arthritis, Crohn’s disease, type I diabetes and systemic lupus erythematosus. Additionally, a second angle of investigation has focused on unraveling the molecular pathways used by vitamin D in order to find new potential therapeutic targets. This review will not only provide an overview of the clinical trials that have been performed, but also discuss the current knowledge about the molecular mechanisms underlying the immunomodulatory effects of vitamin D and how these advances can be used in the treatment of autoimmune diseases.

Objective: Both Th1 cells and Th17 cells have been recognized in rheumatoid arthritis (RA); however, it remains unclear whether Th1 cells and/or Th17 cells are involved in driving disease chronicity and destructiveness. The aim of this study was to identify and characterize the functional role of Th17 cells in early RA.Methods: Flow cytometry analysis was performed on peripheral blood mononuclear cells (PBMCs) from treatment‐naive patients with early RA and age‐matched healthy volunteers. PBMCs from these patients, naive T cells, and primary CCR6− Th1 cells and CCR6+ Th17 cells were sorted and cultured in the absence or presence of synovial fibroblasts from patients with early RA (RASFs), and cytokine expression and gene transcription were analyzed. In addition, tumor necrosis factor α (TNFα)– and interleukin‐17A (IL‐17A)–blocking experiments were performed.Results: In the PBMCs of treatment‐naive patients with early RA, an increased fraction of IL‐17A–and TNFα–producing CCR6+ Th17 cells was observed. When cocultured with RASFs, these primary Th17 cells were potent inducers of IL‐6 and IL‐8 and the tissue‐destructive enzymes matrix metalloproteinase 1 (MMP‐1) and MMP‐3, whereas primary Th1 cells or naive T cells were not. Importantly, specific up‐regulation of IL‐17A but not TNFα or interferon‐γ was observed in RASF/Th17 cell cocultures. In addition to TNFα blocking, IL‐17A neutralization was required to further down‐regulate Th17 activity in RASF/Th17 cell cocultures.Conclusion: Th17 cells, but not Th1 cells, cooperated with RASFs in a proinflammatory feedback loop, revealing a potential mechanism by which human Th17 cells drive chronic destructive disease in patients with RA. Furthermore, the neutralization of IL‐17A activity is essential in current anti‐TNF therapies to suppress Th17 cell activity in patients with early RA and potentially other Th17 cell–mediated disorders.

Objective: To examine the immunologic mechanism by which 1,25‐dihydroxyvitamin D₃ (1,25[OH]₂D₃) may prevent corticosteroid‐induced osteoporosis in patients with early rheumatoid arthritis (RA), with a focus on T cell biology.Methods: Peripheral blood mononuclear cells (PBMCs) and CD4+CD45RO+ (memory) and CD4+CD45RO− (non‐memory) T cells separated by fluorescence‐activated cell sorting (FACS) from treatment‐naive patients with early RA were stimulated with anti‐CD3/anti‐CD28 in the absence or presence of various concentrations of 1,25(OH)₂D₃, dexamethasone (DEX), and 1,25(OH)₂D₃ and DEX combined. Levels of T cell cytokines were determined by enzyme‐linked immunosorbent assay and flow cytometry.Results: The presence of 1,25(OH)₂D₃ reduced interleukin‐17A (IL‐17A) and interferon‐γ levels and increased IL‐4 levels in stimulated PBMCs from treatment‐naive patients with early RA. In addition, 1,25(OH)₂D₃ had favorable effects on tumor necrosis factor α (TNFα):IL‐4 and IL‐17A:IL‐4 ratios and prevented the unfavorable effects of DEX on these ratios. Enhanced percentages of IL‐17A– and IL‐22–expressing CD4+ T cells and IL‐17A–expressing memory T cells were observed in PBMCs from treatment‐naive patients with early RA as compared with healthy controls. Of note, we found no difference in the percentage of CD45RO+ and CD45RO− cells between these 2 groups. Interestingly, 1,25(OH)₂D₃, in contrast to DEX, directly modulated human Th17 polarization, accompanied by suppression of IL‐17A, IL‐17F, TNFα, and IL‐22 production by memory T cells sorted by FACS from patients with early RA.Conclusion: These data indicate that 1,25(OH)₂D₃ may contribute its bone‐sparing effects in RA patients taking corticosteroids by the modulation of Th17 polarization, inhibition of Th17 cytokines, and stimulation of IL‐4.

Objective: To examine the role of interleukin‐17 receptor (IL‐17R) signaling in cartilage destruction and its interrelationship with synovial IL‐1 expression during chronic reactivated streptococcal cell wall (SCW)–induced arthritis.Methods: SCW arthritis was repeatedly induced in wild‐type (WT) and IL‐17R–deficient (IL‐17R^–/–) mice. At different time points, joint inflammation was assessed by using calipers to measure joint swelling. On day 42, mice were killed, and knee joints were removed for histologic analysis. Quantitative polymerase chain reaction (PCR) analyses for different proinflammatory mediators and matrix metalloproteinases (MMPs) were performed on inflamed synovium from WT and IL‐17R^–/– mice after 5 repeated injections of SCW fragments.Results: IL‐17R signaling did not play a significant role in acute joint swelling induced by a single injection of SCW fragments directly into the joint. However, repeated local injections of SCW fragments into the knee joints of IL‐17R^–/– mice resulted in fewer infiltrating cells in the joint compared with WT mice. Moreover, histologic analysis on day 42 revealed a significant suppression of the degree of chondrocyte death and an absence of cartilage surface erosion in IL‐17R^–/– mice. Quantitative PCR analysis revealed impaired synovial expression of IL‐1, IL‐6, cyclooxygenase 2, stromelysin (MMP‐3), gelatinase B (MMP‐9), and collagenase 3 (MMP‐13) in IL‐17R^–/– mice.Conclusion: These data show a critical role of IL‐17R signaling in driving the synovial expression of proinflammatory and catabolic mediators, such as IL‐1 and different MMPs, during progression from an acute, macrophage‐driven joint inflammation to a chronic, cartilage‐destructive, T cell–mediated synovitis. Prevention of IL‐17R signaling warrants consideration as a therapeutic target in chronic destructive arthritis.