Vitamin D and inflammation

Joint Bone Spine 77 (2010) 552–557 Review Vitamin D and inflammation Xavier Guillot a,b,∗ , Luca Semerano a,b , Nathalie Saidenberg-Kermanac’h a,b , ...
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Joint Bone Spine 77 (2010) 552–557

Review

Vitamin D and inflammation Xavier Guillot a,b,∗ , Luca Semerano a,b , Nathalie Saidenberg-Kermanac’h a,b , Géraldine Falgarone a,b , Marie-Christophe Boissier a,b a b

EA4222, Li2P, PRES Paris-Cité, université Paris 13, 93000 Bobigny, France Service de rhumatologie, hôpital Avicenne, CHU Avicenne, AP–HP, 125, rue de Stalingrad, 93009 Bobigny cedex, France

a r t i c l e

i n f o

Article history: Accepted 7 September 2010 Available online 9 November 2010 Keywords: 1,25 dihydroxyvitamin D3 Vitamin D receptor 1␣-hydroxylase 25-hydroxylase Dendritic cell Macrophage T cell B cell

a b s t r a c t Calcitriol, or 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3) is a well-known endocrine regulator of calcium homeostasis. More recently, local calcitriol production by immune cells was shown to exert autocrine or paracrine immunomodulating effects. Immune cells that produce calcitriol also express the vitamin D receptor (VDR) and the enzymes needed to metabolize vitamin D3 (1␣-, 25-, and 24-hydroxylases). Studies of animal models and cell cultures showed both direct and indirect immunomodulating effects involving the T cells, B cells, and antigen-presenting cells (dendritic cells and macrophages) and affecting both innate and adaptive immune responses. The overall effect is a switch from the Th1/Th17 response to the Th2/Treg profile. The immunomodulating effects of vitamin D may explain the reported epidemiological associations between vitamin D status and a large number of autoimmune and inflammatory diseases. Such associations have been suggested by observational studies not only in rheumatoid arthritis, lupus, inflammatory bowel disease, and type 1 diabetes; but also in infections, malignancies, transplant rejection, and cardiovascular disease. In animal models for these diseases, vitamin D supplementation has been found to produce therapeutic effects. Thus, vitamin D is a key focus for public health efforts and may hold promise for the treatment of dysimmune diseases. © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.

1. Introduction

2. Vitamin D metabolism and role in calcium homeostasis

Vitamin D is a secosteroid hormone produced chiefly in the skin upon exposure to ultraviolet B radiation. Vitamin D can also be supplied by the diet or by supplements. The crucial role for vitamin D in calcium-phosphate homeostasis and bone metabolism is well established. Serum vitamin D levels of at least 30 ng/ml (75 nmol/L) are considered optimal to limit the release of parathyroid hormone (PTH) and to promote the intestinal absorption of calcium [1–3]. Recent observational studies suggest extraosseous effects of vitamin D. Thus, vitamin D deficiency was associated with the risk and/or severity of many diseases including cancer, cardiovascular disease, sarcopenia, osteoarthritis, infections, and transplant rejection. Vitamin D-deficient individuals were at increased risk for autoimmune diseases such as diabetes, multiple sclerosis (MS), inflammatory bowel disease (IBD), and connective tissue diseases (e.g., rheumatoid arthritis [RA] and systemic lupus erythematosus [SLE]). The presumptive extraosseous effects of vitamin D may be largely ascribable to the immunomodulating properties of vitamin D, whose mechanisms have been elucidated by animal studies and cell culture experiments.

Vitamin D regulates calcium homeostasis by influencing bone turnover and interacting with the parathyroid glands, kidney, and gastrointestinal tract. The two biologically relevant forms of vitamin D are ergocalciferol or vitamin D2, found in a number of plants and mushrooms, and cholecalciferol or vitamin D3. Vitamin D3 can be ingested or produced in the skin upon exposure to ultraviolet B radiation (which converts 7-dehydrocholesterol to previtamin D3). In the bloodstream, vitamin D is carried by a specific binding protein (VDBP). To become biologically active, vitamin D must first be hydroxylated at position 25, to calcidiol (25(OH)D), a reaction that occurs chiefly in the liver. Calcidiol is the main circulating form of vitamin D but is biologically inactive. The active form is produced chiefly in the proximal tubule of the kidney by hydroxylation at position 1 to calcitriol (1,25 dihydroxy-vitamin D (1,25(OH)2 D)). Calcitriol acts by binding to the vitamin D receptor (VDR), which is found in most cells in the body. In the small bowel, the calcitriol-VDR interaction leads to increased expression of calcium-binding protein (Ca-BP) and of other proteins that promote the transport of calcium from the gut lumen to the bloodstream. Calcitriol binding to the VDR on osteoblasts stimulates RANK-ligand expression, thereby promoting the maturation of preosteoclasts to osteoclasts, which release calcium stores from bone to maintain calcium homeostasis [1]. Vitamin D acts on its target

∗ Corresponding author. E-mail address: [email protected] (X. Guillot).

1297-319X/$ – see front matter © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2010.09.018

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Table 1 Effects of 1,25(OH)2 D3 on immune cells. Cell

Effects of 1,25(OH)2 D3

References

Dendritic cells

↓ Decreased proliferation ↓ Decreased differentiation ↓ survival ↓ maturation ↓ Decreases in CD40, CD80, CD86, MHC-2: ↓ decreased T-cell stimulation ↓ Decreased IL-12; Th1 response inhibition indirect ↑ Increased IL-10 and Fox-P3: Treg induction ↓ Th17 cell induction ↓ Decreases in IL-6 and IL-23: decreased Th17 response ↓ Decreases in TNF and IL-1 ↓ Decreased MHC-2: ↓ decreased antigen presentation ↑ Increases in cathelicidin, phagocytosis, hemotaxis ↑ Stimulation of response to infection ↓ Decreases in TLRs 9/4/2 ↑ Increased transcription of IL-5 ± IL-4 in T cells: ↑ Stimulation of Th2 response ↓ Decreased Th1 cell proliferation (direct), decreases in IL-2 and IFNy (RNA and proteins): decreased Th1 response ↑ Increase in IL-10-producing Tr1 cells ↓ Decreased Th17 differentiation and IL-17 production Homing ↓ Decreased cytotoxicity of CD8 T cells ↓ Decreased proliferation ↓ Decreased differentiation to plasma cells ↓ Decreased immunoglobin production

[15–20]

Macrophages

Fig. 1. Mechanism of action of vitamin D within the nucleus of target cells.

cells as a steroid hormone, by binding to its nuclear receptor VDR. VDR then undergoes heterodimerization, usually with the retinoid X receptor (RXR), and binds to specific DNA sequences (vitamin-D response elements, VDREs) located in promoter regions, thereby controlling the transcription of target genes involved in calcium metabolism (e.g., binding proteins) and in the immune response (Fig. 1). 3. Immunomodulating effects of vitamin D

T cells

B cells

[12–14]

[18–26]

[27]

3.1. Enzyme metabolism In addition to regulating calcium homeostasis, vitamin D has many other metabolic effects, which were identified more recently when researchers investigated the immunomodulating properties of vitamin D first described about 20 years ago [1,4,5–7]. Vitamin D contributes to regulate the proliferation, differentiation, and function of immune cells, both directly and indirectly (Table 1). Vitamin D can accumulate in the microenvironment of lymphoid organs, where it exerts specific autocrine and/or paracrine effects without inducing unwanted systemic events (such as hypercalcemia and increased bone resorption). Activated T cells (and probably B cells) can perform only the last vitamin D-activating reaction, hydrolyzing 25(OH)D3 to 1,25(OH)2 D3, whereas macrophages and some dendritic cells (DCs) have both of the enzymes needed to convert vitamin D to 1,25(OH)2 D3. The enzyme 1-alpha-hydroxylase has been found in macrophages and activated DCs, where 1,25(OH)2 D3 can be produced locally, leading to paracrine effects [7]. In contrast to renal cells, antigen-presenting cells are not subject to negative regulation of 1-alpha-hydroxylase by PTH or 1,25(OH)2 D3. In antigen-presenting cells, 1-alphahydroxylase is induced by many factors, including interferon gamma (IFN␥), and undergoes downregulation as the cell matures [8]. 3.2. Role and expression of the vitamin D receptor When activated by 1,25(OH)2 D3, the VDR regulates gene expression in the vast array of tissues targeted by vitamin D. The VDR is expressed by many types of immune cells including circulating monocytes, macrophages, DCs, and activated T cells [9]. In knockout mice for the VDR, 1,25(OH)2 D3 can no longer induce the differentiation of hematopoietic bone marrow progenitors to monocytes/macrophages. However, VDR knockout mice exhibit normal immune-cell subsets and similar rates of allogeneic and xenogeneic graft rejection to those seen in wild-type mice [10]. VDR knockout mice with experimentally induced asthma have no

airway inflammation, circulating eosinophilia, or bronchial hyperreactivity, despite high levels of IgE and Th2 cytokines. Thus, vitamin D may play a key role in the allergic response [11].

3.3. Effects on macrophages Macrophages and DCs are regulated by 1,25(OH)2 D3, which therefore plays a crucial role in innate immune responses. Thus, 1,25(OH)2 D3 promotes monocyte-to-macrophage differentiation, stimulates macrophages to produce the immunosuppressant prostaglandin E2, and downregulates the expression of granulocyte-macrophage colony-stimulating factor. In addition, 1,25(OH)2 D3 diminishes the production by macrophages of proinflammatory cytokines and chemokines. Vitamin D deficiency impairs macrophage maturation and the production of macrophage-specific membrane antigens, lysosomal acid phosphatase, and hydrogen peroxide required for antimicrobial activity. Adding 1,25(OH)2 D3 increases the expression of membrane markers, enzymes, and free oxygen radicals and enhances chemotaxis and phagocytosis [12]. Activated macrophages produce 1,25(OH)2 D3 in response to interferon ␥ (IFN␥) and activation of the toll-like receptors (TLRs). Adding 100 nM of 1,25(OH)2 D3 to human monocyte cultures inhibits the expression of the innate-immunity receptors TLR2, TLR4, and TLR9 and alters the TLR9-dependent production of IL-6 [13]. Other effects of 1,25(OH)2 D3, in contrast, stimulate innate immune responses: thus, 1,25(OH)2 D3 downregulates the expression of class 2 major histocompatibility complex (MHC) antigens at the cell surface and induces the production of cathelicidin, a peptide involved in the antimicrobial response. In addition, 1,25(OH)2 D3 can impair the antigen-presenting function of macrophages by downregulating the membrane expression of class 2 MHC molecules [14].

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3.4. Effects on dendritic cells The proliferation and differentiation of DCs are diminished by 1,25(OH)2 D3, which also inhibits the differentiation of monocytes to DCs and the differentiation, maturation, and survival of DCs, thus decreasing T-cell stimulation by DCs. Another effect of 1,25(OH)2 D3 is indirect inhibition of the Th1 response via inhibition of IL-12 by DCs. This inhibitory effect involves direct interaction of 1,25(OH)2 D3 with the VDR and NFkappaB, which interferes with IL-12 gene transcription [15]. In addition to inhibiting IL12, 1,25(OH)2 D3 increases IL-10 production by DCs. The net result is a decrease in the Th1 response and probably the induction of type 1 regulatory cells (Tr1) that produce IL-10. By acting on co-stimulation molecules, 1,25(OH)2 D3 affects T-cell/DC interactions, diminishing the production of proinflammatory cytokines (e.g., IL-1 and TNF␣) and the membrane expression of the class 2 MHC molecules CD40, CD80, and CD86. The result is decreased production of IL-2 and IFN␥ and increased production of IL-10 and TGF␤ [16–17]. Downregulation of CD40, CD80, and CD86 in antigen-presenting cells (including DCs) diminishes T-cell activation. In addition, 1,25(OH)2 D3 can promote the induction by DCs of CD4+CD25+ regulatory T cells (Treg) [18]. In a murine colitis model, 1,25(OH)2 D3 increased the expression of Fox2 and IL-10, two crucial factors for Treg induction [19]. This induction of tolerogenic DCs and Treg decreased the risk of rejection in a murine organ transplantation model [20].

3.5. Effects on T cells Vitamin D exerts direct effects on T and B cells and modifies their response to activation, thereby playing a key role in adaptive immune responses. Quiescent CD4+ T cells express the VDR at a low level, and their activation is associated with a five-fold increase in the VDR expression level. The effect of 1,25(OH)2 D3 on T cells is both indirect, via the DCs, and direct, via inhibition of T-cell proliferation. To date, 102 genes targeted by 1,25(OH)2 D3 have been identified in CD4+ T cells [21]. Furthermore, 1,25(OH)2 D3 affects T-cell differentiation, inhibiting the Th1 response (characterized by cell proliferation, transcription of the genes encoding IFN␥ and IL-2, and protein expression of these genes) and stimulating the Th2 response (IL-4, IL-5, and IL-10) by increasing the production of IL-5 and IL-10, as well as indirectly by diminishing the production of IFN␥ [22]. In combination with glucocorticoids, 1,25(OH)2 D3 induces Tr1 cells that produce IL-10 and suppress the immune response. This mechanism may contribute to explain the beneficial effects of vitamin D in autoimmune disease mod-

Fig. 2. Effects of vitamin D on immune cells.

els [23]. In VDR knockout mice, CD4+ T cells produce more IFN␥ and less IL-2, IL-4, and IL-5 compared to wild-type mice [24]. In addition, 1,25(OH)2 D3 indirectly inhibits the Th1 response by inhibiting IL-2 production by antigen-presenting cells and inhibits the Th17 response by blocking the production of IL-6 and IL-23 [19]. In cell culture experiments, 1,25(OH)2 D3 induces Treg in the presence of IL-2, by upregulating the transcription of Fox-P3 and CTLA4 [25]. T-cell homing is affected by 1,25(OH)2 D3. In humans, for instance, 1,25(OH)2 D3 acts synergistically with IL-12 to induce the expression of the skin homing marker CCR10 at the keratinocyte surface. Keratinocytes express the CCR10 ligand CCL27, a T-cell homing chemokine. Thus, 1,25(OH)2 D3 may promote T-cell circulation or retention within the epidermis [7]. Finally, the cytotoxic response mediated by CD8+ T cells is inhibited by 1,25(OH)2 D3 [26]. Overall, 1,25(OH)2 D3 inhibits the Th1 and Th17 proinflammatory responses and promotes the Th2, Treg, and Tr1 immunomodulating responses. The net result is downregulation of the effector T-cell immune response (Fig. 2). 3.6. Effects on B cells Effects of 1,25(OH)2 D3 on B cells include inhibition of B-cell proliferation, differentiation to plasma cells, and production of immunoglobulins, most notably in patients with SLE [27]. Many studies have found significantly lower serum 25(OH)D levels in patients with autoimmune diseases compared to healthy controls. Vitamin D supplementation has been reported to prevent autoim-

Table 2 Effects of vitamin D on autoimmune diseases. Vitamin D deficiency

Therapeutic effect (supplementation)

Animal models

Effect of supplementation in these models

References

More common Disease prevalence increases with latitude Correlates with disease activity (DAS28 and CRP) SLE More common Correlates with disease activity (SLEDAI) Type 1 diabetes More common

Pain CRP

Collagen-induced arthritis (mice)

Prevention Decreased arthritis

[28–38]

MRL/lpr mice

[44–50]

Prevention

NOD mice

MS

Prevention Decreased relapse rate Decreased relapse rate

EAE (mice)

Increased survival Decreased proteinuria Halts progression Induces Treg Decreases IL-12 Prevention and treatment IL-10-dependent Prevention Weight gain and increased survival Efficacy increased by concomitant calcium

RA

IBD

Disease prevalence increases with latitude Correlates with risk of developing MS More common Disease prevalence increases with latitude Correlates with relapse rate

IL-10 knockout mice

[51–53]

[54–59] [39–43]

RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; MS: multiple sclerosis; IBD: inflammatory bowel disease; DAS28: Disease Activity Score, 28 joints; CRP: serum C-reactive protein level; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; EAE: experimental autoimmune encephalomyelitis; IL: interleukin.

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mune diseases or to decrease their severity (Table 2), and vitamin D deficiency has been associated with many autoimmune diseases [1]. 4. Rheumatoid arthritis The prevalence of vitamin D deficiency is increased among patients with RA compared to the general population [28]. However, whether vitamin D deficiency is a cause or a consequence of the diseases remains unclear. In the Iowa Women’s Health Study, a higher vitamin D intake as assessed using a food frequency questionnaire was associated with a lower risk of RA [29]. However, a serum-bank case-control study from The Netherlands found no correlation between serum 25(OH)D3 levels and the development of RA [30]. In an evaluation of the Nurse’s Health Study cohort including 190 patients with SLE and 722 with RA, there was no correlation between vitamin D intake estimated from semi-quantitative food frequency questionnaires and the risk of SLE or RA [31]. In RA patients, serum 25(OH)D3 levels correlated negatively with disease activity [32]. In interventional trials, supplementation with 1 ␮g 1,25(OH)2 D3 had no significant effect [33], whereas higher doses were associated with decreased pain and significant declines in C-reactive protein levels [34]. In the murine model of collagen-induced arthritis, supplementation with 1,25(OH)2 D3 prevents arthritis development and halts arthritis progression [35–36]. In human chondrocyte cultures, vitamin D metabolites act via the VDR to regulate the transcription of numerous genes involved in chondrocyte metabolism. The results of this regulatory effect include modulation of proteoglycan and collagen synthesis and of the expression of specific matrix metalloproteinases. The VDR is expressed in the human rheumatoid synovium, at the junction between the cartilage and the pannus, by macrophages, chondrocytes, and synoviocytes; in contrast, VDR expression is not found in controls [37]. Joint fluid macrophages can produce 1,25(OH)2 D3. High levels of vitamin D metabolites have been found in joint fluid from patients with arthritis [38], suggesting a pathophysiological role for 1,25(OH)2 D3 in rheumatoid lesions. 5. Inflammatory bowel disease The prevalence of IBD is higher in areas that receive less sunlight, such as the northernmost parts of Europe and America [39]. Patients with IBD have lower serum 25(OH)D3 levels than do healthy controls [40]. This characteristic may be related to a combination of factors including decreased intestinal absorption, lower dietary intakes, and limited sun exposure. Patients with newly diagnosed IBD also have low serum 25(OH)D3 levels compared to controls [41]. In a recent double-blind randomized controlled trial in 108 patients with Crohn’s disease, daily oral supplementation with 1200 IU/d of 25(OH)D3 increased the mean serum 25(OH)D3 levels from 69 to 96 nmol/L and diminished the relapse rates over the 1year follow-up (13% vs. 29%; P = 0.06) compared to the placebo [42]. In IL-10 knockout mice, vitamin D deficiency was associated with accelerated bowel inflammation, whereas vitamin D3 supplementation had therapeutic effects [24]. In mice with experimentally induced colitis, a low calcemic vitamin D analog exhibited both preventive and therapeutic effects [43]. 6. Systemic lupus erythematosus In the US, African Americans have a three-fold higher incidence of SLE with earlier disease onset and higher morbidity and mortality rates compared to Caucasians [44]. A genetic factor does not seem involved, as SLE is rare in West Africa. The most likely expla-

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nation is vitamin D deficiency due to limited sunlight exposure and decreased penetration of ultraviolet B radiation through darker skin. Vitamin D deficiency is common in patients with SLE, regardless of disease duration, but may be a consequence of the disease, related for instance to photosensitivity requiring protection from sunlight [45]. A cross-sectional study found no significant difference in serum 25(OH)D3 levels between 25 women with SLE and 25 women with fibromyalgia [46]. Serum 25(OH)D3 levels may correlate negatively with disease activity [47]. In one study, serum 25(OH)D3 levels were lower in patients with undifferentiated connective tissue disease than in controls [48]. Vitamin D deficiency may be involved in the subsequent development in these patients of differentiated connective tissue diseases (RA, Sjögren’s syndrome, SLE, overlap syndromes, systemic vasculitides, and antiphospholipid syndrome). In addition, involvement of the skin and pleural membrane correlated negatively with serum 25(OH)D3 levels in this study [48]. In murine models of SLE, beneficial effects of vitamin D supplementation include decreased proteinuria and increased survival times [49–50]. 7. Diabetes and multiple sclerosis Serum 25(OH)D3 levels are often lower in patients with type 1 diabetes than in healthy controls. Vitamin D supplementation during childhood is associated with a decreased risk of type 1 diabetes. Thus, in a 30-year birth-cohort study (1966–1997), the relative risk of type 1 diabetes was 0.12 in the individuals who had received 2000 IU/day of supplemental vitamin D during their first year of life, compared to those given no vitamin D supplements [51]. Individuals with suspected rickets during the first year of life had a relative risk of 3.0 [51]. In mice with diabetes (NOD), administration of a 1,25(OH)2 D3 analog diminished the expressions of IL-12 and IFN␥, prevented DC maturation and pancreatic islet infiltration by Th1 cells, and halted disease progression [52]. Treg cells were probably involved in this effect, as they were found in increased numbers in the nodes draining the pancreas [53]. The prevalence of MS varies considerably with latitude, from 1–2/100,000 near the equator to more than 200/100,000 north of the 50th parallel [54]. Among patients with MS, 77% had serum 25(OH)D3 levels lower than 50 nmol/L [55]. In a study of seven million US military personnel, the risk of MS correlated negatively with serum 25(OH)D3 levels in Caucasians. However, these individuals had severe vitamin D deficiency, with serum 25(OH)D3 levels lower than 10 ng/ml, whereas the optimal level is estimated to be 90–100 nmol/L [56] Vitamin D supplementation decreases the risk of MS and, in MS patients, diminishes the relapse rate [57]. In the experimental autoimmune encephalitis murine model of MS, vitamin D supplementation exerts preventive and therapeutic effects that are mediated by IL-10 [58]. 8. Therapeutic implications To ensure optimal bone health, the serum 25(OH)D3 level should be at least 30 ng/ml (75 nmol/L), with the ideal range being estimated at 30–60 ng/ml. Vitamin D poisoning occurs at levels greater than 150 ng/ml [1]. Only fragmentary information is available on the serum 25(OH)D3 level required for vitamin D to exert immunomodulating effects. In one study, the risk of MS decreased by 41% for each 20 ng/ml increase in serum 25(OH)D3, starting at a threshold level of about 24 ng/ml (60 nmol/L) [56]. When serum 25(OH)D levels fall below 20 ng/ml (50 nmol/L), human monocytes and macrophages are unable to initiate some of the innate immune responses. This fact may explain the excess risk of tuberculosis in populations with vitamin D deficiency such as African-Americans [14]. No serum 25(OH)D threshold has been documented for RA.

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However, in one study, each 10 ng/ml increase in serum 25(OH)D was associated with a 0.3-point decrease in mean DAS28 and a 25% decrease in serum C-reactive protein [32]. The wide variety of vitamin D effects on the immune response suggests that vitamin D may hold therapeutic promise in many autoimmune diseases. Conceivably, increasing the vitamin D intake may diminish the incidence and severity of several diseases such as RA, type 1 diabetes, IBD, and MS. Obtaining immunomodulating effects in vitro requires local concentrations of 1,25(OH)2 D3 of about 10−10 M. To obtain such concentrations in vivo requires supraphysiological doses of vitamin D3, which are associated with an unacceptable risk of hypercalcemia. Therefore, vitamin D analogs that do not induce hypercalcemia have been developed. Another option may be to combine vitamin D3 with immunomodulators such as cyclosporine or bisphosphonates [43]. In vivo studies of murine models suggest that not only vitamin D, but also an adequate intake of dietary calcium, contribute to modulate the immune response in the gastrointestinal tract and central nervous system. Concomitant calcium supplementation enhances the ability of vitamin D to prevent IBD and MS [59]. Vitamin D exerts immunomodulating effects that may hold promise in many diseases characterized by inflammation, including autoimmune diseases, infections, malignancies, and cardiovascular diseases. These immunomodulating effects may be related to anti-Th1 and anti-Th17 effects, pro-Th2 effects, and induction of Treg and Tr1 cells [60]. Randomized controlled trials are under way to determine the best treatment modalities (dosage, target levels, pharmacological forms, and desirability of concomitant calcium supplementation). Conflict of interest statement The authors declare no conflicts of interest. References [1] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266–81. [2] Audran M, Briot K. Critical reappraisal of vitamin D deficiency. Joint Bone Spine 2010;77:115–9. [3] Souberbielle JC, Friedlander G, Kahan A, et al. Evaluating vitamin D status. Implications for preventing and managing osteoporosis and other chronic diseases. Joint Bone Spine 2006;73:249–53. [4] Maruotti N, Cantatore FP. Vitamin D and the immune system. J Rheumatol 2010;37(3):1–5. [5] Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 2007;66:1137–42. [6] Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 2008;8:685–98. [7] Sigmundsdottir H, Pan J, Debes GF, et al. DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat Immunol 2007;8:285–93. [8] Hewison M, Freeman L, Hughes SV, et al. Differential regulation of vitamin D receptor and its ligand in human monocyte-derived dendritic cells. J Immunol 2003;170:5382–90. [9] Provvedini DM, Tsoukas CD, Deftos LJ, et al. 1,25-dihydroxyvitamin D3 receptors in human leukocytes. Science 1983;221:1181–3. [10] Mathieu C, van Etten E, Gysemans C, et al. In vitro and in vivo analysis of the immune system of vitamin D receptor knockout mice. J Bone Miner Res 2001;16:2057–65. [11] Wittke A, Weaver V, Mahon BD, et al. Vitamin D receptor-deficient mice fail to develop experimental allergic asthma. J Immunol 2004;173:3432–6. [12] Helming L, Bose J, Ehrchen J, et al. 1alpha,25-dihydroxyvitamin D3 is a potent suppressor of interferon gamma-mediated macrophage activation. Blood 2005;106:4351–8. [13] Dickie LJ, Church LD, Coulthard LR, et al. Vitamin D3 down-regulates intracellular Toll-like receptor 9-induced IL-6 production in human monocytes. Rheumatology (Oxford) 2010;49:1466–71. [14] Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006;311:1770–3. [15] Griffin MD, Lutz W, Phan VA, et al. Dendritic cell modulation by 1 alpha,25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependant pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci U S A 2001;98:6800–5. [16] Gauzzi MC, Purificato C, Donato K, et al. Suppressive effect of 1 alpha,25dihydroxyvitamin D3 on type I IFN-mediated monocyte differenciation into

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