The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 13, 2019
REVIEW ARTICLE

Vitamin D, Inflammation and Immunity: Review of Literature and Considerations on Recent Translational and Clinical Research Developments



Amelia C. Trombetta, Sabrina Paolino, Maurizio Cutolo*
Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genoa, Genoa, Italy

Abstract

The most relevant and recent literature findings linking exposure to sunlight, Vitamin D (VD), inflammation and immune system in health and disease, are reviewed.

Reduced sunlight exposure determined hypo-vitaminosis D to be common among patients or even healthy subjects, especially at higher latitudes. Numerous studies support the hypothesis that VD insufficiency could contribute to the higher autoimmune diseases incidence in the same geographic areas.

In the present review, the ways in which VD was reported to influence immune system, contributing to organism homeostasis or disease development are addressed. In fact, some of the hormone activities were recognised to determine stimulation or inhibition of immune system components.

Several diseases, where an association with VD deficiency was studied, are summarised. Finally, the rationale for optimization of substitutive/additive therapy with VD analogues and the last innovations regarding these drugs are mentioned.

Keywords: Vitamin D, 25(OH)D, 1,25(OH)2D, Hypo-vitaminosis D, Autoimmunity, Inflammation, Rheumatic diseases.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
Issue: Suppl-1, M2
First Page: 201
Last Page: 213
Publisher Id: TORJ-12-201
DOI: 10.2174/1874312901812010201

Article History:

Received Date: 30/9/2017
Revision Received Date: 21/1/2018
Acceptance Date: 23/3/2018
Electronic publication date: 27/12/2018
Collection year: 2018

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© 2018 Trombetta et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Research Laboratory and Academic Division of Clinical Rheumatology, Department of Internal Medicine, IRCCS Policlinico San Martino, University of Genova, Viale Benedetto XV, 16132 Genova, Italy; Tel: +39 010 3537994, Fax: +390103537994; E-mail: mcutolo@unige.it




1. INTRODUCTION

Vitamin D3 (VD3) is a steroidal hormone, synthesized mainly in the skin from 7-dehydrocholesterol through ultraviolet B (UVB) radiation, and in smaller percentage provided by the diet. Further metabolic passages include conversion in the liver to 25-hydroxyVD3 (25(OH)D3), its circulating form, and activation to 1,25-dihydroxyVD3 (1,25(OH)2D3) by the 1-α-hydroxylase enzyme, in kidney proximal tubule cells [1Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3): 266-81.[http://dx.doi.org/10.1056/NEJMra070553] [PMID: 17634462] ].

The metabolite measured in blood to establish VD levels is 25(OH)D, being representative of the organism VD storage [2Souberbielle JC, Body JJ, Lappe JM, et al. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev 2010; 9(11): 709-15.[http://dx.doi.org/10.1016/j.autrev.2010.06.009] [PMID: 20601202] ]. The usual target range for 25(OH)D is 30-60 ng/mL or 75-150 nmol/L [3Holick MFVD. Vitamin D: Evolutionary, physiological and health perspectives. Curr Drug Targets 2011; 12(1): 4-18.[http://dx.doi.org/10.2174/138945011793591635] [PMID: 20795941] ].

As reported before, cutaneous synthesis provides 80%-100% of VD requirements, but it is to be mentioned that the natural solar source for starting the metabolic pathway is not equally distributed all over the world [4Kimlin MG. Geographic location and vitamin D synthesis. Mol Aspects Med 2008; 29(6): 453-61.[http://dx.doi.org/10.1016/j.mam.2008.08.005] [PMID: 18786559] ]. Environmental factors associated with changing solar zenith angle, such as season, latitude, time of day, determine UVB radiation strength and its consequent capability of stimulating VD synthesis. In fact, UVB reaches to the earth surface only when the sun is sufficiently high to penetrate all atmosphere layers. This situation verifies only in the middle of the day and, beyond the 40th parallel in mid and high latitude regions, only for a few months, from the middle of spring until the end of summer. Therefore, almost in all Europe and a large portion of North America and of the former Soviet Union countries, exposure to sun includes UVB only during this short time period [5Webb AR. Who, what, where and when-influences on cutaneous vitamin D synthesis. Prog Biophys Mol Biol 2006; 92(1): 17-25.[http://dx.doi.org/10.1016/j.pbiomolbio.2006.02.004] [PMID: 16766240] ].

Relevantly, those are the same regions where the highest prevalence of autoimmune diseases is observed.

Likewise, other steroidal hormones, VD3 appear to influence immune responses, in addition to its well-known effect on calcium and bone metabolism [6Cutolo M, Paolino S, Sulli A, Smith V, Pizzorni C, Seriolo B. Vitamin D, steroid hormones, and autoimmunity. Ann N Y Acad Sci 2014; 1317: 39-46.[http://dx.doi.org/10.1111/nyas.12432] [PMID: 24739090] , 7Cutolo M, Pizzorni C, Sulli A. Vitamin D endocrine system involvement in autoimmune rheumatic diseases. Autoimmun Rev 2011; 11(2): 84-7.[http://dx.doi.org/10.1016/j.autrev.2011.08.003] [PMID: 21864722] ].

Studies performed in the last twenty years of the past century, on patients with granulomatous diseases, such as sarcoidosis, in which high VD serum levels are present, showed expression of the 25OHD-1-α-hydroxylase enzyme in granulomas forming macrophages [8Barbour GL, Coburn JW, Slatopolsky E, Norman AW, Horst RL. Hypercalcemia in an anephric patient with sarcoidosis: Evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N Engl J Med 1981; 305(8): 440-3.[http://dx.doi.org/10.1056/NEJM198108203050807] [PMID: 6894783] ]. In fact, conversion of 25-OHD to 1,25(OH)D occurs in immune system cells, expressing a different form of 1-α-hydroxylase enzyme and capable of converting the precursor to the active form. The extra-renal enzyme is not regulated by parathyroid hormone, but seems to be induced by cytokines, such as interferon (IFN)-γ, interleukin (IL)-1, or Tumour Necrosis Factor (TNF)-α [9van Etten E, Stoffels K, Gysemans C, et al. Regulation of VD homeostasis: Implications for the immune system. Nutr Rev 2008; 66(10 suppl 2): S125-YS134.]. Lately, in sarcoidosis, presence of a high number of T regulatory cells (Tregs) was demonstrated, together with the peripheral energy of immune system cells [10Miyara M, Amoura Z, Parizot C, et al. The immune paradox of sarcoidosis and regulatory T cells. J Exp Med 2006; 203(2): 359-70.[http://dx.doi.org/10.1084/jem.20050648] [PMID: 16432251] ].

Interestingly, 1-α-hydroxylase enzyme forms were also described in keratinocytes and consequently, they were considered as a source for autocrine synthesis of 1,25(OH)2D [11Schauber J, Dorschner RA, Coda AB, et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest 2007; 117(3): 803-11.[http://dx.doi.org/10.1172/JCI30142] [PMID: 17290304] ].

A pleiotropic role for VD3 is supported also by the presence of VD Receptor (VDR) on various cell types, in healthy and diseased tissues like bone marrow, brain, colon, breast, malignant and immune cells [12Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab 2009; 94(1): 26-34.[http://dx.doi.org/10.1210/jc.2008-1454] [PMID: 18854395] ]. In immune system cells, VDR is present on monocytes and macrophages, dendritic cells, T cells and B cells. Consequently, it was postulated that VD can have, in the periphery, a paracrine or autocrine action, binding on responsive elements (VDRE), located on DNA, and changing the way immune system genes are expressed [13Mora JR, Iwata M, von Andrian UH. Vitamin effects on the immune system: Vitamins A and D take centre stage. Nat Rev Immunol 2008; 8(9): 685-98.[http://dx.doi.org/10.1038/nri2378] [PMID: 19172691] ].

Several studies testified the correlation between acquired VD deficiency and reduced immune function or autoimmunity development, cancer and even cardiovascular diseases [14Cannell JJ, Vieth R, Umhau JC, et al. Epidemic influenza and vitamin D. Epidemiol Infect 2006; 134(6): 1129-40.[http://dx.doi.org/10.1017/S0950268806007175] [PMID: 16959053] -18Cutolo M, Straub RH. Insights into endocrine-immunological disturbances in autoimmunity and their impact on treatment. Arthritis Res Ther 2009; 11(2): 218.[http://dx.doi.org/10.1186/ar2630] [PMID: 19435479] ].

Also, the potential for confounding factors was investigated, since the presence of a systemic inflammatory response was reported to be associated with lower levels of micronutrients like albumin or lipid soluble vitamins, in plasma [19Galloway P, McMillan DC, Sattar N. Effect of the inflammatory response on trace element and vitamin status. Ann Clin Biochem 2000; 37(Pt 3): 289-97.[http://dx.doi.org/10.1258/0004563001899429] [PMID: 10817241] ].

1.1. Vd and Innate Immunity

VD has both stimulatory and inhibitory effects on innate immune cells. Macrophages, monocyte-derived dendritic cells (DCs) and dermal DCs own the whole enzyme supply needed to convert VD3 into 1,25(OH)2VD3 Figs. (1 and 2) [20van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: Basic concepts. J Steroid Biochem Mol Biol 2005; 97(1-2): 93-101.[http://dx.doi.org/10.1016/j.jsbmb.2005.06.002] [PMID: 16046118] , 21Fritsche J, Mondal K, Ehrnsperger A, Andreesen R, Kreutz M. Regulation of 25-hydroxyvitamin D3-1 α-hydroxylase and production of 1 α,25-dihydroxyvitamin D3 by human dendritic cells. Blood 2003; 102(9): 3314-6.[http://dx.doi.org/10.1182/blood-2002-11-3521] [PMID: 12855575] ].

Fig. (1)
Cell-to cell interactions in immune responses modulated by VD.


According to in vitro studies, VD could contribute in the induction of differentiation of immature myeloid cells into monocytes and macrophages [22Kreutz M, Andreesen R. Induction of human monocyte to macrophage maturation in vitro by 1,25-dihydroxyvitamin D3. Blood 1990; 76(12): 2457-61.[PMID: 2265241] ]. Moreover, VD3 deficiency and hypo-functional VDR polymorphisms are involved in susceptibility to Mycobacterium tuberculosis and Mycobacterium leprae [23Wilkinson RJ, Llewelyn M, Toossi Z, et al. Influence of vitamin D deficiency and vitamin D receptor polymorphisms on tuberculosis among gujarati asians in West London: A case-control study. Lancet 2000; 355(9204): 618-21.[http://dx.doi.org/10.1016/S0140-6736(99)02301-6] [PMID: 10696983] ]. Interestingly, studies on Mycobacterium tuberculosis resistance showed that an important role is exercised by VD in the innate immune system. In fact, VD seems to be implicated in toll-like receptors (TLRs) dependent pathways, leading to synthesis of bactericidal peptides like cathelicidin and beta defensin 4, in circulating monocytes and tissue macrophages. Binding of macrophages TLR2 or TLR4 with microbial peptides determines hyper-expression of 1-α-hydroxylase and VDR. The result is the formation of a heterodimer by 1,25OHD-VDR and retinoid X receptor (RXR) that is able to act over VDRE on cathelicidin and beta defensin 4 genes, enhancing their transcription. The cited mechanism is determinant for the killing of intracellular bacteria [24Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311(5768): 1770-3.[http://dx.doi.org/10.1126/science.1123933] [PMID: 16497887] ]. Moreover, induction of superoxide production by THP-1 cells infected with live Mycobacterium tuberculosis and treated with VD3 was described [15Villamor E. A potential role for vitamin D on HIV infection? Nutr Rev 2006; 64(5 Pt 1): 226-33.[http://dx.doi.org/10.1111/j.1753-4887.2006.tb00205.x] [PMID: 16770943] ].

Other studies postulated a VD3 mediated downregulation of TLRs expression on monocytes, of TLRs mediated innate immune responses and consequently also a limitation of T helper (Th)1 activity [25Sadeghi K, Wessner B, Laggner U, et al. Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns. Eur J Immunol 2006; 36(2): 361-70.[http://dx.doi.org/10.1002/eji.200425995] [PMID: 16402404] ].

VD is able to suppress the synthesis of IL-12, reduce IFN-α secretion and increase the production of IL-10 by DCs. Nutritional supplements containing VD determine higher IL-10 blood levels [26Aranow C. Vitamin D and the immune system. J Investig Med 2011; 59(6): 881-6.[http://dx.doi.org/10.2310/JIM.0b013e31821b8755] [PMID: 21527855] , 27Ben-Zvi I, Aranow C, Mackay M, et al. The impact of VD on dendritic cell function in patients with systemic lupus erythematosus. PLoS One 2010; 16(5): e9193.]. IL-10 is known to down-regulate inflammatory responses reducing antigen presentation by DCs and macrophages [28Trinchieri G, Sher A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 2007; 7(3): 179-90.[http://dx.doi.org/10.1038/nri2038] [PMID: 17318230] ]. DCs are also inhibited in their differentiation, maturation and immuno-stimulatory function following MHC class II molecules and CD40, CD80 and CD86 reduced expression [29Penna G, Adorini L. 1 α,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 2000; 164(5): 2405-11.[http://dx.doi.org/10.4049/jimmunol.164.5.2405] [PMID: 10679076] ] (Figs. 1 and 2).

A regulatory function was also reported for VD on leukocyte migration, explained possibly by a reduced peripheral chemokine synthesis: decreased synthesis of CCL2, CCL3, CXCL10 in Experimental Autoimmune Encephalomyelitis (EAE) and of CCL2, CCL5, CXCL10 in non-obese diabetic (NOD) mice [30Pedersen LB, Nashold FE, Spach KM, Hayes CE. 1, 25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking. J Neurosci Res 2007; 85(11): 2480-90.[http://dx.doi.org/10.1002/jnr.21382] [PMID: 17600374] , 31Giarratana N, Penna G, Amuchastegui S, Mariani R, Daniel KC, Adorini L. A vitamin D analog down-regulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development. J Immunol 2004; 173(4): 2280-7.[http://dx.doi.org/10.4049/jimmunol.173.4.2280] [PMID: 15294940] ].

Fig. (2)
The multiple activities physiologically carried out by VD towards immune system cells are summarized in the figure. In red all immuno-regulating, in green all immuno-stimulating activities. IL= interleukine; IFN= interferon; Th= T helper; Tregs= T regulatory.


1.2. Vd and Adaptive Immunity

Activated T and B cells possess only the enzymatic activity for converting 25(OH)D3 to 1,25(OH)2D3 [32van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: Basic concepts. J Steroid Biochem Mol Biol 2005; 97(1-2): 93-101.[http://dx.doi.org/10.1016/j.jsbmb.2005.06.002] [PMID: 16046118] ].

VD was correlated with reduced lymphocytes Th1 and Th17 responses and increased Th2 and Tregs activation [33Mathieu C, van Etten E, Decallonne B, et al. Vitamin D and 1, 25-dihydroxyvitamin D3 as modulators in the immune system. J Steroid Biochem Mol Biol 2004; 89-90(1-5): 449-52.[http://dx.doi.org/10.1016/j.jsbmb.2004.03.014] [PMID: 15225818] ]. Inhibitory effects are especially exercised on memory T cells, in concordance with their higher VDR expression [34Veldman CM, Cantorna MT, DeLuca HF. Expression of 1, 25-dihydroxyvitamin D(3) receptor in the immune system. Arch Biochem Biophys 2000; 374(2): 334-8.[http://dx.doi.org/10.1006/abbi.1999.1605] [PMID: 10666315] ]. In vitro, VD3 inhibits T cell proliferation, IL-2 and IFN-γ secretion and CD8 T cell cytotoxicity [35Rigby WF, Stacy T, Fanger MW. Inhibition of T lymphocyte mitogenesis by 1, 25-dihydroxyvitamin D3 (calcitriol). J Clin Invest 1984; 74(4): 1451-5.[http://dx.doi.org/10.1172/JCI111557] [PMID: 6332829] , 36Meehan MA, Kerman RH, Lemire JM. 1,25-Dihydroxyvitamin D3 enhances the generation of nonspecific suppressor cells while inhibiting the induction of cytotoxic cells in a human MLR. Cell Immunol 1992; 140(2): 400-9.[http://dx.doi.org/10.1016/0008-8749(92)90206-5] [PMID: 1531943] ].

The decrease IL-2 and IFNγ production is mediated by binding of the VDR–rXr complex to promoters of genes encoding IL-2 and IFNγ [37Alroy I, Towers TL, Freedman LP. Transcriptional repression of the interleukin-2 gene by vitamin D3: Direct inhibition of NFATp/AP-1 complex formation by a nuclear hormone receptor. Mol Cell Biol 1995; 15(10): 5789-99.[http://dx.doi.org/10.1128/MCB.15.10.5789] [PMID: 7565732] , 38Cippitelli M, Santoni A. Vitamin D3: A transcriptional modulator of the interferon-γ gene. Eur J Immunol 1998; 28(10): 3017-30.[http://dx.doi.org/10.1002/(SICI)1521-4141(199810)28:10<3017::AID-IMMU3017>3.0.CO;2-6] [PMID: 9808170] ]. The effect on Th17 cells was attributed to inhibition of IL-6 and IL-23 production [39Daniel C, Sartory NA, Zahn N, Radeke HH, Stein JM. Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile. J Pharmacol Exp Ther 2008; 324(1): 23-33.[http://dx.doi.org/10.1124/jpet.107.127209] [PMID: 17911375] ].

CD8+ T cell deficiency characterizes many autoimmune diseases. An interesting hypothesis on autoimmune diseases development was proposed in 2012. The Authors postulated that VD lower levels at higher latitudes could facilitate the development of auto-reactive B cells, by aggravating a deficient control of Epstein Barr virus infection from CD8 T cells [40Pender MP. CD8+ T-Cell deficiency, epstein-Barr virus infection, VD deficiency, and steps to autoimmunity: A unifying hypothesis. Autoimmune Dis 2012; 2012: 189096.[http://dx.doi.org/10.1155/2012/189096] [PMID: 22312480] ].

VD has also inhibitory effects on B cells and plasma-cells, reducing their proliferation, differentiation and Ig secretion. In B cells, VDR receptor activated signal cascade leads to impaired class switch recombination, with following reduced IgE synthesis. Up-regulation of IL-10 production in DCs can contribute to this process, inhibiting IL-4 mediated IgE synthesis [41Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE. Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 2007; 179(3): 1634-47.[http://dx.doi.org/10.4049/jimmunol.179.3.1634] [PMID: 17641030] ]. Interestingly, it was demonstrated that cultures of activated B lymphocytes produce calcitriol and express IL-10 in response to autocrine and exogenous calcitriol production (Figs. 1 and 2). The relevant immuno-modulatory role of B cells, through production of IL-10, was demonstrated in ulcerative colitis treated with anti-CD20 (Rituximab). Mucosal B cell reduction and following fall of local IL-10 levels led to higher disease activity after treatment [42Jones G, Strugnell SA, DeLuca HF. Current understanding of the molecular actions of vitamin D. Physiol Rev 1998; 78(4): 1193-231.[http://dx.doi.org/10.1152/physrev.1998.78.4.1193] [PMID: 9790574] ]. Expression of 1-α hydroxylase in B cells seems to be dependent on T cell help, through stimulation with CD-40 and IL-4 [43Heine G, Niesner U, Chang HD, et al. 1,25-dihydroxyvitamin D(3) promotes IL-10 production in human B cells. Eur J Immunol 2008; 38(8): 2210-8.[http://dx.doi.org/10.1002/eji.200838216] [PMID: 18651709] ].

Also, VD substitutive therapy is reported to reduce Th1 and Th17 and increase Tregs responses. Consequently, also an indirect effect on differentiation, proliferation and antibody production could be postulated for B cells during treatment with VD analogues [30Pedersen LB, Nashold FE, Spach KM, Hayes CE. 1, 25-dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking. J Neurosci Res 2007; 85(11): 2480-90.[http://dx.doi.org/10.1002/jnr.21382] [PMID: 17600374] , 44Reihani H, Rastin M, Mahmoudi M, et al. Influence of 1 alpha, 25-dihydroxyvitamin D3 on T helper 17 cells and related cytokines in systemic lupus erythematosus. Iran J Immunol 2015; 12(2): 82-93.[PMID: 26119191] ].

2. HYPOVITAMINOSIS D AND AUTOIMMUNE DISEASES

From the clinical point of view, hypo-vitaminosis D was associated with higher risk of auto-immune rheumatic diseases, especially for Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Systemic Sclerosis (SSc), Idiopathic Inflammatory Myopathies (IIM), but also Multiple Sclerosis (MS), Inflammatory Bowel Diseases (IBD), type 1 diabetes and other autoimmune endocrine diseases [45Cutolo M. Further emergent evidence for the vitamin D endocrine system involvement in autoimmune rheumatic disease risk and prognosis. Ann Rheum Dis 2013; 72(4): 473-5.[http://dx.doi.org/10.1136/annrheumdis-2012-202538] [PMID: 23440106] -51Cutolo M. Vitamin D or hormone D deficiency in autoimmune rheumatic diseases, including undifferentiated connective tissue disease. Arthritis Res Ther 2008; 10(6): 123.[http://dx.doi.org/10.1186/ar2552] [PMID: 19090978] ].

Interestingly, VD deficiency was associated with an increased autoimmune response also in healthy individuals. In these subjects, it was demonstrated that VD deficiency was associated with increased auto-immune response with Anti-Nuclear Antibody (ANA) positivity and higher interferton (IFN)-α activity [43Heine G, Niesner U, Chang HD, et al. 1,25-dihydroxyvitamin D(3) promotes IL-10 production in human B cells. Eur J Immunol 2008; 38(8): 2210-8.[http://dx.doi.org/10.1002/eji.200838216] [PMID: 18651709] ].

It is to be cited that also VDR mutations with reduced function were reported in several autoimmune diseases [26Aranow C. Vitamin D and the immune system. J Investig Med 2011; 59(6): 881-6.[http://dx.doi.org/10.2310/JIM.0b013e31821b8755] [PMID: 21527855] , 52Penna G, Amuchastegui S, Giarratana N, et al. 1,25-Dihydroxyvitamin D3 selectively modulates tolerogenic properties in myeloid but not plasmacytoid dendritic cells. J Immunol 2007; 178(1): 145-53.[http://dx.doi.org/10.4049/jimmunol.178.1.145] [PMID: 17182549] ].

Many studies on animal models attest the usefulness of supplementation with VDR agonists in prevention and treatment of arthritis, autoimmune diabetes, EAE, IBDs, psoriasis and SLE [53Larsson P, Mattsson L, Klareskog L, Johnsson C. A vitamin D analogue (MC 1288) has immunomodulatory properties and suppresses Collagen-Induced Arthritis (CIA) without causing hypercalcaemia. Clin Exp Immunol 1998; 114(2): 277-83.[http://dx.doi.org/10.1046/j.1365-2249.1998.00706.x] [PMID: 9822288] -59Adorini L, Penna G. Control of autoimmune diseases by the vitamin D endocrine system. Nat Clin Pract Rheumatol 2008; 4(8): 404-12.[http://dx.doi.org/10.1038/ncprheum0855] [PMID: 18594491] ].

Interestingly, Sainaghi et al. demonstrated, in a large retrospective study, on patients affected by autoimmune rheumatic diseases, a greater trend to development of higher parathyroid hormone (PTH) responses, compared to unaffected subjects with similarly low VD levels. In the study, the Authors observed that VD plasmatic concentrations, age and an autoimmune rheumatic disease, were independent predictors for hyperparathyroidism. Therefore, a hypothesis for an impairment of VD metabolism in course of inflammation has been developed, characterized by a scarce suppressive activity of VD on PTH secretion. Consequently, the research concludes that VD concentrations should always be assessed together with that of PTH, calcium and phosphate, to evaluate VD metabolism correctly. Moreover, the Authors postulate that VD supplementation should, therefore, be targeted to obtain PTH suppression [60Sainaghi PP, Bellan M, Antonini G, Bellomo G, Pirisi M. Unsuppressed parathyroid hormone in patients with autoimmune/inflammatory rheumatic diseases: Implications for vitamin D supplementation. Rheumatology 2011; 50(12): 2290-6.[http://dx.doi.org/10.1093/rheumatology/ker314] [PMID: 22019806] ]

A following study from the same group, demonstrated in autoimmune rheumatic diseases affected patients, that a treatment with a single oral dose of cholecalciferol 300,000 IU, followed by oral cholecalciferol 800-1000 IU daily for 6 months, was a more effective regime for determining PTH suppression [61Sainaghi PP, Bellan M, Nerviani A, et al. Superiority of a high loading dose of cholecalciferol to correct hypovitaminosis d in patients with inflammatory/autoimmune rheumatic diseases. J Rheumatol 2013; 40(2): 166-72.[http://dx.doi.org/10.3899/jrheum.120536] [PMID: 23242183] ].

2.1. Systemic Lupus Erythematosus

Many clinical studies focused on the relation between hypo-vitaminosis D and SLE [62Cutolo M, Otsa K, Paolino S, Yprus M, Veldi T, Seriolo B. Vitamin D involvement in rheumatoid arthritis and systemic lupus erythaematosus. Ann Rheum Dis 2009; 68(3): 446-7.[http://dx.doi.org/10.1136/ard.2008.093476] [PMID: 19213751] ]. SLE patients are by definition VD deficient, because instructed on sun avoidance and use of sunscreens [43Heine G, Niesner U, Chang HD, et al. 1,25-dihydroxyvitamin D(3) promotes IL-10 production in human B cells. Eur J Immunol 2008; 38(8): 2210-8.[http://dx.doi.org/10.1002/eji.200838216] [PMID: 18651709] , 63Cutolo M, Otsa K. Review: vitamin D, immunity and lupus. Lupus 2008; 17(1): 6-10.[http://dx.doi.org/10.1177/0961203307085879] [PMID: 18089676] ].

Some authors studied the seasonality of disease flares, showing that SLE reactivation was correlated with lower VD serum levels, in wintertime [64Dall’Ara F, Andreoli L, Piva N, Piantoni S, Franceschini F, Tincani A. Winter lupus flares are associated with low vitamin D levels in a retrospective longitudinal study of Italian adult patients. Clin Exp Rheumatol 2015; 33(2): 153-8.[PMID: 25664429] ].

A meta-analysis of eleven heterogeneous articles showed in most of the papers an inverse correlation between serum VD levels and SLE disease activity [65Sahebari M, Nabavi N, Salehi M. Correlation between serum 25(OH)D values and lupus disease activity: An original article and a systematic review with meta-analysis focusing on serum VitD confounders. Lupus 2014; 23(11): 1164-77.[http://dx.doi.org/10.1177/0961203314540966] [PMID: 24961748] ].

Regarding organ specific aspects, an association was found by several studies between VD levels, general cardiovascular risk, vascular stiffness and endothelial dysfunction, in SLE patients [66Wu PW, Rhew EY, Dyer AR, et al. 25-hydroxyvitamin D and cardiovascular risk factors in women with systemic lupus erythematosus. Arthritis Rheum 2009; 61(10): 1387-95.[http://dx.doi.org/10.1002/art.24785] [PMID: 19790113] , 67Sabio JM, Vargas-Hitos JA, Martinez-Bordonado J, et al. Association between low 25-hydroxyvitamin D, insulin resistance and arterial stiffness in nondiabetic women with systemic lupus erythematosus. Lupus 2015; 24(2): 155-63.[http://dx.doi.org/10.1177/0961203314551811] [PMID: 25216653] ]. Moreover, hypo-vitaminosis D was also associated with SLE with cognitive impairment, fatigue and sleep disorders [68Tay SH, Ho CS, Ho RC, Mak A. 25-Hydroxyvitamin D3 deficiency independently predicts cognitive impairment in patients with systemic lupus erythematosus. PLoS One 2015; 10(12): e0144149.[http://dx.doi.org/10.1371/journal.pone.0144149] [PMID: 26636681] , 69Ruiz-Irastorza G, Gordo S, Olivares N, Egurbide MV, Aguirre C. Changes in vitamin D levels in patients with systemic lupus erythematosus: Effects on fatigue, disease activity, and damage. Arthritis Care Res 2010; 62(8): 1160-5.[http://dx.doi.org/10.1002/acr.20186] [PMID: 20235208] ].

In SLE patients, several prospective studies (each with a different treatment schedule) were performed on VD supplementation, with contrasting results. Terrier et al. described an increase in naive T CD4+ and regulatory T cells and a decrease in Th1, Th17 and B memory cells numbers [70Terrier B, Derian N, Schoindre Y, et al. Restoration of regulatory and effector T cell balance and B cell homeostasis in systemic lupus erythematosus patients through vitamin D supplementation. Arthritis Res Ther 2012; 14(5): R221.[http://dx.doi.org/10.1186/ar4060] [PMID: 23075451] ].

Andreoli et al. described higher levels of Tregs cells and Th2 cytokines after long term monthly treatment with cholecalciferol [71Piantoni S, Andreoli L, Scarsi M, et al. Phenotype modifications of T-cells and their shift toward a Th2 response in patients with systemic lupus erythematosus supplemented with different monthly regimens of vitamin D. Lupus 2015; 24(4-5): 490-8.[http://dx.doi.org/10.1177/0961203314559090] [PMID: 25801892] ].

An intensive regimen of VD supplementation in SLE patients with inactive disease, showed to obtain sufficient levels of serum 25(OH)D, but no effect on disease activity or serology [72Andreoli L, Dall’Ara F, Piantoni S, et al. A 24-month prospective study on the efficacy and safety of two different monthly regimens of vitamin D supplementation in pre-menopausal women with systemic lupus erythematosus. Lupus 2015; 24(4-5): 499-506.[http://dx.doi.org/10.1177/0961203314559089] [PMID: 25801893] ].

On the other hand, Aranow et al. described failure of a VD supplementation, up to 4,000 IU daily, in diminishing the IFN signature in VD-deficient SLE patients in a 12-week double-blind, placebo-controlled trial. The Authors hypothesized that higher VD levels sustained for a longer period may be required to affect immunologic outcomes [73Aranow C, Kamen DL, Dall’Era M, et al. Randomized, double-blind, placebo-controlled Trial of the effect of vitamin D3 on the interferon signature in patients with systemic lupus erythematosus. Arthritis Rheumatol 2015; 67(7): 1848-57.[http://dx.doi.org/10.1002/art.39108] [PMID: 25777546] ].

Polymorphisms of VDR seem to account for the individual response to VD, and it was found that some are associated with increased risk of SLE development and to disease phenotype [74Hu W, Niu G, Lin Y, Chen X, Lin L. Impact of the polymorphism in vitamin D receptor gene BsmI and the risk of systemic lupus erythematosus: An updated meta-analysis. Clin Rheumatol 2016; 35(4): 927-34.[http://dx.doi.org/10.1007/s10067-015-3157-x] [PMID: 26712498] , 75Carvalho C, Marinho A, Leal B, et al. Association between Vitamin D Receptor (VDR) gene polymorphisms and systemic lupus erythematosus in Portuguese patients. Lupus 2015; 24(8): 846-53.[http://dx.doi.org/10.1177/0961203314566636] [PMID: 25661837] ].

2.2. Rheumatoid Arthritis

Multicentre studies have shown significantly lower 25(OH)D serum levels in RA patients compared to matched controls [76Cutolo M, Otsa K, Uprus M, Paolino S, Seriolo B. Vitamin D in rheumatoid arthritis. Autoimmun Rev 2007; 7(1): 59-64.[http://dx.doi.org/10.1016/j.autrev.2007.07.001] [PMID: 17967727] ]. It was recently demonstrated that VD serum concentrations appear to correlate with clinimetric indexes for quality of life, disease activity and disability in a cohort of RA European patients [77Vojinovic J, Tincani A, Sulli A, et al. European multicentre pilot survey to assess vitamin D status in rheumatoid arthritis patients and early development of a new patient reported outcome questionnaire (D-PRO). Autoimmun Rev 2017; 16(5): 548-54.[http://dx.doi.org/10.1016/j.autrev.2017.03.002] [PMID: 28279841] , 78Cutolo M, Otsa K, Yprus M, Seriolo B. Vitamin D and rheumatoid arthritis: Comment on the letter by Nielen et al. Arthritis Rheum 2007; 56(5): 1719-20.[http://dx.doi.org/10.1002/art.22569] [PMID: 17469165] ]. The Authors constructed a new Patient Reported Outcome (PRO) questionnaire for RA patients’ self-estimation of the risk for VD insufficiency/deficiency-related clinical implications (D-PRO) [70Terrier B, Derian N, Schoindre Y, et al. Restoration of regulatory and effector T cell balance and B cell homeostasis in systemic lupus erythematosus patients through vitamin D supplementation. Arthritis Res Ther 2012; 14(5): R221.[http://dx.doi.org/10.1186/ar4060] [PMID: 23075451] ].

Many studies have linked a higher risk of RA development to higher latitudes especially in winter months [79Cutolo M, Otsa K, Laas K, et al. Circannual vitamin d serum levels and disease activity in rheumatoid arthritis: Northern versus Southern Europe. Clin Exp Rheumatol 2006; 24(6): 702-4.[PMID: 17207389] ]. Lower UV-B light exposure was extensively studied as a risk factor for RA development in prospective cohort studies, the Nurses’ Health Study (NHS) and the NHSII, confirming a significantly decreased risk with higher UVB exposure especially in the absence of sun-protective behaviours [80Arkema EV, Hart JE, Bertrand KA, et al. Exposure to ultraviolet-B and risk of developing rheumatoid arthritis among women in the Nurses’ Health Study. Ann Rheum Dis 2013; 72(4): 506-11.[http://dx.doi.org/10.1136/annrheumdis-2012-202302] [PMID: 23380431] ].

It was also demonstrated in RA that winter or spring season of symptom onset can act as an independent predictive factor for joint structural damage progression at 6 months and radiographic progression at 12 months [81Mouterde G, Lukas C, Logeart I, et al. Predictors of radiographic progression in the ESPOIR cohort: The season of first symptoms may influence the short-term outcome in early arthritis. Ann Rheum Dis 2011; 70(7): 1251-6.[http://dx.doi.org/10.1136/ard.2010.144402] [PMID: 21515603] ].

Presence of severe 25(OH)D deficiency (<10 ng/ml) was associated with worsening of symptoms like musculoskeletal pain in RA, while improvements are seen after supplementation [82Haque UJ, Bartlett SJ. Relationships among vitamin D, disease activity, pain and disability in rheumatoid arthritis. Clin Exp Rheumatol 2010; 28(5): 745-7.[PMID: 20883640] , 83Gopinath K, Danda D. Supplementation of 1,25 dihydroxy vitamin D3 in patients with treatment naive early rheumatoid arthritis: A randomised controlled trial. Int J Rheum Dis 2011; 14(4): 332-9.[http://dx.doi.org/10.1111/j.1756-185X.2011.01684.x] [PMID: 22004229] ]. Pre-treatment of human macrophages with oestrogens can reproduce the hormonal milieu of the inflamed RA joints, where aromatase is activated and pro-inflammatory cytokines are released. It was demonstrated that VD treatment blocks completely oestrogen related aromatase activation [84Capellino S, Straub RH, Cutolo M. Aromatase and regulation of the estrogen-to-androgen ratio in synovial tissue inflammation: Common pathway in both sexes. Ann N Y Acad Sci 2014; 1317: 24-31.[http://dx.doi.org/10.1111/nyas.12398] [PMID: 24684533] , 85Villaggio B, Soldano S, Cutolo M. 1,25-dihydroxyvitamin D3 downregulates aromatase expression and inflammatory cytokines in human macrophages. Clin Exp Rheumatol 2012; 30(6): 934-8.[PMID: 23253631] ].

2.3. Systemic Sclerosis

In SSc patients, low VD serum concentrations have been shown [86Vacca A, Cormier C, Piras M, Mathieu A, Kahan A, Allanore Y. Vitamin D deficiency and insufficiency in 2 independent cohorts of patients with systemic sclerosis. J Rheumatol 2009; 36(9): 1924-9.[http://dx.doi.org/10.3899/jrheum.081287] [PMID: 19648299] ]. Arnson et al. demonstrated, in a large multinational SSc patients’ population, that lower serum VD concentrations were inversely correlated with the extent of cutaneous fibrosis [87Arnson Y, Amital H, Agmon-Levin N, et al. Serum 25-OH vitamin D concentrations are linked with various clinical aspects in patients with systemic sclerosis: A retrospective cohort study and review of the literature. Autoimmun Rev 2011; 10(8): 490-4.[http://dx.doi.org/10.1016/j.autrev.2011.02.002] [PMID: 21320645] ].

A correlation with severe nailfold video-capillaroscopic alterations and worse quality of life parameters were reported in patients with diffuse SSc form and with lower 25(OH)D serum concentrations [88Sampaio-Barros MM, Takayama L, Sampaio-Barros PD, Bonfá E, Pereira RM. Low vitamin D serum levels in diffuse systemic sclerosis: A correlation with worst quality of life and severe capillaroscopic findings. Rev Bras Reumatol Engl Ed 2016; 56(4): 337-44.[http://dx.doi.org/10.1016/j.rbre.2016.05.006] [PMID: 27476627] ].

Moreover, in a large study on SSc patients from two European reference centres, serum 25(OH)D deficiency was found to correlate with severe lung involvement, peripheral vascular, kidney and gastrointestinal Medsger’s disease severity scale parameters. Furthermore, 25(OH)D serum levels were reported to correlate with seasonality, while a supplementation with standard doses of oral cholecalciferol was found not effective in normalising serum 25(OH)D values [89Seriolo B, Molfetta L, Cutolo M. Seasonal variations in serum levels of 25-hydroxyvitamin D in patients with systemic sclerosis. Clin Rheumatol 2011; 30(3): 445-6.[http://dx.doi.org/10.1007/s10067-011-1684-7] [PMID: 21234627] , 90Trombetta AC, Smith V, Gotelli E, et al. Vitamin D deficiency and clinical correlations in systemic sclerosis patients: A retrospective analysis for possible future developments. PLoS One 2017; 12(6): e0179062.[http://dx.doi.org/10.1371/journal.pone.0179062] [PMID: 28598975] ].

2.4. Idiopathic Inflammatory Myopathies

VD deficiency was reported in patients with Idiopathic Inflammatory Myopathies (IIM) like Polymyositis (PM), Dermatomyositis (DM), Inclusion Body Myositis (IBM) compared to controls matched for age, gender and month of serum sampling. VD levels were found to be lower in patients more close to diagnosis than in those with established disease, suggesting that low levels of VD may constitute a risk factor for developing IIM. As for RA, the IIM cases were found to be diagnosed more frequently during winter or spring. Finally, higher serum anti-Jo-1 antibodies title were shown to be correlated with lower serum 25(OH)D levels [49Azali P, Barbasso Helmers S, Kockum I, et al. Low serum levels of vitamin D in idiopathic inflammatory myopathies. Ann Rheum Dis 2013; 72(4): 512-6.[http://dx.doi.org/10.1136/annrheumdis-2012-201849] [PMID: 22993226] ].

2.5. Multiple Sclerosis

Multiple studies strongly suggested that an insufficient exposure to sun or VD assumption, during the first part of life, constitutes a major risk for MS development [91Munger KL, Zhang SM, O’Reilly E, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004; 62(1): 60-5.[http://dx.doi.org/10.1212/01.WNL.0000101723.79681.38] [PMID: 14718698] , 92Nielsen NM, Munger KL, Koch-Henriksen N, et al. Neonatal vitamin D status and risk of multiple sclerosis: A population-based case-control study. Neurology 2017; 88(1): 44-51.[http://dx.doi.org/10.1212/WNL.0000000000003454] [PMID: 27903815] ].

Supplementation with VD has shown to have multiple positive immunological effects in patients affected by MS. Higher Tregs count, IL-10 cytokine activity and reduction of the pro-inflammatory Th17 lymphocytes, of IL-17 and of B-cell immunoreactivity were achieved [93Muris AH, Smolders J, Rolf L, Thewissen M, Hupperts R, Damoiseaux J. Immune regulatory effects of high dose vitamin D3 supplementation in a randomized controlled trial in relapsing remitting multiple sclerosis patients receiving IFNβ the SOLARIUM study. J Neuroimmunol 2016; 300: 47-56.[http://dx.doi.org/10.1016/j.jneuroim.2016.09.018] [PMID: 27806875] -95da Costa DS, Hygino J, Ferreira TB, et al. Vitamin D modulates different IL-17-secreting T cell subsets in multiple sclerosis patients. J Neuroimmunol 2016; 299: 8-18.[http://dx.doi.org/10.1016/j.jneuroim.2016.08.005] [PMID: 27725127] ]. Additionally, low serum 25 (OH)D and a recent Epstein-Barr Virus (EBV) infection were found to be associated with blood donors with the first clinical MS manifestation [96Sotirchos ES, Bhargava P, Eckstein C, et al. Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology 2016; 86(4): 382-90.[http://dx.doi.org/10.1212/WNL.0000000000002316] [PMID: 26718578] -97Décard BF, von Ahsen N, Grunwald T, et al. Low vitamin D and elevated immunoreactivity against epstein-barr virus before first clinical manifestation of multiple sclerosis. J Neurol Neurosurg Psychiatry 2012; 83(12): 1170-3.[http://dx.doi.org/10.1136/jnnp-2012-303068] [PMID: 22888143] ].

3. VD SUBSTITUTIVE/ADDITIVE THERAPY

A recent consensus conference confirmed the necessity of VD and calcium supplementation in patients on therapy with steroids or other drugs that may reduce bone mineral density. 25OHD levels are considered to be measured once a year and replaced in those patients with insufficient/deficient levels [98Cooper C, Bardin T, Brandi ML, et al. Balancing benefits and risks of glucocorticoids in rheumatic diseases and other inflammatory joint disorders: new insights from emerging data. An expert consensus paper from the european society for clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Aging Clin Exp Res 2016; 28(1): 1-16.[http://dx.doi.org/10.1007/s40520-015-0522-1] [PMID: 26746234] , 99Cutolo M, Plebani M, Shoenfeld Y, Adorini L, Tincani A. Vitamin D endocrine system and the immune response in rheumatic diseases. Vitam Horm 2011; 86: 327-51.[http://dx.doi.org/10.1016/B978-0-12-386960-9.00014-9] [PMID: 21419278] ].

A Cochrane Review in 2014 stated that VD3 seemed to decrease mortality in elderly people living independently or in institutional care, while VD2, alfacalcidol and calcitriol had no statistically significant beneficial effects on mortality [100Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev 2014; 10(1): CD007470.[PMID: 24414552] ].

The existence of a synergism between VD3 and glucocorticoids was demonstrated: when VD3 is assumed combined with dexamethasone, there seems to be significant additive effects on inhibition of lymphocyte proliferation and Th1 cytokine production [101Jirapongsananuruk O, Melamed I, Leung DY. Additive immunosuppressive effects of 1,25-dihydroxyvitamin D3 and corticosteroids on TH1, but not TH2, responses. J Allergy Clin Immunol 2000; 106(5): 981-5.[http://dx.doi.org/10.1067/mai.2000.110101] [PMID: 11080724] ].

Moreover, it was demonstrated, even in healthy subjects, that VD supplementation (140,000 IU at baseline and after 4 weeks) seems to determine significant increase of Tregs percentage, suggesting a possible use of VD as additional therapy in autoimmune diseases [102Prietl B, Pilz S, Wolf M, et al. Vitamin D supplementation and regulatory T cells in apparently healthy subjects: V itamin D treatment for autoimmune diseases? Isr Med Assoc J 2010; 12(3): 136-9.[PMID: 20684175] , 103Cutolo M. Hormone therapy in rheumatic diseases. Curr Opin Rheumatol 2010; 22(3): 257-63.[http://dx.doi.org/10.1097/BOR.0b013e328336ec24] [PMID: 20075732] ].

Different results of in vitro and animal models studies on VD supplementation, compared to studies performed on humans, may be justified by the fact that, while in the first two cases the active form of the molecule is used, in the second most of the times the precursor activity is evaluated. This difference determines the existence of a phase of the study where the quantitative and qualitative characteristics of the molecule activity are poorly controllable. Part of such variability may be due to the individual VDR receptor polymorphisms and/or to epigenetic changes.

However, peripheral conversion of pro-VD in calcitriol sustain the use of the first as a therapeutic agent, being a storage molecule with longer half-life and reduced hypercalcaemic effect [16Sly LM, Lopez M, Nauseef WM, Reiner NE. 1alpha,25-Dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phosphatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase. J Biol Chem 2001; 276(38): 35482-93.[http://dx.doi.org/10.1074/jbc.M102876200] [PMID: 11461902] ].

A link between inflammation and neoplastic transformation is increasingly supported by recent literature and VD anti-proliferative actions suggested its possible use also in different types of cancers [104Cutolo M, Paolino S, Pizzorni C. Possible contribution of chronic inflammation in the induction of cancer in rheumatic diseases. Clin Exp Rheumatol 2014; 32(6): 839-47.[PMID: 25496746] , 105Cutolo M. The challenges of using vitamin D in cancer prevention and prognosis. Isr Med Assoc J 2012; 14(10): 637-9.[PMID: 23193787] ]. VD3 showed anti-melanoma activity in experimental models, and defects in VD signalling seemed to contribute to tumour progression and disease outcome [106Slominski AT, Brożyna AA, Skobowiat C, et al. On the role of classical and novel forms of VD in melanoma progression and management. J Steroid Biochem Mol Biol 2017; 30164-4. S0960-0760]. Studies on animal models of breast cancer have shown several tumour suppressive actions of VDR agonists, while human VD deficiency is common in breast cancer patients and low VD status was reported to enhance the risk for neoplasms development or progression [107Narvaez CJ, Matthews D, LaPorta E, Simmons KM, Beaudin S, Welsh J. The impact of vitamin D in breast cancer: Genomics, pathways, metabolism. Front Physiol 2014; 5: 213.[http://dx.doi.org/10.3389/fphys.2014.00213] [PMID: 24982636] ]. VD/VDR deficiency was reported also in prostate cancer patients together with higher C reactive protein and IL-8 levels, providing evidence for an association among prostate cancer, VD deficiency and inflammation [108Xie DD, Chen YH, Xu S, et al. Low vitamin D status is associated with inflammation in patients with prostate cancer. Oncotarget 2017; 8(13): 22076-85.[http://dx.doi.org/10.18632/oncotarget.16195] [PMID: 28423553] ].

CONCLUSION

In conclusion, from available literature it can be observed clearly that VD is a determinant factor for immunomodulation. It has to be said that inflammatory reactions could ‘consume’ VD in autoimmune diseases, and hypovitaminosis could be a consequence. However, this would not be coherent with the results of genetic studies specifically linking genotypes regulating VD metabolism to higher autoimmunity susceptibility and with the findings of the numerous epidemiological studies cited [109Ghashut RA, Talwar D, Kinsella J, Duncan A, McMillan DC. The effect of the systemic inflammatory response on plasma vitamin 25(OH)D concentrations adjusted for albumin. PLoS One 2014; 9(3): e92614.[http://dx.doi.org/10.1371/journal.pone.0092614] [PMID: 24667823] ]. Moreover, the beneficial effects of VD supplementation, observed in several conditions, further testify for a major role of VD in immuno-modulation [110Cianferotti L, Bertoldo F, Bischoff-Ferrari HA, et al. Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: research for evidence and a scientific statement from the European society for clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Endocrine 2017; 56(2): 245-61.[http://dx.doi.org/10.1007/s12020-017-1290-9] [PMID: 28390010] ].

The increasing interest for VD and VDR in bone biology, metabolic diseases, immunological disorders and cancer, took pharmaceutical companies to develop over more than 3,000 VD analogues in the last 30 years.

Next studies will probably continue to concentrate on new direct VDR agonists with a better biological profile for applications in therapy. Knowledge of structures of the VDR ligand-binding domain and its ligands will lead to the creation of VDR agonists with increased affinity for VDR receptor and augmented molecular metabolic stability.

As a consequence, a higher preventive and therapeutic potential, also for extra-skeletal chronic diseases, such as autoimmune and cardiovascular diseases, cancer, diabetes and infections, will be obtained.

DCs= dendritic cells; Th= T CD4+ helper cell subsets (Th1, Th2, Th3-Treg, Th17) originating from naïve T cell (Th0). Thin arrows (left) indicate cytokines that induce differentiation of Th0 cells and thicker arrows (right) indicate cytokines produced by activated Th cell subsets. B cells and Natural Killer T cells (NKT) are also reported.

Red circles indicate cytokines/activities inhibited by VD while green circles indicate cytokines enhanced by VD.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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