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International Journal of Epidemiologic Research, 2016; 3(1): 69-85.

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The role of D3 and vitamin B9 (Folic acid) in immune system

Reza Mansouri1, Maryam Moogooei1*, Mozhgan Moogooei2, Nastaran Razavi3, Amir Hossein Mansourabadi1 1Immunology Dept., Shahid Sadoughi University of Medical Sciences, Yazd, I.R. Iran; 2Immunology Dept., Rafsanjan University of Medical Sciences, Rafsanjan, I.R. Iran; 3Research and Technology Deputy, Shahrekord University of Medical Sciences, Shahrekord, I.R. Iran. Received: 1/Nov/2015 Accepted: 27/Dec/2015

ABSTRACT Background and aims: are essential constituents of our diet that Longley have

been known to influence the immune system. Vitamin D3 and B9 have received particular Review attention in recent years as these vitamins have been shown to have an unexpected and crucial effect on the immune response. 1, 25(OH)2D3 metabolizing enzymes and vitamin

D receptor (VDR) are present in many cell types including various immune cells such as

article antigen-presenting-cells, T cells, B cells. Methods: In this mini review, we study 30 novel articles since 2009 to 2015 about the

essential roles of vitamins in modulating a broad range of immune processes, such as lymphocyte activation, T-helper-cell differentiation and regulation of the immune response. 4+ Results: 1, 25(OH)2D3 has direct effect on CD T (T-helper) cells for suppressing various cytokines such as IFN-γ, IL-17, IL-21 and IL-22, while enhancing the regulatory Tcells. In vitro studies show that Treg cells could be differentiated from naive T cells in vitamin B9-reduced condition. Conclusions: These findings provide a new link between diet and the immune system, which could maintain the immunological homeostasis and clarify the beneficial roles of vitamins in informing the design of vitamin analogs as pharmacologic agents for the generation and maintenance of a healthy immune condition.

Keywords: Vitamin D3, Vitamin B9, Immune system, Regulatory .

INTRODUCTION Vitamins are organic compounds that commensal bacteria. Some vitamins (e.g. the host organism cannot synthesize in vitamin B family and ) are sufficient quantities and that therefore need water-soluble, whereas others (e.g., vitamins to be supplied exogenously by the diet or A, D, E, and K) are hydrophobic. Both

*Corresponding author: Maryam Moogooei, Immunology Dept., Shahid Sadoughi University of Medical Sciences, Yazd, I.R. Iran, Tel: 00982188683492, E-mail: [email protected] 69 Mansouri R, et al. The vitamin D3 and vitamin B9 in immune system hydrophilic and hydrophobic vitamins and vitamins and their metabolites in immune their metabolites have diverse functions in responses.3 many biologic events, including is a group of fat soluble immunologic regulation responses is better. vitamins responsible for absorption of than regulation. Indeed, vitamin deficiency calcium and phosphate in the small intestine results in high susceptibility to infection and and stimulates osteoclast differentiation.4 immune diseases.1 Until the mid-1930s, Two major forms of vitamin D exist. when the first commercial yeast-extract Vitamin D2 (), found in plants, vitamin B complex and semi-synthetic is produced by ultraviolet B irradiation of vitamin C supplement tablets were sold, and can be consumed as a vitamins were obtained solely through food supplement or in fortified foods.5 Vitamin intake, and changes in diet (which, for D3 () is synthesized in the example, could occur during a particular human epidermis or consumed in the form growing season) usually greatly altered the of natural (for example, fish) or fortified types and amounts of vitamins ingested. food sources or as a supplement.4 Despite its However, vitamins have been produced as name, vitamin D is not really a vitamin, commodity chemicals and made widely it is the precursor to the potent steroid available as inexpensive semisynthetic and hormone (also known as synthetic-source dietary and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), food supplements and additives, since the which mediates numerous actions in many 6 middle of the 20th century. Thirteen tissues of the body. Cutaneous vitamin D3 vitamins are universally recognized at generated by high energy UVB photons present. Vitamins are classified by their provides 90% of the human vitamin biological and chemical activity, not their requirement. The biological half-life of structure. The largest number of vitamins, 25-OHD3 is 2 months, so this metabolite the B complex vitamins, function as effectively integrates sunlight’s energy precursors for enzyme cofactors, that help signal over time.7 With the finding of the enzymes in their work as catalysts in (VDR) in nearly every metabolism.2 In this role, vitamins may be tissue and the more recent discovery of tightly bound to enzymes as part of thousands of VDR binding sites throughout prosthetic groups: For example, is the genome controlling hundreds of genes, part of enzymes involved in making fatty the interest in vitamin D and its impact on acids. They may also be less tightly bound multiple biologic processes has accelerated to enzyme catalysts as coenzymes, tremendously as evidenced by the detachable molecules that function to carry thousands of publications each year for the chemical groups or electrons between past several years.5 molecules. For example, folic acid may In the human skin, cholecalciferol is carry methyl, formyl, and methylene groups synthesized from 7-dihydrocholesterol when in the cell. Although these roles in assisting exposed to UVB. The production of vitamin enzyme-substrate reactions are vitamins' D3 (D3) in the skin is not an enzymatic best-known function, the other vitamin process. Vitamin D3 (cholecalciferol) is functions are equally important. Previously produced through a two-step process in vitamins were thought to regulate the which the B ring is broken by UV light immune system in an indiscriminant (spectrum 280-320 UVB) radiation from the manner, but accumulating evidence has sun, forming pre-D3 that isomerizes to D3 in revealed specific functions of individual a thermosensitive but noncatalytic process.8

70 International Journal of Epidemiologic Research, 2016; 3(1): 69-85.

Cholecalciferol is biologically inactive and tissues of the body, including bone, immediately binds to vitamin D binding pancreatic β cells, parathyroid gland, brain, proteins or albumin.9 It then enters the skin, prostate, testes, heart, skeletal muscle circulation and is hydroxylated in the , tissue, breast, liver, lung, intestine, kidneys, catalyzed by the enzymes CYP2R1 and adipose cells and immune response cells, CYP27A1, which results in the production such as macrophages, dendritic cells and of the inactive form 25 hydroxy vitamin D activated B- and T-cells.16 It is comprised of (25 (OH)D) which represents the main 3 domains: the N-terminal DNA binding circulating vitamin D metabolite and is the domain with two zinc fingers that bind to the most reliable parameter to define human grooves of the DNA at discrete sites vitamin D status.10 In the kidney, 25 (OH)D (VDREs), the C-terminal ligand binding is further converted to the circulating domain, and the hinge region binding of biologically active compound calcitriol these two domains together. The ligand (1, 25(OH)2D) by the enzyme 1-α- binding domain structure has been solved by hydroxylase (CYP27B1) which is under x-ray crystallography.17 It is comprised of strict control of parathyroid hormone and the 12 helices. The terminal helix serves as a phosphaturic hormone fibroblast growth gating mechanism closing around the factor 23 (FGF-23).11 Calcitriol levels are incorporated ligand and forming an interface tightly regulated in a renal negative for coactivators as well as facilitating the feedback loop, including inhibition of interaction of VDR with its heterodimer CYP27B1 by high levels of calcitriol and partner, generally RXR. Although VDR FGF-23 and stimulation of the enzyme preferentially binds to RXR, creating a CYP24A1 (24-hydroxylase) which VDR-RXR dimer, VDR can also bind other metabolizes calcitriol into the inactive, water receptors of the nuclear receptor soluble form, , which is then superfamily, which include thyroid, vitamin excreted in the bile.12 Circulating levels of A, PPAR-γ and other orphan receptors.18 calcitriol are mainly determined by renal The VDR-RXR dimer can regulate genes in CYP27B1 activity.13 However, other cell several systems and tissues. Although there types including immune cells, also express is substantial variability in quence of CYP27B1 and are able to convert the VDREs, the most prevalent motif for the inactive, circulating form 25(OH)D into the VDRE sequence consists of two half-sites, active hormone in an autocrine or paracrine each with the six-nucleotide consensus manner. Especially in immune cells, such as sequence, GGTCCA, separated by 3 other macrophages and dendritic cells, a lack of nucleotides of any sequence. This motif is feedback mechanisms compared to kidney known as Direct Repeat 3 (DR3), although cells allows the production of high local other configurations of VDRE-binding sites, concentrations of calcitriol needed for including DR6 and DR4, exist in some immune modulation.14 vitamin D-regulated genes.19 VDR binding Vitamin D receptor (VDR) is a to its VDRE then recruits coregulatory transcription factor and member of the complexes required for its genomic activity. steroid hormone and nuclear hormone These complexes can be both gene and cell receptor family. The VDR was identified in specific, enabling the selectivity of 1969 and its crystal structure was cloned in 1,25(OH)2D action from cell type to cell 1987 and binding to its natural ligand were type. These complexes include a subunit that characterized in 2000.15 Since its discovery, directly binds to the VDR generally through researchers have detected the VDR in many an LXXLL motif along with a number of

71 Mansouri R, et al. The vitamin D3 and vitamin B9 in immune system subunits that contain enzyme activity such normal monocytes/macrophages. However, as histoneacetyl transferases (coactivators confirmation of such a mechanism was only such as the SRC family) ordeacetylases obtained in 2006 when Robert Modlin and (corepressors such as SMRT and NCoR), colleagues carried out DNA array analyses methyl transferases and demethylases, to define innate immunity genes that were ATPase-containing nucleosomal-remodeling specifically modulated in monocytes by activity (SWI/SNF), and links to RNA Mycobacterium tuberculosis (M. tb). In a polymerase II.5 seminal investigation both the VDR and the In common with natural killer cells gene for 1α-hydroxylase (CYP27B1) were (NK) and cytotoxic T-lymphocytes shown to be induced following activation of (cytotoxic T-cells), macrophages and their the principal pathogen recognition receptor monocyte precursors play a central role in for M. tb, toll-like receptor 2/1 (TLR2/1.23 initial non-specific immune responses to Subsequent experiments confirmed that pathogenic organisms or tissue damage-so precursor 25OHD3 was able to induce called cell-mediated immunity. Consistent intracrine VDR responses in monocytes that with the earlier seminal observations of had been treated with a TLR2/1 activator. In extra renal 1α-hydroxylase activity in particular, the TLR2/1–25OHD3 patients with sarcoidosis, the effects of combination stimulated expression of the vitamin D on macrophage function have antibacterial protein cathelicidin, so that been central to many of the new vitamin D was able to promote monocyte observations implicating vitamin D in the killing of M. tb. Notably, the ability to regulation of immune responses. Their role promote expression of the antibacterial is to phagocytose pathogens or cell debris protein following a TLR2/1 challenge was and then eliminate or assimilate the resulting directly influenced by the 25OHD3 status of waste material. In addition, macrophages the donor serum used for monocyte culture. can interface with the adaptive immune More recently, scientists have shown that system by utilizing phagocytic material for vitamin D supplementation in vivo can also antigen presentation to T-lymphocytes enhance TLR2/1-induced cathelicidin (T-cells). expression. Cathelicidin was identified For many years, the key action of several years ago as a target for vitamin D on macrophages was thought to transcriptional regulation by 1,25(OH)2D3- be its ability to stimulate differentiation of liganded VDR, in that its gene promoter precursor monocytes to more mature contains a functional vitamin D response phagocytic macrophages.20,21 This concept element (VDRE).24 Interestingly, this VDRE was supported by observations showing occurs within a small interchangeable differential expression of VDR and nuclear element (SINE) sequence which 1α-hydroxylase during the differentiation of only appears to be present in the cathelicidin human monocytes macrophages.22 The latter gene promoter of higher primates, report also emphasized early studies suggesting that vitamin D regulation of this showing that normal human macrophages facet of innate immunity is a relatively 25 were able to synthesize 1,25(OH)2D3 when recent evolutionary development. stimulated with interferon gamma (IFN-γ). Recent reports have not only underlined Localized activation of vitamin D, coupled the importance of cathelicidin as a target for with expression of endogenous VDR was vitamin D but also suggest that this strongly suggestive of an autocrine or mechanism may be more complex than intracrine system for vitamin D action in initially thought. As yet, the precise signal

72 International Journal of Epidemiologic Research, 2016; 3(1): 69-85. system by which TLR activation induces be due to the rapid non-immune induction of expression of VDR and 1α-hydroxylase 1α-hydroxylase and VDR which occurs remains unclear. Promoter-reporter analysis within the placenta during early gestation.32 of the events involved in transcriptional Dendritic cells (DCs) are antigen regulation of CYP27B1 suggests that TLR4- presenting cells (APCs) are important in mediated induction of the enzyme involves initiating CD4+ T cells responses. Expression JAK-STAT, MAP kinase and nuclear factor of VDR by purified tissue DCs was first kapa β (NF-κβ) pathways, and that these reported in 1987. Subsequent studies using synergize with IFN-γ mediated induction of populations of DCs isolated from skin CYP27B1.26 However, other studies have (Langerhans cells) provided evidence that proposed that TLR2/1 induction of 1,25(OH)2D3 could act to attenuate antigen 1α-hydroxylase occurs indirectly as a presentation.33 In functional studies, consequence of TLR2/1 induced interleukin-15 1,25(OH)2D3 treatment of human DCs in (IL-15) which is a potent inducer of vitro results in reduced expression of the CYP27B1 and 1α-hydroxylase activity.27 In cost imulatory molecules CD80 and CD86 a similar fashion, interleukin 17A (IL-17A) and decreased expression of HLA-DR and has been shown to enhance 1,25(OH)2D3 the maturation marker CD83, all associated mediated induction of cathelicidin, although with an immature DC phenotype.34 this response does not appear to involve Vitamin D inhibits differentiation and transcriptional regulation of 1α-hydroxylase maturation of human DCs invitro by or increased VDR sensitivity.28 suppressing the IL-12 production from DCs Regulation of the antibacterial protein and increasing IL-10 production.35 This is an by 1,25(OH)2D3 has been described for a important immunosuppressive activity as wide variety of cell types other than IL-12 is an important cytokine in inducing 34 macrophages, including , lung, Th1 development. 1,25(OH)2D3 inhibits epithelial cells, myeloid cell lines, and the differentiation, maturation, and immune placental trophoblasts.29,30 In some cases, stimulatory capacity of DCs. Canning et al. this appears to involve an intracrine confirm that 1,25(OH)2D3 suppresses response similar to that reported for monocyte differentiation into DCs, thereby monocytes. However, the mechanisms generating immature DCs. This suppresses 36 controlling local synthesis of 1,25(OH)2D3 DC ability to stimulate T-cell proliferation. in these cells vary considerably. In Most of the direct immune modulatory keratinocytes, low baseline expression of properties of 1,25(OH)2D3 on DCs are 1α-hydroxylase is enhanced following proposed to occur in myeloid (mDCs) and epidermal wounding by transforming growth not plasmacytoid DCs (pDCs). A study by factor beta (TGFβ).31 The resulting rise in Penna and et al. suggest that although both 1,25(OH)2D3 concentrations upregulates primary human blood-derived mDCs and expression of TLR2 and TLR4 by pDCs express comparable levels of VDR keratinocytes, thereby priming these cells and upregulate the primary response gene for further innate immune responses to CYP24 upon culture with 1,25(OH)2D3, pathogens or tissue damage. By contrast, in only the tolerogenic properties of mDCs are 37 trophoblasts, induction of cathelicidin and modulated upon culture with 1,25(OH)2D3. subsequent bacterial killing by 25OHD3 1,25(OH)2D3 negatively regulates the appears to be due to constitutive differentiation, maturation, and immune 1α-hydroxylase activity, which is not further stimulatory capacity of DCs by decreasing enhanced by TLR activation. The latter may the expression of MHC class II, CD40,

73 Mansouri R, et al. The vitamin D3 and vitamin B9 in immune system

CD80, and CD86.38 In addition, T cells. 3) Direct, paracrine effects of 1,25(OH)2D3 decreases the synthesis of calcitriol on T cells following conversion of IL-6, IL-12, and IL-23.39 25(OH)D to calcitriol by monocytes or The other major type of adaptive dendritic cells. 4) Indirect effects on antigen immune cells, T cells, is also thought to be presentation to T cells mediated via an important target for the immune localized APC affected by calcitriol. modulatory effects of different forms of In principle, vitamin D exposure leads vitamin D. The development of lymphocytes to a shift from a pro inflammatory to a more takes place in the thymus with VDR being tolerogenic immune status, including very expressed in medullary thymocytes but not diverse effects on T cell subtypes: Calcitriol in the less mature cortical thymocytes. suppresses T helper (Th) cell proliferation, However, once cells leave the thymus and differentiation and modulates their cytokine enter the circulation as T or B cells VDR production.42 In particular, treatment of expression is lost until these cells are T cells with calcitriol or analogs inhibits the activated to proliferate by mitogens Indeed, secretion of pro inflammatory Th1 [IL2, 1,25D is a potent inhibitor of T-cell interferon-γ (IFN- γ), tumor necrosis factor proliferation, blocking the transition from α (TNF- α)], Th9 (IL9) and Th22 (IL22) early G1 phase to late G1 phase, but having cytokines,43 but promotes the production of no effect on transition from Go (resting) to more anti-inflammatory Th2 cytokines (IL3, early G1 or from late G1 to S phase. Weak IL4, IL5, IL10).44,45 The decrease in the TCR signaling via the mitogen-activated production of IL-2 and IFNγ by protein kinase p38 pathway induced VDR 1,25(OH)2VD3 is partially mediated by expression. The T cells subsequently binding of the VDR–RXR complex to the up-regulated phospholipase C-gamma1 VDRE in the promoters of genes encoding (PLC-γ1) expression 75-fold , enabling them IL-2. IL17 producing Th17 cells are also to flux calcium and become fully activated. affected by vitamin D. Inhibition of Th17 PLC-γ1 induction appeared to be activity seems to play a major role in the VDR-dependent. The dependence of T cell treatment of autoimmune diseases as shown activation on VDR expression has not been in non-obese diabetic (NOD) mice.46 demonstrated in vivo.40 Recently, calcitriol was found to directly VDR expression by these cells is very suppress IL17 production on a low in resting conditions but upon activation transcriptional level,47 and activated human and proliferation, T and B cells up-regulate T-cells exposed to calcitriol produced VDR expression significantly, allowing significantly decreased levels of IL17, regulation of up to 500 vitamin D responsive interferon-γ and IL21.48 The same study also genes which influence differentiation and revealed a change toward a tolerogenic proliferation of these cells.41 Since 1983 it phenotype, including increased expression has been described that 1,25(OH)2D of genes typicaland regulatory markers inhibited T cell proliferation and the FOXP3, CTLA-4, and IL-10 for regulatory secretion of select cytokines after mitogen T cells (Tregs), by adding a combination of stimulation four potential mechanisms by calcitriol and IL2 to human primary T cell which vitamin D may influence T cell cultures. In addition, 1,25(OH)2D function have been proposed: 1) direct, upregulated the gut homing receptor CCR9 endocrine effects on T cells mediated via and inhibited CXCR3 on T cells potentially systemic calcitriol. 2) Direct, intracranial changing the homing properties of the Th 49 conversion of 25(OH)D to calcitriol by cells. Vitamin D and 1,25(OH)2D inhibited

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Th1 and Th17 responses, induced T reg 1,25(OH)2D3 from 25(OH)D3 in vitro and responses, and controlled proliferation and respond to this through the vitamin D Th cell localization.39 receptor (VDR) in an autocrine fashion.23 INKT cells are also vitamin D targets Elevated levels of 1,25(OH)2D3 in .Development and function of iNKT cells association with hypercalcemia have been depends on expression of the VDR and observed in patients with sarcoidosis, 50,51 vitamin D. In vitro, 1,25(OH)2D tuberculosis, and other infections and inhibited iNKT cell derived IL-17 and inflammatory diseases in which the induced IL-4 and IL-5. The requirement for pathology is characterized by granuloma the VDR in the development of iNKT cells formation, supporting the hypothesis that was traced to regulation of the survival of activated macrophages can produce maturing iNKT cells in the thymus. Vitamin significant amounts of 1,25(OH)2D3 in D also controls iNKT cell expansion during vivo.56 Like APC, activated T cells express development.51 the VDR and CYP27B1.7 However, whether Vitamin D has also been proposed as a T cells can convert 25(OH)D3 to regulator of Th2 mediated disease such as 1,25(OH)2D3 in physiological relevant allergy and asthma. In vitro, 1,25(OH)2D concentrations and respond to this in an treatment of T cells has been shown to autocrine fashion is a matter of debate. Most increase IL-4 secretion by human and mouse studies on the effect of vitamin D on Th cells.41,52 IL-13 has been shown to be T cells have not addressed this question as induced or decreased by 1,25(OH)2D they investigated the direct effects of treatment of human T cells.53 25- supra-physiological concentrations of hydroxyvitamin D3 (25(OH)D3) is the 1,25(OH)2D3 and not how 25(OH)D3 affects inactive precursor of 1,25(OH)2D3 and is T cell responses. One study has shown that considered the best parameter for evaluation isolated T cells have the ability to convert of the vitamin D status of a subject. The 25(OH)D3 to 1,25(OH) 2D3 in normal range of serum 25(OH)D3 concentrations that actually affect vitamin D concentrations is 25–170 Nm.54 The serum responsive genes in an autocrine fashion.40 concentration of the active 1,25(OH)2D3 is In agreement, scientists found that purified approximately 1000-fold lower (60–110 CD4+ T cells have the ability to produce pM) and far below the effective substantial amounts of 1,25(OH)2D3 when 57 concentration of 1,25 (OH)2D3 found in in activated in the presence of 25(OH)D3. In vitro studies. Thus, in most in vitro studies contrast, another recent study found that more than a 100-fold higher concentration of although activated T cells do express 1,25 (OH)2D3 than found in serum is often CYP27B1, the expression level is not required to obtain an effect.55 It has sufficiently high to allow production of therefore been suggested that the level of 1,25(OH)2D3 in concentrations that affect circulating 1,25(OH)2D3 is too low to affect vitamin D responsive genes. The authors immune responses in vivo, and that found that 25(OH)D3 only affected T cell sufficient levels are obtained by local responses when APC were present, and 10 conversion of 25(OH)D3 to 1,25 (OH)2D3. suggested that APC locally secrete sufficient In accordance, it has been shown that amounts of 1,25(OH)2D3 to directly activated antigen presenting cells (APC) influence the surrounding T cells in a express the 25(OH) D-1α hydroxylase paracrine fashion. Other important players CYP27B1 that converts 25(OH)D3 to influencing the bioavailable levels of 1,25(OH)2D3, and that APC can produce vitamin D are the vitamin D-binding protein

75 Mansouri R, et al. The vitamin D3 and vitamin B9 in immune system

(DBP) and albumin. 25(OH)D3 and Autoimmune diseases are characterized 1,25(OH)2D3 circulate bound to DBP by a loss of immune homeostasis resulting (85–90%) and albumin (10–15%) with less in corrupted self-antigen recognition than 1% in their free form.58 Studies of DBP followed by the destruction of body tissue knock-out mice have shown that DBP acts by auto reactive immune cells. A as a vitamin D reservoir by protecting combination of genetic predisposition, 62 25(OH)D3 and 1,25 (OH)2D3 from epidemiological risk factors, and degradation and renal secretion.15 However, environmental contributors contributes to DBP also sequesters 25(OH)D3 and the development of autoimmune diseases. 1,25(OH) 2D3 and inhibits their action on One important factor may be the availability monocytes, DC and keratinocytes in vitro.15 of sufficient vitamin D levels as various How DBP affects T cell responses to epidemiological studies suggest associations 25(OH)D3 still needs to be determined. The between vitamin D deficiency and a higher objectives of this study were to further incidence of autoimmune diseases, such as elucidate whether T cells have the ability to T1D, MS, systemic lupus erythematosus convert 25(OH)D3 to 1,25(OH)2D3 in (SLE), rheumatoid arthritis (RA) and proportions that affect a panel of vitamin D inflammatory bowel disease (IBD).63 responsive genes in an autocrine fashion and In animal models for T1D, MS, SLE, to investigate how DBP regulates T cell IBD and autoimmune uveitis, administration responses to 25(OH)D3. of calcitriol either prevented or ameliorated Like T-cells, active but not inactive autoimmunity. Studies with vitamin D B-cells express the VDR. Consequently, deficient or VDR knock-out animals show initial studies indicated that 1,25(OH)2D3 increased inflammation and susceptibility to could directly regulate B-cell proliferation T1D and Crohn’s disease, disturbed T cell and immunoglobulin (Ig) production.59 In homing and lack of host protection from B-cells, anti-proliferative effects of calcitriol bacterial invasion and infection.64 such as inhibition of differentiation, Serum 25(OH)D is considered the most proliferation, initiation of apoptosis and accurate marker for vitamin D status.65 decreased immunoglobulin production were While the Endocrine Society advocates that initially considered to be exclusively levels below 20 ng/mL (50 nmol/L) should indirectly mediated by T helper (Th) cells.60 define deficiency, levels ranging from 20 to expression of CYP27b1 was also detected in 29.9 ng/mL (52–72 nmol/L) should define B-cells, indicating that B cells may be insufficiency and levels above 30 ng/mL capable of autocrine/intracranial responses (75 nmol/L) should define sufficiency, the to vitamin D. More recent studies confirmed Institute of Medicine (IOM) considers levels additional direct effects of calcitriol on B of >20 ng/mL to be sufficient for the cell homoeostasis, including inhibition of majority of the general population.49 This memory- and plasma-cell generation, as well latter classification is based largely on as promotion of apoptosis of vitamin D’s effects on bone and mineral immunoglobulin-producing B cells.61 This homeostasis. The optimal 25(OH)D serum control on B cell activation and proliferation level regarding other aspects of human may be clinically important in autoimmune health is still under debate.66 For immune- diseases as B-cells producing auto reactive mediated diseases, experts suggest that even antibodies play a major role in the higher serum 25(OH)D levels may be pathophysiology of autoimmunity.12 needed to lead to positive effects.67

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Calcitriol is well known for its diverse of them have significant adverse effects. pharmacological activities, including is considered as a highly modulation of cell growth, neuromuscular effective topical agent for the treatment of and immune function and reduction of hyper proliferative skin diseases, such as inflammation. Calcitriol and its analogs .74 Calcipotriol exerts only exert potent effects on cellular negligible systemic effects on calcium differentiation and proliferation regulate homeostasis. Thus, eliminating the risk of apoptosis and produce immune modulatory the main significant side effects of effects.68 hypercalciuria, hypercalcemia and bone Vitamin D has several important roles calcium mobilize.75 in the skin. Many in vitro and in vivo studies The role of vitamin D and its analogs in demonstrate dose-dependent effects of cancer treatment and prevention was vitamin D on cell proliferation and investigated in different research tracks differentiation.11,69 Although the mechanisms including clinical and epidemiological that mediate the anti-proliferative and studies. According to extensive pro-differentiating effects of vitamin D epidemiological research reports,64 it was analogs on keratinocytes are not completely found that there is a clear association understood, it is well known that these between various factors responsible for effects are at least in part genomic and vitamin D levels in the body (e.g. geography mediated by VDRs (1,25-dihydroxyvitamin and latitude, history of sun exposure, 11 D3). Vitamin D can reduce the risk of skin lifestyle) and increased morbidity from infection through modulating the production cancer. It was also found that vitamin D and of various antimicrobial peptides and the its analogs inhibit proliferation of cancer cytokine response.70 It is possible that cells derived from multiple tissues.76 Further vitamin D could enhance T helper type 2 studies are required to clarify the molecular responses. Vitamin D deficiency is related to mechanisms of the anticancer activity of a high number of skin disorders, including vitamin D and its various analogs. From the skin cancer, autoimmune skin disorders, current literature on the subject, it appears photo dermatoses, atopic and that the compound is not suitable for use in psoriasis. Vitamin D and its analogs have cancer as a single or primary anticancer already been successfully used in the agent but as an adjuvant in combination therapy of , psoriasis, chemotherapy, where it can aid the actions vitiligo, acne and rosacea.71 Most of the of other cytotoxic agents, particularly those studies are devoted to treatment of psoriasis. of the alkylating agents (which are not cell The highly variable nature of psoriasis and cycle specific). The anticancer vitamin D its individual presentations in patients can analogs include new calcipotriol-derived make choosing the most appropriate compounds, diastereomeric and geometric treatment difficult. Currently available analogs of calcipotriol, seocalcitiol, synthetic vitamin D analogs that have been 20-hydroxyvitamin D2 analog, 5-butyloxazole found to be safe and effective in topical unit analog and additional analogs containing treatment of psoriasis include calcipotriol a structurally modified side chain.77-79 The (or calcipotriene), max-acalcitol, dominant side effects of vitamin D, and hexafluoro-1a, 25-dihydroxyvitamin hypercalcemia and hypercalciuria, resulted 72 D3. According to the literature, the rate of in limiting the use of vitamin D in cancer treatment success with vitamin D and its treatment.80 To overcome this problem, analogs varies from 4% to 53%,73 and many more than 3000 vitamin D analogs have

77 Mansouri R, et al. The vitamin D3 and vitamin B9 in immune system been synthesized in recent years.81 Some of deficiency of vitamin D. The ability of a these analogs have been found to be more potent vitamin D analog: 2α-Methyl-19-nor- effective and less toxic than vitamin D, (20S)-1,25-dihydroxyvitamin D3 (2AMD), justifying their development and to prevent type 1 diabetes was determined in introduction to the market.82 BGP-13 and an Ins2/non-obese diabetic (NOD) model. BGP-15, calcipotriol derived vitamin D3 2AMD suppresses development of type 1 analogs, are good examples of more- diabetes, preserves islet cells and has a effective and less-toxic analogs than vitamin significant impact on B cell survival and D.76 BGP-15 is a calcipotriol-based analog function.85 A detailed mechanism of where the 24-OH has been substituted by a antidiabetic activity of vitamin D in type 2 chloride atom on the side chain of the diabetes is unclear Lifestyle factors leading calcipotriol molecule. BGP-13 and BGP-15 to type 2 diabetes, including obesity, aging have been shown to induce apoptosis and and lack of physical activity. It can also inhibit prostate and breast cancer growth in cause vitamin D deficiency. It is only known vitro and in mice in vivo.77 Antitumor that vitamin D regulates direct and indirect effects of vitamin D and its analogs were action on insulin-producing cells in the also demonstrated in humans, when they pancreas. Vitamin D can directly influence were used either alone or in combination the muscle and fat cells, and can improve with other chemotherapy drugs Vitamin D insulin action through reducing insulin activity is expressed also by causing tumor resistance as well as reducing inflammation regression and inhibition of tumor growth, which is commonly present in patients with in addition to counteracting their mutagenic type 2 diabetes.86 A small-scale post hoc effect by inducing apoptotic cell death. analysis of a bone study revealed that daily Some evidence suggests that this vitamin calcium (500 mg) and vitamin D (700 IU) could be used in high doses as a supplementation for three years prevented a prophylactic agent for prevention of further rise in fasting blood glucose in a colorectal, prostate and breast cancer subgroup with impaired fasting blood development. Only large-scale long-term glucose (100–125 mg/dl) at a baseline.87 research will reveal which vitamin D Multiple Sclerosis (MS) is a chronic analogs, either alone or in combination with and a common inflammatory disorder of the other drugs, could serve as effective central nervous system (CNS) characterized therapeutic agents for cancer.83 with myelin loss, progressive neurological Type 1 diabetes is an autoimmune dysfunction, gliosis, and unstable degrees of disease characterized by the immune- axonal pathology that initiated by auto mediated destruction of insulin-producing b reactive T cells that recognize central cells from islets of Langerhans in the nervous system antigens.88 Various genetic pancreas. As mentioned above, vitamin D and environmental risk factors appear to plays a vital part in the normal functioning interact and contribute to MS. In genetics, of the immune system and its deficiency several human leukocyte antigen alleles could lead to impaired functioning of the (more particularly HLA-DRB1*1501) could immune system. It was shown that vitamin favor the disease whereas others could be D mediates insulin secretion and glucose protective. Some of the genes involved in uptake,84 and also regulates insulin receptor vitamin D metabolism (e.g. CYP27B1) also gene expression. Epidemiological studies have a significant role in MS.89 Based on have shown a direct correlation between the epidemiological studies, three environmental increase in the prevalence of the disease and risk factors were identified: 1) previous

78 International Journal of Epidemiologic Research, 2016; 3(1): 69-85.

Epstein-Barr virus infection 2) vitamin D receptor 4, a vitamin B9 insufficiency 3) and cigarette smoking. receptor, is highly expressed on the Some clinical findings strongly suggest surfaces of Treg cells, implying a specific that vitamin D status influences the relapse function of this vitamin in these cells. In rate and radiological lesions in MS particular, recent study revealed that patients. It was suggested that changes in vitamin B9 is crucial in the maintenance of vitamin D serum concentrations are Treg cells. In the absence of vitamin B9, correlated with MS.90 Although the results naive Tcells can differentiate in to Treg of adequately powered randomized clinical cells, but differentiated Treg cells fail to trials using vitamin D supplementation survive owing to the decreased expression have not yet been reported, vitamin D is a of anti-apoptotic molecules (Bcl-2).93,94 promising candidate as modulator of A recent study demonstrated an disease activity in MS. additional function of the vitamin B family Vitamin B is recognized as a family in the control of immune responses via comprising eight different members. All of mucosa- associated invariant T (MAIT) are water-soluble, and they are cells. MAIT cells are unconventional T cells involved in various pathways of cell that express a semi-invariant αβ T cell metabolism. Vitamin B is essential for the receptor that is restricted by the MHC class synthesis, replication, and repairing of I-related molecule MR1. These cells are nucleotides for DNA and RNA and is thus mostly found in the intestine, liver, and required for cell proliferation and survival. lung.65 Because MAIT cells can react Vitamin B9 deficiency also inhibits the rapidly to bacterial infections (e.g. activity of CD8+ T cells and reduces the Escherichia coli, Klebsiella pneumoniae, proliferative responses of lymphocytes and and Mycoplasma tuberculosis), it was natural killer cell activity; in turn ,this supposed that the antigen presented to MR1 inhibition is associated with decreased was bacteria-derived molecules. However, a resistance to infections. Consequently, recent study clarified that, in fact, bacterially deficiency leads to various produced metabolites of vitamin B9 and impairments of immunity, such as vitamin B2 bound to MR1 are presented as lymphoid atrophy and reduced numbers of antigen to MAIT cells. Furthermore, like lymphocytes (3); conversely, vitamin B6 vitamin B2 derivatives, the vitamin B9 supplementation bolsters these weakened metabolite, and 6-formyl pterin. (6-FP) bind immune responses. Like vitamin B6, to MR1 but, unlike vitamin B2 derivatives, vitamin B9 (also known as folate and folic fails to activate MAIT cells.96 These findings acid) is essential for nucleic acid and suggest that, depending on their metabolism protein synthesis,91 and in adequate levels by commensal bacteria and presentation by of vitamin B9 dramatically alter the MR1, members of the vitamin B family can immune response. Among the vitamins B, act either as positive or negative regulatory vitamin B6 is essential for metabolism of ligands for MAIT cells.97 nucleic acids, amino acids, and lipids and thus influences cell growth Vitamin B9 is CONCLUSION derived from both diet and commensal Clinical evidence has long indicated that 92 bacteria. Additionally, the vitamin B9 in adequate vitamin intake disrupts host receptor folate receptor 4 (FR4) is both a immunity. Thus, they predispose humans to marker of Treg cells and is infectious and inflammatory diseases. 93 immunologically functional. Accumulating evidence has revealed the

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How to cite the article: Mansouri R, Moogooei M, Moogooei M, Razavi N. The role of vitamin D3 and vitamin B9 (Folic acid) in immune system. Int J Epidemiol Res. 2016; 3(1): 69-85.

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