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Vitamin D and Immune System
Mosaad YM1*, Mostafa M1, Elwasify M1, Youssef HM2 and Omar NM3
1Clinical Immunology Unit, Clinical Pathology Department and Mansoura Research Center for Cord Stem Cells, Faculty of Medicine, Mansoura University, Mansoura,
Egypt
2Department of Rheumatology and Rehabilitation, Mansoura University Hospital, Egypt and Department of Rheumatology, Aberdeen Royal Infirmary, Aberdeen, UK
3Medical Physiology Department, Mansoura Faculty of Medicine, Mansoura, Egypt
*Corresponding author: Mosaad YM, Clinical Immunology Unit, Clinical Pathology Department and Mansoura Research Center for Cord Stem Cells, Faculty of
Medicine, Mansoura University, Mansoura, Egypt, Tel: +20106243435; E-mail: youssefmosaad@yahoo.com
Received date: Jan 30, 2017; Accepted date: March 01, 2017; Published date: March 07, 2017
Copyright: © 2017 Mosaad YM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Vitamin D interaction with immune system is a well-established although it is a non-classical effect of Vitamin D.
Several reports have documented the role of 1,25 hydroxycholecalciferol (OH)2D3 in mediating innate and adaptive
immune systems. The 25-hydroxyvitamin D3 (25OHD3) is the main circulating metabolite of Vitamin D and is the
most reliable measurement of an individual’s Vitamin D status. It mediates its effect through autocrine or paracrine
synthesis of 1, 25(OH)2D3. Therefore, the ability of Vitamin D to influence human immunity is possibly dependent on
the vitamin D status of individuals. The vitamin D receptor (VDR) is expressed on various immune cells including B
cells, T cells and antigen presenting cells. However, its highest concentration is in immature immune cells of the
thymus and mature CD-8 T lymphocytes. These cells can synthesize active Vitamin D metabolite which can act in
an autocrine way in a local milieu. As Vitamin D has immune-modulatory effects on both innate and adaptive
immune responses, its deficiency or significant insufficiency can be associated with autoimmunity and infection. In
autoimmune disease, the immune cells are responsive to ameliorative effects of vitamin D.
Keywords: Vitamin D; Immune system; Innate; Adaptive;
Physiology; Kidney; Autoimmune; Infection
Introduction
Vitamin D was considered as vitamin and was known to be one of
the four fat soluble vitamins. However, research work showed that
Vitamin D is a prohormone and it is established now that it has many
other biologic actions outside the musculoskeletal system [1,2].
Vitamin D3 (cholecalciferol), which is the natural form of Vitamin
D, is present in low amount in animal food sources and almost absent
in vegetables, and Vitamin D2 (ergocalciferol) is present in some
vegetables. Vitamin D3 is produced in the skin through the action of
sun rays on a derivative of cholesterol, 7-dehydrocholesterol, to
produce previtamin D3. en, previtamin D3 is slowly isomerized to
vitamin D3; cholecalciferol. is dual source of Vitamin D, through
sunlight in the skin and diet intake, secures sucient levels of Vitamin
D in the body, although the major source for production of vitamin D3
is through the skin. Exposure of the precursor 7-dehydrocholesterol in
the basal and suprabasal layers of the epidermis to ultraviolet B (UVB)
light with a wavelength of 290-315 nm is needed for the formation of
the previtamin D3. us, the level of production of vitamin D3 in the
skin is mainly aected by the amount of UVB radiation to which the
skin is exposed. Other factors aecting this cutaneous synthesis of
vitamin D3 include geographical area, season of the year and time of
the day [3].
Vitamin D3 itself is biologically inactive. us, aer being
synthesized in the skin, vitamin D3 binds to the vitamin D-binding
protein (DBP) in the blood to be transported into the liver where the
rst hydroxylation at position 25 occurs producing the major
circulating metabolite 25-hydroxy vitamin D3 (25(OH)D3). Although
the circulating level of 25(OH)D3 is 500-1000-fold greater than the
subsequent 1α, 25 dihydroxy D3, but its bioactivity is 3 times less than
the active one. is might be explained on the basis that the serum
DBP has more anity to 25(OH)D3, rendering it biologically inactive
in vivo. e second hydroxylation at position 1 occurs mainly in the
kidney to form 1α, 25 dihydroxy D3 (1,25(OH)2D3); the most active
circulating metabolite form of vitamin D [4]. Studies have shown that
the renal hydroxylation is localized to the proximal tubules, and in
some species the cortical nephron proximal to the loop of Henle is also
involved [5]. Indeed, researchers have shown that the enzyme, 25 (OH)
1 alpha hydroxylase, is present in at least 10 tissues in addition to the
renal tubules, producing 1,25(OH)2D3 in a paracrine fashion. However,
this paracrine-generated 1,25(OH)2D3 does not normally spill over
into the circulatory system, and consequently, the plasma
concentration of 1,25(OH)2D3 does not increase in a measurable way
[6]. e biologic importance of such locally produced 1,25(OH)2D3
emerged from its ability to promote cell dierentiation in prostate
cancer and colon cancer cells [7,8].
ere are more than 35 additional vitamin D3 metabolites are
formed by the body. However, it is evident now that all these
metabolites are either less active or rapidly cleared and they are
considered intermediates in the degradation of the active form, 1,
25(OH)2D3. e most important of these metabolites are 24R, 25-
(OH)2D3 and 1, 24, 25-trihydroxyvitamin D3 produced by the enzyme
CYP24, which is induced by the vitamin D hormone itself [10]. e
24R,25-(OH)2 D3 has been shown to be an essential hormone in the
process of bone fracture healing. e 24R,25-dihydroxyvitamin D3
most likely initiates its biological responses via binding to the ligand
binding domain of a postulated cell membrane receptor VDR mem
24,25, similar to the better studied, but still not cloned cell membrane
receptor for 1,25-dihydroxy vitamin D3, VDRmem 1,25. For clinical
Vitamins & Minerals Mosaad et al., Vitam Miner 2017, 6:1
DOI: 10.4172/2376-1318.1000151
Review Article OMICS International
Vitam Miner, an open access journal
ISSN: 2376-1318
Volume 6 • Issue 1 • 1000151
purpose, the serum concentration of 25-hydroxyvitamin D levels is the
accepted biomarker to test the Vitamin D status among population. It
is the major circulating form of Vitamin D that reects both dietary
Vitamin D intake and the endogenous Vitamin D production [11]. For
simplication, authors through the following parts of this chapter will
refer to 25(OH)D3 as vitamin D and to 1,25(OH)2D3 as active Vitamin
D.
e production of active Vitamin D is largely controlled by the
calcium homeostasis. However, the main factor regulating production
of active vitamin D3 is the level of 1,25(OH)2D3 itself. us, when its
circulating level in the blood is high, its production by the kidney is
down regulated and vice versa. Next is the parathyroid hormone which
stimulates the activity of renal 1 hydroxylase in response to a fall in
serum calcium level. Serum calcium level would aect the activity of
renal hydroxylation step in relation to this dual feedback between
calcium level and parathyroid hormone. Other factors that regulate the
production of active Vitamin D include also phosphate level and fetal
growth factor 23 [1].
e degradation of active D3 hormone and its metabolites is
induced by vitamin D3 itself in target tissues. Researchers have
indicated that pulses of the Vitamin D hormone program its own death
through induction of the 24-hydroxylase which metabolize Vitamin D
to its excretion product calcitroic acid [11]. Also, 25(OH)D3 can be
degraded through this pathway. e regulation of expression of 24-
Hydroxylase is an important factor in the determination of the
circulating concentrations of the hormonal form of Vitamin D. Early
studies says that there is a possible hepatic catabolic pathway where
clearance of vitamin D metabolites is conjugated with bile acids in the
bile [12].
e vitamin D3 hormone functions through a single vitamin D
receptor (VDR), which has been cloned for several species including
humans, rats, and chickens. It is a member of the class II steroid
hormones, being closely related to the retinoic acid receptor and the
thyroid hormone receptor. Like other receptors, it has a DNA-binding
domain called the C-domain, a ligand-binding domain called the E-
domain, and an F-domain, which is one of the activating domains.
VDRs are either nuclear receptors (VDRnuc) regulating gene
transcription (classic genomic response) or cell membrane receptors
(VDRmem) regulating non-genomic responses [13]. e VDRnuc,
mediating the genomic responses of the hormone D3, is a protein of 50
kDa, which binds 1,25(OH)2D3 with high anity. It does not bind
either previtamin D3 or vitamin D2. It has been reported that about 36
tissues possess VDR and more interestingly research work has shown
that VDR can regulate the expression of about 500 genes of the 20488
in the human genome [14]. On the other hand, the rapid non-genomic
eects of 1,25(OH)2D3 are mediated by its binding with VDR that is
located on the cell membrane. is membrane receptor is the classic
receptor found in the nucleus but is found to be associated with
caveolae present in the plasma membrane of a variety of cells [15].
Interestingly, it has been found that both nuclear and caveolae VDR
share in the rapid modulation of osteoblast ion channel responses by 1,
25(OH)2D3 [16].
us, in target tissues, the binding of the 1,25(OH)2D3 hormone
with VDR initiates a complex cascade of molecular events resulting in
alterations in the rate of transcription of specic genes or gene
networks. An essential point in this series is the interaction of VDR
with retinoid X receptor (RXR) forming a heterodimeric complex that
binds to specic DNA sequence elements [vitamin D response element
(VDREs)] in vitamin D-responsive genes. is binding will ultimately
inuence the rate of RNA polymerase II-mediated transcription [9].
In addition to the known physiologic action of Vitamin D in
regulating calcium homeostasis, evidences from recent research have
shown that Vitamin D has wider physiologic eects attributed to the
wide distribution of the VDR as shown before. Because of this wider
scope of biologic actions of Vitamin D, there is now what is termed and
accepted as Vitamin D endocrine system signifying its functioning as a
pluripotent hormone in 5 systems [17]. ese systems include the
adaptive immune system, the innate immune system, insulin secretion
by the pancreatic β cell, multifactorial heart functioning and blood
pressure regulation, and brain and fetal development [17]. e biologic
eects of Vitamin D regarding the immune system will be discussed
later in this chapter. Here, we will try to focus more on its known
function in controlling the serum calcium level.
Acting with parathyroid hormone (PTH), active Vitamin D
hormone increases serum calcium concentration through multiple
mechanisms. First, active Vitamin D is the only hormone that mediates
induction of calcium binding protein (calbindin) involved in intestinal
calcium absorption. Whether active Vitamin D regulates the synthesis
of calbindin at the gene level or through the activation of increased
intracellular calcium levels is not well understood. Also, it stimulates
active intestinal absorption of phosphate. Furthermore, active Vitamin
D with PTH stimulates reabsorption of the last 1% of ltered load of
calcium in renal distal convoluted tubules, saving a reasonable portion
to calcium pool in the body [18].
In conditions of decreased serum calcium level with dietary
deciency of calcium, both hormones, D3 and PTH, act to mobilize
calcium from bones to the blood. A decrease in serum calcium level
below the normal range (9-11 mg/dl) will be sensed by Calcium-
sensing proteins in the cell membranes of parathyroid gland cells [19].
Consequently, this will initiate cascade reactions through these
transmembrane proteins-G protein coupled system, stimulating the
secretion of PTH. Circulating PTH will mediate a very important
eect; activation of renal 1 α hydroxylase, increasing production of
active Vitamin D hormone. en, together with PTH, active Vitamin D
stimulates mobilization of bone calcium and renal reabsorption of
calcium. Active Vitamin D hormone stimulates osteoblasts to produce
receptor activator nuclear factor κB ligand (RANKL) which by its turn
stimulates osteoclastogenesis and activates resting osteoclasts inducing
bone resorption [20]. Another bone action of active Vitamin D is
recruiting osteoclasts from the monocyte-macrophage lineage of cells
[21]. is additional action of recruitment of osteoclasts might explain
the eect of toxic levels of Vitamin D resulting in hypercalcemia rather
than hyperostosis [21]. On the other hand, active Vitamin D induces
the synthesis of alkaline phosphatase, osteocalcin, and matrix g-
glutamic acid-containing protein in the osteoblasts, but inhibits the
synthesis of type I collagen [22]. Accordingly, it seems that active
Vitamin D is exerting a dual role in bone through modulation of the
normal interaction between osteoblast and osteoclast function.
us, the Vitamin D hormone plays an important role in allowing
individuals to mobilize calcium from bone when it is absent from the
diet. When serum calcium is increased, this will inhibit the sensing
mechanism in parathyroid gland, and consequently the renal
production of active D3. On the other hand, in conditions of
abnormally high plasma calcium concentrations, the C-cells of the
thyroid gland secrete calcitonin, which blocks bone calcium
mobilization. Interestingly, under normocalcemic conditions,
Citation: Mosaad YM, Mostafa M, Elwasify M, Youssef HM, Omar NM (2017) Vitamin D and Immune System. Vitam Miner 6: 151. doi:
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ISSN: 2376-1318
Volume 6 • Issue 1 • 1000151
Calcitonin activates the renal 1α hydroxylase enzyme producing the
Vitamin D hormone for non-calcemic needs [23].
Vitamin D expression on immune system
e serum level of Vitamin D was correlated inversely with level of
parathyroid hormone and this observation has urged the introduction
of a new term called Vitamin D insuciency [24-26]. e Vitamin D
insuciency is dened by sub-optima level of Vitamin D that is not
rachitic [4]. Geographical, social, or economic factors can aect the
Vitamin D status in dierent populations and Vitamin D insuciency
is considered as worldwide epidemic [25-28]. Vitamin D has important
function other than calcium and bone homeostasis and
epidemiological studies documented the possible link between Vitamin
D insuciency and various human diseases including autoimmune,
infectious, cardiovascular, neurologic, immune deciency and even
cancer [28-30].
Vitamin D has a paracrine or autocrine function beside the
endocrine function. e active Vitamin D manifests its diverse
biological eects by binding to the VDR. In the same time, many
tissues beside the kidney express 1-α-hydroxylase and can convert the
25 D to 1,25 D [31]. VDR is expressed in organs and tissues involved in
bone metabolism and in more than thirty-ve target tissues that are
not involved in bone metabolism and explains the pleiotropic eect of
Vitamin D hormone [32,33]. ese tissues include T/B lymphocytes,
antigen presenting cells (APCs), monocytes, hematopoietic cells,
cardiac and skeletal muscle cells, endothelial cells, islet cells of the
pancreas, neurons and placental cells [33]. VDR activation either
directly or indirectly regulate about 100-1250 genes that represent
about 0.5-5% of the total human genome and include the genes
responsible for the regulation of cellular proliferation, dierentiation,
apoptosis and angiogenesis [32,34]. Because the immune cells express
VDR and can synthesize the active Vitamin D metabolite and in the
same time, Vitamin D can modulate the innate and adaptive immune
responses, it is reasonable that the Vitamin D deciency will be
associated with increased autoimmunity and increased susceptibility to
infection [29].
e VDR gene is located on chromosome 12 and is a member of
trans-acting transcriptional regulatory factors that include the steroid
and thyroid hormone receptors [35]. e VDR gene contains 11 exons
and spans approximately 75 kb. e exons 1A, 1B, and 1C are present
in the noncoding 5-prime end and its translated product is encoded by
8 additional exons. Exons 2 and 3 are involved in DNA binding, and
exons 7-9 are involved in binding to Vitamin D [35-37]. Vitamin D
binds to VDR and then dimerise with the retinoid X receptor (RXR).
is complex of vitamin D-VDR-RXR translocates to the nucleus and
binds in the promoter of Vitamin D responsive genes to Vitamin D
responsive elements (VDRE) with subsequent expression of these
Vitamin D responsive genes [29].
DNA sequence variations “polymorphisms” which occur frequently
in the population, can have modest and subtle but true biological
eects. eir abundance in the human genome as well as their high
frequencies in the human population have made them targets to
explain variation in risk of common diseases. Recent studies have
indicated many polymorphisms to exist in the VDR gene [38]. Over
470 VDR single nucleotide polymorphisms (SNPs) are known [38,39].
eir distribution and frequency vary among ethnic groups. Most of
the work done on VDR polymorphisms has been conducted in
Caucasian populations and has focused on six SNPs: rs10735810 or
FokI in exon 2, rs1544410 or BsmI in intron 8, rs731236 or TaqI in
exon9, rs7975232 or ApaI in intron 8, rs757343 or Tru91 in intron 8
and the poly (A) mononucleotide repeat in the 3′-untranslated region
(UTR) [40,41].
e discovery of the VDR in the cells of the immune system and the
fact that activated dendritic cells produce the Vitamin D hormone
suggested that Vitamin D could have immunoregulatory properties.
e most evident eects of the D-hormone on the immune system
seem to be in the down-regulation of the 1-driven autoimmunity.
Low serum levels of Vitamin D might be partially related, among other
factors, to prolonged daily darkness (reduced activation of the pre-
vitamin D by the ultra violet B sunlight), dierent genetic background
(i.e. VDR polymorphism) and nutritional factors and explain to the
latitude-related prevalence of autoimmune diseases such as
rheumatoid arthritis by considering the potential immunosuppressive
roles of Vitamin D. e Vitamin D plasma levels have been found
inversely correlated at least with the RA disease activity showing a
circannual rhythm (more severe in winter). Recently, greater intake of
Vitamin D was associated with a lower risk of RA as well as a
signicant clinical improvement was strongly correlated with the
immunomodulating potential in Vitamin D-treated RA patients
[40,42].
In immune cells, activation of VDR leads to production of
downstream gene products. ese proteins have potent anti-
proliferative, pro-dierentiative, and immunomodulatory eects [43].
Active Vitamin D inhibits several intracellular pathways such as the
nuclear factor-κB (NF-κB) signaling pathway, X-box binding protein 1
(XBP1) and endoplasmic reticulum to nucleus signaling 1 (ERN1).
is inhibition has been observed in T cells, monocytes or
macrophages [44] and subsequently may inuence the expression of
various essential secreted molecules on the cell surface. On the other
hand, the active Vitamin D has no inhibitory eect on the expression of
other transcriptional regulators such as Paired box-5 (PAX-5), B-cell
lymphoma 6 (BCL-6), activation, and IFN-regulatory factor 4 (IRF4)
[43].
Vitamin D and innate immune system
e innate immune system is the immediate, non-specic rst line
of the defense against pathogens and includes complement,
antimicrobial peptides produced by neutrophils and macrophages, in
addition to antigen presentation [45]. It is important to review the
levels of innate defense to understand the role of Vitamin D in innate
immune response. e epithelial cells of the skin, gut, respiratory and
urinary tract is the rst line of defense which protects against invasion
by organisms. e active Vitamin D is important in up-regulating
genes of the proteins required for the tight, gap and adheres junctions
[46].
e Vitamin D is a potent stimulator of antimicrobial peptides in
innate immunity and sucient level of Vitamin D is necessary for
production of cathelicidin and some types of defensins (defensins
hBD-2) [46-48]. In mammals, pathogens have pathogen-associated
molecular patterns (PAMP's) that trigger pathogen recognition
receptors called toll-like receptors (TLRs). In humans, triggering of
TLR2/1 and TLR4 results in increased expression of 1-α-hydroxylase
and VDR. Induction of 1-α-hydroxylase induces the production of
active Vitamin D. en complex of vitamin D-VDR-RXR translocates
to the nucleus and binds to VDREs of genes of cathelicidin and beta
defensin 4 with subsequent transcription of these proteins [29,49]. It is
now clear that the transcription of cathelicidin is dependent on
sucient Vitamin D and transcription of beta defensin 4 requires
Citation: Mosaad YM, Mostafa M, Elwasify M, Youssef HM, Omar NM (2017) Vitamin D and Immune System. Vitam Miner 6: 151. doi:
10.4172/2376-1318.1000151
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Vitam Miner, an open access journal
ISSN: 2376-1318
Volume 6 • Issue 1 • 1000151
binding of NFkB to appropriate response elements on the beta
defensin 4 RNA [29,50].
e active Vitamin D enhances the secretion of hydrogen peroxide
in monocytes and increases oxidative burst [51]. Also, Vitamin D has a
role in the attraction of other immune cells to promote wound healing
or ght infection and is essential in activating antigen specic T-cell
[52,53]. Vitamin D prevents inammatory response overreaction and
prevents further cell or tissue damage by inammation [54]. Vitamin D
also suppress the inammation by limiting excessive production of
proinammatory cytokines such as TNFα and IL-12 [46,55].
e macrophages recognize lipopolysaccharide (LPS) of bacterial
infection through TLRs. As mentioned above, engagement of TLRs
leads to a cascade of events that produce peptides with potent
bactericidal activity (e.g., cathelicidin and beta defensin 4). ese
peptides co-localize with the ingested bacteria inside the phagosome
where they disrupt bacterial cell membranes [56].
Vitamin D appears to show promise in aiding the body's own
natural defenses against viruses, bacteria and fungi and there is
evidence that Vitamin D may strengthen the physical epithelial barrier
via stimulating junction genes. With increasing antibiotic-resistant
bacteria, there is a need for the development of new strategies for
treatment of infections. Cathelicidin (LL-37) has a potent anti-
endotoxin and some direct antimicrobial activity [57]. In critically ill
patients, correlation was reported between low levels of Vitamin D and
those of LL-37 and there was an evidence for the regulation of LL-37
levels by vitamin D status [56]. Also, the LL-37 is known to be eective
against Methicillin-resistant
S. aureus
(MRSA), that may cause serious
illness such as pneumonia, toxic shock syndrome, food poisoning or
staphylococcal-scalded skin syndrome and no strains show complete
resistance to LL-37 until now [46,58-60].
e eects of Vitamin D on macrophage function have been central
to many of the new observations implicating Vitamin D in the
regulation of immune responses. In common with natural killer cells
(NK) and cytotoxic T-lymphocytes (cytotoxic T-cells), macrophages
and their monocyte precursors play a central role in initial non-specic
immune responses to pathogenic organisms or tissue damage-so called
cell-mediated immunity. eir role is to phagocytose pathogens or cell
debris and then eliminate or assimilate the resulting waste material. In
addition, macrophages can interface with the adaptive immune system
by utilizing phagocytic material for antigen presentation to T-
lymphocytes (T-cells) [28].
It was thought that the key action of Vitamin D on macrophages was
to stimulate dierentiation of precursor monocytes to more mature
phagocytic macrophages and this was supported by dierential
expression of VDR and 1α-hydroxylase during the dierentiation of
human monocytes macrophages [61]. Also, stimulation of human
macrophages with interferon gamma (IFNγ) resulted synthesis of
active Vitamin D, localized activation of Vitamin D and expression of
endogenous VDR (i.e., autocrine or intracrine action of Vitamin D)
[62,63].
Macrophages possess both enzymes essential to produce active
Vitamin D leading to intracrine and paracrine eects. e high
expression of VDR by monocytes ensures sensitivity of these cells to
the dierentiating eects of active Vitamin D. In the same time, the
active Vitamin D down-regulates the expression of granulocyte-
macrophage colony-stimulating factor (GM-CSF), stimulates
production of immunosuppressant prostaglandin E2 from
macrophages and modulates macrophage responses, thus, inhibiting
the release of more inammatory cytokines and chemokines
[42].erefore, Vitamin D deciency will impair the antimicrobial
function of macrophages due to decreased capacity to mature, to
produce lysosomal enzymes, to secrete H2O2 and to produce specic
surface antigens by down-regulating the expression of HLA-II [64,65].
Monocytes isolated from normal human peripheral blood
mononuclear cells (PBMCs) when treated with cytokines such as IFN-
γ [66] or bacterial antigens such as lipopolysaccharide [61] can
synthesize active Vitamin D [54]. e presence of CYP27B1 in
macrophages is important for the physiological action of active
Vitamin D in immune-regulation. In activated macrophages, the
CYP27B1 expression is regulated by immune inputs, mainly IFN-γ and
agonists of TLRs, the pattern recognition receptors [67].
e immune system is responsive to the circulating levels of Vitamin
D as evidenced by; stimulation of TLR1/2 heterodimers in human
macrophages by bacterial lipopeptides induced expression of CYP27B1
and VDR; the downstream VDR-driven responses were strongly
dependent on serum concentration of active Vitamin D cultured in the
presence of human serum and these responses were attenuated or
absent in Vitamin D-decient individuals and were restored by active
Vitamin D supplementation [26,28,68].
In human cells, the expression of the co-receptor of TLR4 and
CD14, is strongly regulated by active Vitamin D and a correlation was
found between induction by LPS and expression of CYP27B1 via
TLR4/CD14 receptor complexes [67,68]. Treatment of human
monocytes with active Vitamin D inhibits the expression of TLR2,
TLR4, TLR9 and alters the TLR9-dependent production of IL-6 [69].
While, the active Vitamin D promotes the antimicrobial activities of
myeloid cells, it inhibits TLR2 expression and TLR4 expression on
monocytes, therefore, inducing a state of hypo-responsiveness to
pathogen-associated molecular patterns. is is may be a negative
feedback mechanism, preventing excessive TLR activation and
inammation at a later stage of infection [70]. erefore, the down-
regulation of pattern recognition receptors by active Vitamin D in
APCs may contribute to its ability to attenuate abnormal 1-driven
inammatory responses and potential autoimmunity [71].
In the cells of monocytic and epithelial origins, the active Vitamin D
induces the expression of gene encoding NOD2/CARD15/IBD1. is
pattern recognition receptor detects muramyl dipeptide (MDP), a
lysosomal breakdown product of bacterial peptidoglycan common to
Gram-negative and Gram-positive bacteria. e MDP-induced NOD2
activation stimulates NF-κB, which induces expression of the defensin
β2 gene [72]. One pathway, concerns the inactivation of active Vitamin
D by the enzyme 24-hydroxylase (CYP24), mitochondrial enzyme that
initiates active Vitamin D catabolism. While expression of CYP24, is
sensitive to the presence of active Vitamin D, the negative feedback
loop appears to be defective in macrophages and the 24-hydroxylase
gene is induced by Vitamin D following TLR2/1 activation of
monocytes [73].
While the expression of CYP24 transcripts in macrophages is
induced by active Vitamin D, the corresponding enzymatic activity is
undetectable and the enzyme is trapped in the cytosol in inactive form
[74]. is suggests in macrophage that the active Vitamin D signaling
is maintained for extended time, and would be advantageous for
combating intracellular pathogens such as Mycobacterium
tuberculosis [75].
In M. tuberculosis-infected PBMCs, the active Vitamin D attenuates
the expression of matrix metalloproteinases (MMP) 7 and 10,
Citation: Mosaad YM, Mostafa M, Elwasify M, Youssef HM, Omar NM (2017) Vitamin D and Immune System. Vitam Miner 6: 151. doi:
10.4172/2376-1318.1000151
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Vitam Miner, an open access journal
ISSN: 2376-1318
Volume 6 • Issue 1 • 1000151
suppresses secretion of MMP-7 and inhibits secretion and activity of
MMP-9, induces secretion of IL-10 and prostaglandin E2 [76]. In
human monocytes, neutrophils and other human cell lines, the active
Vitamin D induces genetic expression of antimicrobial peptides
(AMPs), such as defensins and cathelicidin (hCAP). e AMPs display
a broad-spectrum of antimicrobial and antiviral activities including the
inuenza virus and these endogenous antibiotics destroy invading
microorganisms [28,77].
DCs are heterogeneous in their location, phenotype and function
and per their origin, they are divided into two groups: myeloid
(mDCs) and plasmacytoid (pDCs). e mDCs are professional APCs
[78] and the pDCs are more closely associated with immune tolerance
[79,80] All cells of innate immunity are capable of; identifying and
removing foreign substances present in organs, tissues, into the blood
and lymph stream; interacting with pathogens and with each other and
modulating the adaptive immune response by regulating timing, type,
and number of cytokines [81].
It is now documented that the active Vitamin D can change the
function and morphology of DCs to tolerogenic DCs (tolDCs) [82,83].
In the same time, the active Vitamin D and its analogs can inhibit DCs
dierentiation and maturation, therefore, impairing normal turnover
of DCs in tissues and locking them in an immature-like state. In
human and murine DC cultures, vitamin D down-regulate; the
expression of MHC-Class II, co-stimulatory molecules such as CD40,
CD80, CD86; other maturation molecules such as CD1a and CD83
and chemokine (c-x-c motif ) ligand 10 (CXCL10) which is involved in
the recruitment of T helper 1 (1) cells [54,84-87]. On the other
hand, active Vitamin D up-regulate; inhibitory molecules (e.g.,
programmed death-1 ligand (PD-L1) and immunoglobulin-like
transcript 3 (ILT3) on DCs; the secretion of chemokines (CCL2,
CCL18 and CCL22) which are implicated in the recruitment/induction
of regulatory T cells (Tregs), polarization of 2 subset, maintenance
of the immature state of DCs [88,89]. Additionally, Vitamin D-
modulated DCs produce more anti-inammatory cytokine (IL-10) and
less pro-inammatory cytokines IL-12 (1 driving) and IL-23 (17-
driving) and this might dampen 1 and 17 responses, render T
cells anergic and recruit and dierentiate Treg subsets [28,45,78,80].
e mDCs are ecient promoters of naïve T cell function [89] and
the pDCs are more associated with attenuation of T cell function [90].
In vitro, the active Vitamin D regulates mainly mDCs, with associated
suppression of naïve T cell activation. is can be explained by
expression of similar levels of VDR by both mDC and pDC, therefore,
the tolorogenic pDC may respond to active Vitamin D via local,
intracrine mechanisms [28,90]. Also, active Vitamin D generated by
pDCs may not act to regulate pDC maturation but may act in a
paracrine fashion on VDR-expressing T-cells. e ability of Vitamin D
to inuence the dierentiation and function of DCs provides another
layer of innate immune function that complements its antibacterial
properties. However, this interaction between active Vitamin D and
DC will also have downstream eects on cells that interact with APCs,
namely cells from the adaptive immune system [90,91].
Vitamin D and adaptive immune system
e expression of VDR on active and proliferating T and B
lymphocytes suggesting that the active Vitamin D has anti-proliferative
role on these cells. Also, variations in Vitamin D levels can inuence T
cells and in patients with multiple sclerosis (MS) a correlation between
the activity of T regulatory cells (Tregs) and circulating levels of
Vitamin D have been reported [92].ere are four possible
mechanisms explaining how the serum Vitamin D can inuence T-cell
function : direct eect of systemic active Vitamin D on T cells ; indirect
eects of localized DC expression of CYP27B1 and intracrine synthesis
of active Vitamin D on antigen presentation to T cells; paracrine
mechanism through direct eects of active Vitamin D on T cells
following synthesis of the active Vitamin D by CYP27B1-expressing
monocytes or DCs; intracrine conversion of Vitamin D (25OHD) to
active Vitamin D (1,25(OH)2D) by T cells [93].
e VDR expression is undetectable in quiescent T lymphocytes
and upon T cell activation, it increases ve times [94]. e active
Vitamin D regulates T-cell development and migratory function and
1 and 2 cells are direct targets for the active Vitamin D. Direct
actions on T cells represent a dierent route for active Vitamin D to
shape T-cell responses and to control T-cell antigen receptor signaling,
which through the alternative p38 pathway induces VDR expression
[28,93].
When active Vitamin D binds to the VDR, the VDR translocates to
the nucleus and activates phospholipase C-γ1(PLC-γ1) gene. Due to
PLC-γ1 gene activation, PLC-γ1 protein accumulates in the cytoplasm
of primed T cells aer 48 hours of initial activation [94]. e PLC-γ1
has a central role in classical T-cell receptor signaling and T-cell
activation, therefore, the dierences in PLC-γ1 expression in naive and
primed T cells explain the process of functional avidity maturation
observed in T cells. Activation of the VDR by active Vitamin D
changes the cytokine secretion patterns, suppresses eector T-cell
activation and induces Tregs [95,96].
e active Vitamin D inhibits the migration of T cells to lymph
nodes [96]. is can be explained by stimulating expression of
chemokine receptor 10 (CCR10) by active Vitamin D on T
lymphocytes and the CCR10 recognizes the chemokine CCL27
secreted by epidermal keratinocytes [97]. Also, the active Vitamin D
aects the phenotype of T cells by inhibiting the 1, thus, it will able
to promote the translocation and/or retention of T cells within the skin
[98]. In contrast, in the gastrointestinal tract (GIT), the Vitamin D has
a negative eect on chemokines and chemokine receptors [96] and
Vitamin D promotes a T-cell shi from 1 to 2 and may limit the
potential tissue damage associated with 1 cellular immune responses
[42,99].
e active Vitamin D decreases the proliferation and inhibits the
production of IL-2, IFN-γ, tumor necrosis factor-α and IL-5 from 1
cells [97,99]. In the same time, administration of Vitamin D enhances
transforming growth factor-β1 (TGF-β1) and IL-4 transcripts,
therefore, it exerts in an immunosuppressive action and increases the
2 cell function [96].
e initial studies evaluating the eects of Vitamin D on T-cells
focused on the ability of active Vitamin D to suppress T-cell
proliferation and subsequent studies showed that Vitamin D inuences
the phenotype of T-cells by inhibiting 1 cells (i.e., cellular immune
response) and enhancing cytokine of 2 cells (i.e., humoral
immunity) [100]. By switching the immune response from 1 to 2,
the Vitamin D may help to limit the tissue damage associated with
excessive 1 immune responses. However, studies using VDR gene
knockout mice showed reduced 1 levels [101], therefore, the in vivo
eects of Vitamin D on T cells are more complex [28].
17 cells is a third group of cells and is named so because of
their capacity to secrete IL-17 [102]. 17 cells are important for
promoting immune responses to some pathogens and have been linked
to inammatory tissue damage [103]. In vitro treatment of T-cells with
Citation: Mosaad YM, Mostafa M, Elwasify M, Youssef HM, Omar NM (2017) Vitamin D and Immune System. Vitam Miner 6: 151. doi:
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active Vitamin D suppresses 17 development and inhibits
production of IL-17 [104]. Also, in vivo treatment of mouse models of
irritable bowel disease (IBD) with active Vitamin D down-regulates
expression of IL-17 and in CYP27B1 gene knockout mouse, loss of
active Vitamin D leads to elevation of IL-17 [90,105].
T regulatory or suppressor T cells (Tregs) is a fourth group of CD4
T cells and exert suppressor functions. e active Vitamin D modulates
the T-cell phenotype and promotes the development of Tregs [106].
Topical application of active Vitamin D aects the dierentiation and
functions of Tregs, increases the suppressive activity and the in vivo
expansion of antigen-specic Tregs [107]. In mice with induced
experimental autoimmune encephalomyelitis (EAE), oral
administration of active Vitamin D reduces the number of
lymphocytes especially CD4+ T cells in the central nervous system
(CNS) [108]. e explanation for this may be the death of activated T
cells due to intake of active Vitamin D especially with the absence of
17-polarizing conditions or regulation of 17 cell recruitment via
chemokine and chemokine receptors [28,109]. Negative regulation of
the expression of CCR6 on 17 by active Vitamin D may be essential
for the entry of 17 into the CNS and the initiation of EAE [108]. e
active Vitamin D inhibits the lineage commitment of 17 and induces
IL-10 production, which, suppresses EAE initiation [110,111]. In the
same time, the combination of active Vitamin D and dexamethasone
increase the frequency of generation of IL-10-producing Tregs [112].
e active Vitamin D may induce the production of IL-10 via help
to TGF-β via the generation of IL-27 [111]. In either case, the active
Vitamin D requires the presence of TGF-β and IL-6 to increase the
number of IL-27-mediated IL-10-producing T cells and it is possible
that active Vitamin D may cooperate with IL-27 to protect against EAE
through IL-10 [113]. IL-27 blocks the generation of 17 cells through
transcription factor STAT1 and active Vitamin D mediates suppression
of 1 and 17 cell by induction of Foxp3+ Treg-cell expansion
[42,90].
In contrast, active Vitamin D inhibits the expression of TGF-β-
mediated Foxp3 through VDR signal on CD4+ T cells [114]. Also, in
vitro treatment of active Vitamin D decreases the production of
interleukin-2 (IL-2) by activated CD4+ [115] suggesting that IL-2 may
be crucial for inhibiting Treg dierentiation by active Vitamin D [114].
However, both active Vitamin D and IL-2 may have synergistically
limit the production of IL-17. e inhibitory eect of active Vitamin D
is evident on eecto/memory than naïve T cells because the level of
VDR expression on naïve T cells is low. Hence, the VDR signal on the
CD4+ inhibits the expression of IL-17, IL-2, Foxp3 and CCR6 and
enhances the expression of IL-10 [42,115].
Although the expression of VDR by B cells is controversial, the
results indicate that B cells may respond to active Vitamin D in
autocrine/intracrine way [116]. e resting B cells do not contain VDR
[117], the human tonsil B cells express VDR and can be up-regulated
by activation [118], the B-cell lymphoma cell lines SUDHL4 and
SUDHL5 express VDR [119], the human primary B cells express VDR
mRNA at low levels and active Vitamin D up-regulated the expression
[120]. e regulation of VDR expression by active Vitamin D in B cells
suggests that the eects of active Vitamin D may dier according to its
serum level in individuals and the state of B cells (i.e., active or
resting). e VDR up-regulation by active Vitamin D is needed for
inhibition of B-cells proliferation by active Vitamin D and there may be
a threshold level of VDR engagement needed for the anti-proliferative
eect to be apparent [116].
e resting B cells express CYP27B1 mRNA and incubation of B
cells with active Vitamin D up-regulate the expression. erefore, the
activity of Vitamin D on B cells may be aected by VDR expression
and the ability to degrade the active molecule. However, the CYP24A1
level was not altered by B-cell activation indicating that human B cells
can respond directly to active Vitamin D. Also, the increased
susceptibility of activated B cells to many of the eects of active
Vitamin D may be due to up-regulation of VDR and the B lymphocytes
may metabolize the Vitamin D to active Vitamin D and this is a source
for the extra-renal synthesis of active Vitamin D [120].
e active Vitamin D inhibit B cell proliferation and this is
associated with apoptosis of both activated and dividing B cells. In
cultures using combination of IL-21 and anti-CD40 with or without B-
cell receptor cross linking, the active Vitamin D inhibits also the
plasma cell dierentiation and immunoglobulin production. However,
if B cell were treated with active Vitamin D aer 5 days of culture, the
inhibition was not evident. is indicates that the Vitamin D inhibits
the generation of plasma cells but not their subsequent persistence and
is responsible for decreased immunoglobulin secretion [120-122].
e active Vitamin D up-regulate the mRNA level of p27 and down-
regulate the levels CDK4, CDK6 and cyclin D. us, it inhibits the B
cell proliferation by inhibiting the previous cycling B cells from
entering the cell cycle. ese results suggest that the eect of active
Vitamin D on plasma and memory cell dierentiation may be due to
suppression of ongoing B-cell proliferation [120].
Vitamin D and kidney disease
e kidney is the major organ involved in the formation of bioactive
forms of Vitamin D and is the major target organ (VDR is highly
expressed) for the classical and non-classical actions of Vitamin D. e
progression of chronic kidney disease (CKD) and many of the
cardiovascular complications may be linked to Vitamin D deciency
[123]. Patients with CKD have two problems; a high rate of severe
Vitamin D and reduced ability to convert Vitamin D to active Vitamin
D [124]. Vitamin D deciency is observed in nearly all CKD patients;
therefore, Vitamin D is recommended to be prescribed for stage 3-5
CKD patients who have low Vitamin D and high serum PTH levels
[125,126]
Many mechanisms were postulated to explain the decrease in
Vitamin D during the course of CKD [126]. First, Low Vitamin D in a
substrate-product relationship [127]. Patients with CKD will have
impaired production of cholecalciferol in the skin (due to low exposure
to sunlight, impaired response and malnutrition) and decreased
amount of Vitamin D that enter the renal tubules and then uptake in
the circulation (due to decreased renal mass/GFR and decreased
expression of megalin). In addition, proteinuria will damage the
proximal tubular cells and limits the number of megalin receptors and
Vitamin D binding to the megalin receptor [128].
Second, Low 1-α-hydroxylase activity (i.e., decreased active Vitamin
D) and high 24-hydroxylase activity (i.e., increased 24, 25(OH)2D).
erefore, there will be marked reduction in endogenous Vitamin D
and active Vitamin D with increased decay [129]. ird, Elevated
FGF-23 which is a phosphaturic hormone (i.e., keeping serum
phosphate homeostasis in early renal dysfunction) [130]. FGF-23
inhibits 1-α-hydroxylase activity in the renal proximal tubule and
reduce active Vitamin D production and stimulates 24-hydroxylase to
produce 24,25(OH)2D [131].
Citation: Mosaad YM, Mostafa M, Elwasify M, Youssef HM, Omar NM (2017) Vitamin D and Immune System. Vitam Miner 6: 151. doi:
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Finally, active Vitamin D inhibits through feedback mechanism the
1-α-hydroxylase and 25-hydroxylase. A pharmacological dose of active
Vitamin D may down-regulate Vitamin D levels and reduce Vitamin D
availability in extrarenal tissues and organs, thus increasing Vitamin D
deciency [132]. In the same time, lower concentration of Vitamin D,
as the case in CKD patients, will decrease the activity of 1-α-
hydroxylase [126].
Vitamin D status in CKD may have clinical implications on
cardiovascular system (CVS) through its eect on renin-angiotensin-
aldosterone system (RAAS). RAAS have multiple eects on CVS; it
regulates blood pressure, electrolytes, volume homeostasis, endothelial
function, vascular remodeling and bro genesis [133,134]. e active
Vitamin D has a negative eect on the RAAS and this pathway appears
to be regulated by the autocrine function of Vitamin D in CKD
patients [135,136]. Some observations in VDR null mice, both
intrarenal mRNA renin and plasma angiotensin II concentrations,
showed marked increase which were associated with hypertension and
cardiac muscle hypertrophy in VDR null mice. Inhibition the synthesis
of active Vitamin D in wild type mice showed increase in the intrarenal
expression of renin [133-136].
e level of Vitamin D showed an inverse relationship with the
degree of albuminuria in CKD suggesting its anti-proteinuric eects
which may be mediated through RAS-angiotensin II mechanism [136].
In addition, the local synthesized intrarenal angiotensin II has an eect
on the CVS (i.e., its eect on blood pressure, vascular smooth muscle
cells and cardiac myocytes) [123]. erefore, Vitamin D therapy may
aect premature mortality associated with CKD [137].
NF-
κ
B pathway is another pathway in CKD, which may be
regulated by the non-classical autocrine actions of Vitamin D. e NF-
κ
B may play a role in progression of renal disease and in diabetic
nephropathy in CKD patients [124]. Activation of the NF-
κ
b pathway
will trigger secretion of many cytokines, chemokines and other
inammatory factors, which exacerbate tissue injury in CKD [136]. In
hyperglycemia, angiotensin II may activate NF-
κ
B and then activates
angiotensinogen expression in renal cells [138]. Vitamin D inhibits the
activation of NF-
κ
B and its level has inverse relationship with the
degree of tissue inammation present in various types of kidney
disease [124,136,138].
Vitamin D therapy improves the rates of morbidity and mortality in
CKD either through immune-dependent or immune-independent
mechanisms beyond mineral and bone. Vitamin D has a direct
protective action on both renal and cardiovascular tissue and has an
immune-modulatory eect in CKD patients. Vitamin D has anti-
inammatory actions which will reduce the state of chronic
inammation associated with the progression in CKD, therefore,
Vitamin D will limit inltration of renal tissues with immune cells and
inammation-related cardiovascular complications. In addition,
Vitamin D has potent antimicrobial actions and thereby will improve
the ability of those patients to combat infectious pathogens [139].
Active Vitamin D Reno protective eect is mediated via suppression
of RAAS, reduction of proteinuria, protection of structural and
functional integrity of podocytes [140]. Combination of Vitamin D
with RAAS blockades can ameliorate renal brosis [141]. Active
Vitamin D anti-inammatory properties may be due to suppression of
NF-B pathway which via regulation of many inammatory cytokine
enhances both inammation and bro genesis [140, 142]. Active
Vitamin D has immune modulatory eects in CKD patients which will
ameliorate renal brosis and slow-down proteinuria development. is
can be done by enhancing 2 cell dierentiation, decreasing IL-6
expression, decreasing inammatory and oxidative stress, altering T
cell behavior, thus favoring tolerance development and reduce
proinammatory activity (140,143-145].
6-vitamin D and infection
In humans, Vitamin D triggers eective antimicrobial pathways, in
the cells of innate immune system, against bacterial, fungal and viral
pathogens, therefore, it has emerged as a central regulator of host
defense against infections. However, Vitamin D attenuates
inammation and acquired immunity via its potent tolerogenic eects
and hens limits the collateral tissue damage. On the other hand,
Vitamin D promotes aspects of acquired host defense and
epidemiological studies reported association between Vitamin D
deciency and increased risk of various infectious diseases [146].
e relationship between Vitamin D and infection was suggested
about more than 100 years ago, and before the advent of eective
antibiotics, Vitamin D has been used to treat infections such as
tuberculosis [147]. Several studies have been associated between
Vitamin D deciency and increased risk for infection. Upper
respiratory tract infection was reported in individuals with Vitamin D
level below 30 ng/ml [148]. Military recruits from Finland with low
Vitamin D lost more days from active duty (i.e. secondary to upper
respiratory infections) than those with high serum levels [149]. Also,
other studies reported association between low level of Vitamin D and
increased rate of infection with inuenza [150], bacterial vaginosis
[151] and HIV [152].
VDR is an important element in host immune response to dierent
infection. Some organisms either down-regulate or even block its
activity which lead to impairment of innate immune response such as
TB [153], Mycobacterium leprae [154], Epstein-Barr virus (EBV)
[155], Aspergillus fumigatus [156] and HIV infection that completely
inhibits VDR activity [157]. e Vitamin D has been linked to
infection susceptibility through the genetic studies on VDR. Genetic
polymorphisms of VDR were linked to TB susceptibility, extent
infection, response to treatment and time of microbiological resolution
by dierent studies [158-160].
e potential role of Vitamin D in host resistance to infections was
based on the following four ndings: conversion of circulating Vitamin
D to the active Vitamin D requires the CYP27B1 enzyme (cytochrome
27B1, 25-hydroxyvitamin D3 1-α-hydroxylase) and the immune system
is able to produce this enzyme; the majority of immune system cells
express VDR especially aer stimulation; the production of active
Vitamin D in the immune system led to the induction of antibacterial
products such as cathelicidin which in turn inhibited the replication of
Mycobacterium tuberculosis in vitro; and impaired Vitamin D status is
a common health problem across the globe and may be responsible for
the increased incidence of common infectious diseases across the
world [28,42,81].
Active Vitamin D increased the expression of TLR4 and CD14 in
human cells [161] and mouse model [162]. Increased TLR2 expression
by about two folds aer stimulation with Vitamin D in human
keratinocytes. Microarray analysis of VDREs genes showed active
Vitamin D increased CD 14 by more than 20-fold in well-dierentiated
human squamous carcinoma cells [163,164]. Also, the cathelicidin
antimicrobial peptide (CAMP) and β-defensin 2 (DEFB2) genes were
increased in response to active Vitamin D. e CAMP and defensins
act as chemo-attractant for immune cells such as neutrophil and
Citation: Mosaad YM, Mostafa M, Elwasify M, Youssef HM, Omar NM (2017) Vitamin D and Immune System. Vitam Miner 6: 151. doi:
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monocytes and other components of immune response [165]. Liu et al.
found that in African-American, the level of serum Vitamin D was
lower than those in Caucasian and the level of TLR 2/1 activation and
the expression of cathelicidin were also lower. Supplementation of
Vitamin D to succeed to restore the normal activity of TLR 2/1 and
expression of cathelicidin [56].
Kroner et al. [146] proposed a model for the vitamin D-dependent
antimicrobial pathway. In Human, both innate immune mechanism
(i.e., TLR-2/1 ligand and TLR-8 ligand) and adaptive immune
mechanisms (i.e., IFN-γ and CD40 ligand) induce antimicrobial
response in monocytes/macrophages through dierent signaling
pathways. en, up-regulation of CYP27B1 and VDR will occur and
Vitamin D will be converted to active Vitamin D. e Active Vitamin D
will trigger VDR mediated up-regulation of antimicrobial peptides
(CAMP, DEFB4 and NOD2). At the same time, the active Vitamin D
will bind to VDR and mediate down-regulation of hepcidin (HAMP)
which will favor the cellular export of iron, therefore, the intracellular
compartment will be inconvenient for the survival/proliferation of
pathogens. In addition, cathelicidin promotes autophagy, which
enhances auto-phagolysosomal fusion and antimicrobial activity.
Regarding infections, eect of Vitamin D on proinammatory
cytokines remains controversial (i.e., suppress or even enhance). Zhang
et al. [166] reported up-regulation of MKP-1 by Vitamin D to mediate
suppression of pro-inammatory cytokines in monocytes/
macrophages. However, these suppressive eects are attributed to
vitamin D feedback mechanisms to reduce tissue damage [167]. us,
it seems that rst, the Vitamin D triggers antimicrobial host defense
and enhances early inammatory reactions needed for cell recruitment
and ecient coordination of immune responses, later, aer a while,
Vitamin D by negative feedback mechanism, prevents extensive
inammation and tissue destruction [146].
Mangin et al. [168] hypothesized that the extra-renal production of
active Vitamin D increases when nucleated cells are infected by
intracellular bacteria. e kidneys lose its control of active Vitamin D
production and due to rapid conversion of Vitamin D to active Vitamin
D, the level of Vitamin D will decrease. e following mechanisms may
be responsible; inammatory cytokines will activate the CYP27B1
enzyme which will cause more Vitamin D conversion to active [169];
VDR are repressed by microbes and cannot transcribe CYP24A1
enzyme that breaks down the excess active Vitamin D [170]; increased
active Vitamin D will bind to pregnane X receptor (PXR) and will
inhibit conversion of vitamin D3 to 25(OH)D [171] and active Vitamin
D inhibits the hepatic synthesis of Vitamin D [172]. erefore, low
Vitamin D may be a consequence and not a cause of the inammatory
process [168].
7- vitamin D and autoimmunity
Autoimmune diseases (AIDs) are characterized by a loss of self-
tolerance to self-antigen and development of autoreactive immune
cells with subsequent body tissue destruction [173]. Interplay between
endogenous and exogenous factors characterize the mosaic of
autoimmunity. Complex genetic predisposition, hormonal,
epidemiological and environmental risk factors contribute to the
development of AIDs [93].
Epidemiological studies suggested an association between Vitamin
D insuciency/deciency and increased incidence of AIDs such as
SLE, RA, T1D and MS. Vitamin D supplement in AID animal models
prevented or ameliorated autoimmunity. Increased incidence of
inammation and susceptibility to AIDs was observed in VDR knock-
out or Vitamin D decient animals [174]. In the same time, Vitamin D
deciency is considered as an epidemic and the incidence of AIDs was
increased dramatically in the last decades. Also, a link between low sun
exposure and increased incidence of AIDs was reported especially in
Northern latitudes [175]. Epstein-Barr virus (EBV), is one of the most
inducing infectious risk factor for autoimmunity. It was reported that
EBV down-regulates the expression of VDR and thus decreases
benecial eects of Vitamin D [174]. erefore, the availability of
sucient level of Vitamin D represents an exogenous and endogenous
player in AIDs [175].
e Vitamin D has multiple eects on various cell lineages of
immune system and its anti-inammatory and immune-modulatory
roles were suggested to explain the association between Vitamin D and
autoimmunity. Vitamin D inhibits activity of 1 and secretion of
proinammatory cytokines (e.g., IL-2, IFN-γ and NTF-α). On the
other hand, Vitamin D enhances 2 immune response and secretion
of anti-inammatory cytokines (e.g., IL-4, IL-5 and IL-10), therefore,
shi the T cell immune response from an inammatory 1 to anti-
inammatory 2 state. Vitamin D may increase activity of Tregs and
inhibits activity of IL-17. Also, Vitamin D is required for the
development of natural killer T cells (NKT) and increased secretion of
IL-4 and IFN-γ [98,100,145,176,177].
Several associations were reported between serum level of Vitamin
D and AIDs. Low serum level of Vitamin D was associated with
increased incidence, severity and seasonality (i.e., more frequent ares
in springtime due to less sunshine) of MS [178]. e frequency of MS
was 40% less in females with high level of Vitamin D [179] and regular
Vitamin D supplement decreased the risk of developing RA in about
30,000 patients [180]. Also, infants with regular Vitamin D intake had a
reduced incidence of developing T1D [181].
e mechanism explaining how the Vitamin D intake aects the
development of AIDs is still unknown. However, Mahon et al. [182]
described that daily intake of 1000 IU of Vitamin D with 800 mg
Calcium; increased secretion of TGF-β1. e increased level of this
anti-inammatory cytokine was associated with inhibition of harmful
auto-reactive T-cell functions [179,183].
Vitamin D insuciency and deciency have been reported in SLE
patients (38-96% and 8-30% respectively). e observed wide variation
may be due to age of the patients, disease duration, ethnicity,
seasonality, medications, geographic causes and method of assay
[184-187]. Also, Vitamin D deciency was noted in European
American female patients with SLE and in obese healthy controls with
positive anti-nuclear antibodies indicating that Vitamin D deciency
may play a role in initiating autoimmunity [188]. On the other hand,
no associations were found between SLE development and Vitamin D
dietary intake [189,190]. However, these studies were dependent on
questionnaire for dietary Vitamin D intake and the serum levels of
Vitamin D were not reported [179].
ere are several causes that can explain the vulnerability of SLE
patients to Vitamin D deciency; those patients always advised to
avoid exposure to sunlight due to photosensitivity [191]; renal
involvement with subsequent defect in the 1-hydroxylation of Vitamin
D [179]; chronic use of corticosteroid and may be high doses, as the
case in lupus nephritis, decreases dietary absorption from intestine and
increases the catabolism of Vitamin D [192] and the genetic variation
[193].
Citation: Mosaad YM, Mostafa M, Elwasify M, Youssef HM, Omar NM (2017) Vitamin D and Immune System. Vitam Miner 6: 151. doi:
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8-vitamin D and therapy
Vitamin D deciency is very important health problem because it
aects many biological activities and bone mineralization. is
problem is well known in both highly developed and underdeveloped
countries. In winter months, a little Vitamin D is made in individuals
living in northern and southern regions of the planet, therefore,
adequate concentrations of Vitamin D are needed [17]. Many reasons
were suggested to explain the epidemic of Vitamin D deciency; skin
melanin pigmentation, clothing as a barrier to Vitamin D
photosynthesis, pollution as a block for some ultraviolet radiation,
ageing of the skin, inammatory process and latitude that dramatically
inuences the amount of solar radiation available to synthesize vitamin
D3 [168].
e Vitamin D (25(OH)D) is the marker for vitamin D status and its
level determines whether a person is decient, sucient or toxic. Until
now, there is a controversy about the precise level of Vitamin D and the
level of Vitamin D categories (i.e., decient, sucient or toxic).
However, the Vitamin D Council (VDC) [194] recommended
maintaining serum levels of 50 ng/ml as the precise level with the
following reference ranges; decient: 0-40 ng/ml; sucient: 40-80
ng/ml; high Normal: 80-100 ng/ml; undesirable: >100 ng/ml and toxic:
>150 ng/ml. e Endocrine Society denition stated that Vitamin D
deciency means levels below or equal 20 ng/ml and insuciency
means levels equal to 20 -29 ng/ml [195]. e values stated by the
Institute of Medicine denition [196] is lower than the others with
levels less than or equal 12 ng/ml for risk/deciency, levels from 12 to
20 ng/ml for risk/insuciency and levels equal 20 ng/ml for sucient.
e reasons for VDC recommendations regarding the precise level
and categories of Vitamin D categories are; Vitamin D blood levels
between 40-80 ng/ml was maintained in peoples living near the
equator from sun exposure alone and human evolved in this area
synthesizing in the skin a robust quantities of Vitamin D [197]; the
anti-rachitic activity in breast milk occurs at 45 ng/ml or higher, but
not at 38.4 ng/ml or lower [198], therefore the VDC believes that the
maternal status of Vitamin D is necessary to provide anti-rachitic
activity for ospring and should be considered a biomarker for optimal
Vitamin D status in humans; the parathyroid hormone is maximally
suppressed at 40 ng/ml or higher and this should be also considered a
biomarker for optimal vitamin D status [199]. On Sun exposure alone,
human body cannot achieve levels above 100 ng/ml from Vitamin D
[200]. Hypercalcemia and calcuria are the manifestation of Vitamin D
toxicity and no relation was reported between Vitamin D levels up to
257 ng/ml and serum calcium. In the same time, Vitamin D toxicity
have been reported at levels as low as 194 ng/ml [201], therefore, the
threshold of 150 ng/ml should be considered the lower limit of toxicity.
Vitamin D insuciency indicates biochemical low levels without
clinical evidence of deciency (i.e., rickets or osteomalacia). Vitamin D
insuciency may cause muscle weakness, fractures in elderly when
associated with osteoporosis. Also, Vitamin D insuciency and
deciency were reported to be associated with colorectal cancer,
prostate cancer, multiple sclerosis, type 1 diabetes, cardiovascular
diseases and TB [202].
e best indicator for Vitamin D status assessment in patients with a
Vitamin D related disease is to measure the range of 25(OH)D3 serum
concentration in a population of healthy subjects [1]. is view is
supported;1) absence of Vitamin D clinical assay; 2) the serum
concentration of 25(OH)D3 is an accurate indicator for Vitamin D3
derived from cutaneous UV-stimulated synthesis and dietary intake
(the metabolism of vitamin D3 into 25(OH)D3 by the liver vitamin
D-25-hydroxylase is not regulated); 3) a variety of clinical assays are
available to measure 25(OH)D; and 4) the plasma concentrations of
25(OH)D3 correlate with many clinical diseases [203,204].
To achieve adequate Vitamin D status, various strategies have been
suggested; healthy lifestyle with normal body mass index (i.e., a varied
diet with vitamin D-containing foods, adequate outdoor activities and
sun exposure); improving vitamin D status (i.e., dietary
recommendations, food fortication, vitamin D supplementation and
sun exposure) and Vitamin D oral supplementation for high-risk
groups (i.e., pregnant and breastfeeding females, teenagers, young
children and infants, people over 65 years, people with low or no
exposure to sun and dark skin people) [205].
e Institute of Medicine (IOM) recommended daily intakes of 600
IU/day for adults and up to 800 IU/day for elderly people living in
North America. e IOM also stated that adequate amount of Vitamin
D can be supplied from the regular sun exposure for 15 minutes in
summer without sunscreen 3 to 4 times per week and Vitamin D
supplement with D2 or D3 can be used [206,207].
In UK, Vitamin D supplement of 400 IU/day was advised to be
given on for people over 65 years old with the aim of achieving
Vitamin D level about 20 ng/ml [207].
e Endocrine Society Clinician Vitamin D Guideline of 2011
recommended Vitamin D serum of at least 30 ng/ml. is level is
required to achieve a plateau in the reduction of serum PTH with
increasing Vitamin D among healthy adults. Also, at this level of
Vitamin D, it will be possible to reduce falls or fracture rates in older
people [208]. Encouraging data suggested that adequate Vitamin D
supplement can reduce the risks of cancer [209] and the risk of
developing a rst cardiovascular event [207].
While, Vitamin D supplement must be ensured in high risk groups,
however, there is no need to measure serum Vitamin D concentrations
on healthy people [210]. On the other hand, assessment of Vitamin D,
D-status should be done for people presenting for medical advice with
suspicious of Vitamin D deciency as a cause of the problems
presented. Follow-up monitoring is needed; to be sure that a good
clinical response to initial supplement is achieved; if the health
problems or medication require routine Vitamin D supplement or to
ensure that the treatment is adequate [207].
Measuring serum level of 25(OH)D is used currently to assess
Vitamin D status, however, this will not provide enough information
about Vitamin D endocrine function. In the same time, it is not clear
why active Vitamin D is measured, but associations between active
Vitamin D and diseases are present [168,211]. On the other hand,
active Vitamin D is not measured to assess Vitamin D nutritional
status, as marker related to health outcomes or for Vitamin D research.
To assess Vitamin D status as a clinical marker of chronic disease, it is
better to measure both Vitamin D and active Vitamin D in addition to
calcium, phosphorous and PTH when indicated [212,213]. Measuring
serum level of active Vitamin D should be considered in cases with low
Vitamin D serum level and in autoimmune or chronic inammatory
diseases and abnormal laboratory results such as inammatory
markers [168].
Measurement of serum level of Vitamin D is indicated in; when
there is clinical or laboratory suspicious of Vitamin D deciency (e.g.,
rickets in children or osteomalacia in adults, bone pain, low level of
serum calcium or phosphorous or high level of alkaline phosphatase or
Citation: Mosaad YM, Mostafa M, Elwasify M, Youssef HM, Omar NM (2017) Vitamin D and Immune System. Vitam Miner 6: 151. doi:
10.4172/2376-1318.1000151
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Vitam Miner, an open access journal
ISSN: 2376-1318
Volume 6 • Issue 1 • 1000151
PTH); elderly people; patients with osteoporosis and peoples with
increased risk of falls or fractures [214,215].
e physiological serum level of active Vitamin D is in picomole and
nanomole doses of active Vitamin D are needed to obtain its non-
classical eects. Active Vitamin D supra-physiological doses will result
in hypercalcemia. To avoid this and to have tissue and organ targeted
Vitamin D eects, active Vitamin D analogs were developed. Presently,
enormous number of Vitamin D analogs are manufactured and some
analogs have tissue-specic eects, low calcemic side eects and can be
given at higher dose [216].
Vitamin D analogs are commonly used to treat secondary
hyperparathyroidism complicating CKD or ESRD. ey suppress PTH
without inducing severe hypercalcemia. Also, Vitamin D analogs are
used for psoriasis either alone or in combination with topical steroids.
ey have anti-inammatory properties and exert pro-dierentiating
and anti-proliferative eects on keratinocytes. Furthermore, Vitamin D
analogs are used for treating osteoporosis as they increase bone
mineral density. Because of the potent anti-proliferative and pro-
dierentiating eects on normal and malignant cell lines, the active
Vitamin D and its analogs are used also for cancer treatment [216].
Active Vitamin D and Vitamin D analogs modulate several cell
processes such as growth, apoptosis, adhesion, immune function and
signaling pathways. However, comparison of dierent cell lines showed
overlap of few active Vitamin D/analog-regulated genes and this
suggested the cell type and tissue-specic eect of active Vitamin D
and its analogs [216]. For example, results of active Vitamin D analogs
studies using human T-cells showed regulation of genes responsible for
cell growth, cell death, cell signaling and migration indicating that
these analogs aect human T-cells with a migratory signature and
direct them toward sites of inammation [202].
Several studies have tried to explain the exact mechanism of tissue-
specic action of Vitamin D analogs. First, the catabolism of Vitamin D
analogs aects their potency. Modication of active Vitamin D side
chain slow down its catabolism leading to longer exposure to tissues
[217,218]. e metabolites formed aer catabolism are more active
than active Vitamin D [219]. Some analogs more eective in slowing
down the VDR degradation. Some cell types prefer specic catabolism
pathways and enzymes above others and the degradation process may
also contribute to the tissue-specic activity of Vitamin D analogs. e
anity for the Vitamin D binding protein (DBP) also plays a role in the
activity of Vitamin D analogs [216]. Second, the interaction between
Vitamin D analogs and VDR, co-activators and VDREs. Some analogs
promote hetero-dimerization between VDR and retinoid X receptor
(RXR). Vitamin D analogs might also be able to induce tissue-specic
eects by favoring binding to specic VDRE motifs in target gene
promoters. Another mechanism need to be investigated is the eect of
proteomics and epigenetics [216].
Conclusion
VDR is expressed on immune cells (B cells, T cells and antigen
presenting cells) and these immunologic cells are all are capable of
synthesizing and responding to Vitamin D. Vitamin D interaction with
immune system is one of the most well-established non-classical eects
of Vitamin D. Vitamin D can modulate the innate and adaptive
immune responses. e ability of Vitamin D to inuence normal
human immunity will be highly dependent on the vitamin D status of
individuals, therefore, deciency or insuciency of Vitamin D is
associated with increased autoimmunity and infection. e 25-
hydroxyvitamin D3 (25OHD3) is the main circulating metabolite of
Vitamin D and is the most reliable measurement of an individual’s
Vitamin D status. e Vitamin D supplements in decient individuals
will have benecial immune-modulatory eects on the autoimmune
status.
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