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Vitamin D and Immune System

  • Mansoura University & Fakeeh College for Medical Sciences


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.
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,
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:
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.
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
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 sucient 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 aected by the amount of UVB radiation to which the
skin is exposed. Other factors aecting 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, aer 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 anity 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 dierentiation 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
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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 reects both dietary
Vitamin D intake and the endogenous Vitamin D production [11]. For
simplication, 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
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 aect 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 anity. 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
eects 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 specic 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 specic DNA sequence elements [vitamin D response element
(VDREs)] in vitamin D-responsive genes. is binding will ultimately
inuence 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 eects 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
eects 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
deciency 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
eect; 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 eect 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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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 insuciency [24-26]. e Vitamin D
insuciency is dened by sub-optima level of Vitamin D that is not
rachitic [4]. Geographical, social, or economic factors can aect the
Vitamin D status in dierent populations and Vitamin D insuciency
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 insuciency and various human diseases including autoimmune,
infectious, cardiovascular, neurologic, immune deciency 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 eects 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 eect 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, dierentiation,
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 deciency 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
eects. 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 eects 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), dierent 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
signicant clinical improvement was strongly correlated with the
immunomodulating potential in Vitamin D-treated RA patients
In immune cells, activation of VDR leads to production of
downstream gene products. ese proteins have potent anti-
proliferative, pro-dierentiative, and immunomodulatory eects [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 inuence the expression of
various essential secreted molecules on the cell surface. On the other
hand, the active Vitamin D has no inhibitory eect 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)
Vitamin D and innate immune system
e innate immune system is the immediate, non-specic 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
e Vitamin D is a potent stimulator of antimicrobial peptides in
innate immunity and sucient 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
sucient 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:
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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 specic T-cell
[52,53]. Vitamin D prevents inammatory response overreaction and
prevents further cell or tissue damage by inammation [54]. Vitamin D
also suppress the inammation by limiting excessive production of
proinammatory 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 eective
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 eects 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-specic
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 dierentiation of precursor monocytes to more mature
phagocytic macrophages and this was supported by dierential
expression of VDR and 1α-hydroxylase during the dierentiation 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)
Macrophages possess both enzymes essential to produce active
Vitamin D leading to intracrine and paracrine eects. e high
expression of VDR by monocytes ensures sensitivity of these cells to
the dierentiating eects 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 inammatory cytokines and chemokines
[42].erefore, Vitamin D deciency will impair the antimicrobial
function of macrophages due to decreased capacity to mature, to
produce lysosomal enzymes, to secrete H2O2 and to produce specic
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-decient 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
inammation 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
inammatory 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:
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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
inuenza 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
dierentiation 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-inammatory cytokine (IL-10) and
less pro-inammatory 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 dierentiate Treg subsets [28,45,78,80].
e mDCs are ecient 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 inuence the dierentiation 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 eects 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 inuence 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 inuence T-cell
function : direct eect of systemic active Vitamin D on T cells ; indirect
eects of localized DC expression of CYP27B1 and intracrine synthesis
of active Vitamin D on antigen presentation to T cells; paracrine
mechanism through direct eects 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 dierent 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
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 aer 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 dierences 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 eector 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
aects 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 eect 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
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 eects 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 inuences
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
eects 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 inammatory 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 aects the dierentiation and
functions of Tregs, increases the suppressive activity and the in vivo
expansion of antigen-specic 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
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 dierentiation by active Vitamin D [114].
However, both active Vitamin D and IL-2 may have synergistically
limit the production of IL-17. e inhibitory eect of active Vitamin D
is evident on eecto/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 eects of active Vitamin D may dier 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
eect 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 aected 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 eects 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 dierentiation and immunoglobulin production. However,
if B cell were treated with active Vitamin D aer 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 eect of active
Vitamin D on plasma and memory cell dierentiation 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 deciency
[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 deciency 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
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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Volume 6 • Issue 1 • 1000151
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
deciency [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 eect on renin-angiotensin-
aldosterone system (RAAS). RAAS have multiple eects 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 eect 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 eects
which may be mediated through RAS-angiotensin II mechanism [136].
In addition, the local synthesized intrarenal angiotensin II has an eect
on the CVS (i.e., its eect on blood pressure, vascular smooth muscle
cells and cardiac myocytes) [123]. erefore, Vitamin D therapy may
aect premature mortality associated with CKD [137].
B pathway is another pathway in CKD, which may be
regulated by the non-classical autocrine actions of Vitamin D. e NF-
B may play a role in progression of renal disease and in diabetic
nephropathy in CKD patients [124]. Activation of the NF-
b pathway
will trigger secretion of many cytokines, chemokines and other
inammatory factors, which exacerbate tissue injury in CKD [136]. In
hyperglycemia, angiotensin II may activate NF-
B and then activates
angiotensinogen expression in renal cells [138]. Vitamin D inhibits the
activation of NF-
B and its level has inverse relationship with the
degree of tissue inammation 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 eect in CKD patients. Vitamin D has anti-
inammatory actions which will reduce the state of chronic
inammation associated with the progression in CKD, therefore,
Vitamin D will limit inltration of renal tissues with immune cells and
inammation-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 eect 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-inammatory properties may be due to suppression of
NF-B pathway which via regulation of many inammatory cytokine
enhances both inammation and bro genesis [140, 142]. Active
Vitamin D has immune modulatory eects in CKD patients which will
ameliorate renal brosis and slow-down proteinuria development. is
can be done by enhancing 2 cell dierentiation, decreasing IL-6
expression, decreasing inammatory and oxidative stress, altering T
cell behavior, thus favoring tolerance development and reduce
proinammatory activity (140,143-145].
6-vitamin D and infection
In humans, Vitamin D triggers eective 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
inammation and acquired immunity via its potent tolerogenic eects
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
deciency 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 eective
antibiotics, Vitamin D has been used to treat infections such as
tuberculosis [147]. Several studies have been associated between
Vitamin D deciency 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 inuenza [150], bacterial vaginosis
[151] and HIV [152].
VDR is an important element in host immune response to dierent
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 dierent 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 aer 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 aer 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-dierentiated
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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ISSN: 2376-1318
Volume 6 • Issue 1 • 1000151
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 dierent 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, eect of Vitamin D on proinammatory
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-inammatory cytokines in monocytes/
macrophages. However, these suppressive eects 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 inammatory reactions needed for cell recruitment
and ecient coordination of immune responses, later, aer a while,
Vitamin D by negative feedback mechanism, prevents extensive
inammation 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; inammatory 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 inammatory
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 insuciency/deciency 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
inammation and susceptibility to AIDs was observed in VDR knock-
out or Vitamin D decient animals [174]. In the same time, Vitamin D
deciency 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
benecial eects of Vitamin D [174]. erefore, the availability of
sucient level of Vitamin D represents an exogenous and endogenous
player in AIDs [175].
e Vitamin D has multiple eects on various cell lineages of
immune system and its anti-inammatory and immune-modulatory
roles were suggested to explain the association between Vitamin D and
autoimmunity. Vitamin D inhibits activity of 1 and secretion of
proinammatory cytokines (e.g., IL-2, IFN-γ and NTF-α). On the
other hand, Vitamin D enhances 2 immune response and secretion
of anti-inammatory cytokines (e.g., IL-4, IL-5 and IL-10), therefore,
shi the T cell immune response from an inammatory 1 to anti-
inammatory 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 aects 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-inammatory cytokine was associated with inhibition of harmful
auto-reactive T-cell functions [179,183].
Vitamin D insuciency and deciency 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 deciency was noted in European
American female patients with SLE and in obese healthy controls with
positive anti-nuclear antibodies indicating that Vitamin D deciency
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 deciency; 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
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 deciency is very important health problem because it
aects 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 deciency; skin
melanin pigmentation, clothing as a barrier to Vitamin D
photosynthesis, pollution as a block for some ultraviolet radiation,
ageing of the skin, inammatory process and latitude that dramatically
inuences 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 decient, sucient or toxic. Until
now, there is a controversy about the precise level of Vitamin D and the
level of Vitamin D categories (i.e., decient, sucient 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; decient: 0-40 ng/ml; sucient: 40-80
ng/ml; high Normal: 80-100 ng/ml; undesirable: >100 ng/ml and toxic:
>150 ng/ml. e Endocrine Society denition stated that Vitamin D
deciency means levels below or equal 20 ng/ml and insuciency
means levels equal to 20 -29 ng/ml [195]. e values stated by the
Institute of Medicine denition [196] is lower than the others with
levels less than or equal 12 ng/ml for risk/deciency, levels from 12 to
20 ng/ml for risk/insuciency and levels equal 20 ng/ml for sucient.
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 ospring 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 insuciency indicates biochemical low levels without
clinical evidence of deciency (i.e., rickets or osteomalacia). Vitamin D
insuciency may cause muscle weakness, fractures in elderly when
associated with osteoporosis. Also, Vitamin D insuciency and
deciency 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 fortication, 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 deciency 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 inammatory
diseases and abnormal laboratory results such as inammatory
markers [168].
Measurement of serum level of Vitamin D is indicated in; when
there is clinical or laboratory suspicious of Vitamin D deciency (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:
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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 eects. Active Vitamin D supra-physiological doses will result
in hypercalcemia. To avoid this and to have tissue and organ targeted
Vitamin D eects, active Vitamin D analogs were developed. Presently,
enormous number of Vitamin D analogs are manufactured and some
analogs have tissue-specic eects, low calcemic side eects 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-inammatory properties and exert pro-dierentiating
and anti-proliferative eects 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-
dierentiating eects 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 dierent cell lines showed
overlap of few active Vitamin D/analog-regulated genes and this
suggested the cell type and tissue-specic eect 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 aect human T-cells with a migratory signature and
direct them toward sites of inammation [202].
Several studies have tried to explain the exact mechanism of tissue-
specic action of Vitamin D analogs. First, the catabolism of Vitamin D
analogs aects their potency. Modication of active Vitamin D side
chain slow down its catabolism leading to longer exposure to tissues
[217,218]. e metabolites formed aer catabolism are more active
than active Vitamin D [219]. Some analogs more eective in slowing
down the VDR degradation. Some cell types prefer specic catabolism
pathways and enzymes above others and the degradation process may
also contribute to the tissue-specic activity of Vitamin D analogs. e
anity 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-specic
eects by favoring binding to specic VDRE motifs in target gene
promoters. Another mechanism need to be investigated is the eect of
proteomics and epigenetics [216].
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 eects
of Vitamin D. Vitamin D can modulate the innate and adaptive
immune responses. e ability of Vitamin D to inuence normal
human immunity will be highly dependent on the vitamin D status of
individuals, therefore, deciency or insuciency 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 decient individuals
will have benecial immune-modulatory eects on the autoimmune
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Citation: Mosaad YM, Mostafa M, Elwasify M, Youssef HM, Omar NM (2017) Vitamin D and Immune System. Vitam Miner 6: 151. doi:
Page 15 of 15
Vitam Miner, an open access journal
ISSN: 2376-1318
Volume 6 • Issue 1 • 1000151
... (calcitriol) has been documented to mediate in the innate and adaptive immune systems and triggers effective antimicrobial pathways against bacterial, viral, and fungal pathogens in the cells of the innate immune system [1]. ...
... This metabolite in the circulation is a marker of 25(OH)D status. Then, depending on the needs, 25(OH)D undergoes a second hydroxylation in the kidneys by the mitochondrial cytochrome P450 enzyme, 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1), and is converted into 1,25(OH) 2 D [1,3]. Its production is tightly feedback-regulated and its main role is in the regulation of calcium/phosphate and bone homeostasis through genomic activation of a number of genes in its target tissues (intestine, bone, kidney, and parathyroid gland). ...
... A recent review suggests that the ability of vitamin D to influence normal human immunity is highly dependent on the 25(OH)D status of individuals. Deficiency or insufficiency may be associated with increased autoimmunity and infections [1]. Historically, a link between vitamin D and innate immune function was identified through the use of cod liver oil as treatment in children with tuberculosis [21]. ...
Purpose Respiratory tract infections (RTIs) are a major cause of illness worldwide and the most common cause of hospitalization for pneumonia and bronchiolitis. These two diseases are the leading causes of morbidity and mortality among children under 5 years of age. Vitamin D is believed to have immunomodulatory effects on the innate and adaptive immune systems by modulating the expression of antimicrobial peptides, like cathelicidin, in response to both viral and bacterial stimuli. The aim of this review is to summarize the more recently published data with regard to potential associations of 25-hydroxyvitamin D [25(OH)D] with infectious respiratory tract diseases of childhood and the possible health benefits from vitamin D supplementation. Methods The literature search was conducted by using the PubMed, Scopus, and Google Scholar databases, with the following keywords: vitamin D, respiratory tract infection, tuberculosis, influenza, infancy, and childhood. Results Several studies have identified links between inadequate 25(OH)D concentrations and the development of upper or lower respiratory tract infections in infants and young children. Some of them also suggest that intervention with vitamin D supplements could decrease both child morbidity and mortality from such causes. Conclusions Most studies agree in that decreased vitamin D concentrations are prevalent among most infants and children with RTIs. Also, normal to high-serum 25(OH)D appears to have some beneficial influence on the incidence and severity of some, but not all, types of these infections. However, studies with vitamin D supplementation revealed conflicting results as to whether supplementation may be of benefit, and at what doses.
... Indeed, in addition to calcium regulation within the gastrointestinal, renal, and skeletal systems, vitamin D may contribute to several organs' function. For instance, it has been reported to play a relevant role in reducing inflammation and in improving immune function by mediating the innate and adaptive immune responses and triggering effective antimicrobial pathways against pathogens [18]. ...
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Vitamin D deficiency and insufficiency is a global health issue: an association has been demonstrated between vitamin D deficiency and a myriad of acute and chronic illnesses. Data regarding vitamin D status among children hospitalized with non-critical illnesses are scanty. We aimed to: (1) identify profiles of children hospitalized due to non-critical illnesses, using vitamin D levels as the driving outcome; (2) assess the association between patient profiles and length of stay. The study included 854 patients (1–17 years old) who underwent blood tests for detecting vitamin D levels. A regression tree was used to stratify patients. The relationship between vitamin D levels and length of stay was explored using Poisson regression. The regression tree identified three subgroups. Group A (16%): African, North African, Hispanic, and Indian patients. Group B (62%): Caucasian and Asian patients hospitalized for respiratory, metabolic, ill-defined, infective, and genitourinary diseases. Group C (22%): Caucasian and Asian patients hospitalized for digestive, nervous, and musculoskeletal diseases, blood and skin diseases, and injuries. Mean serum vitamin D level (ng/mL) was 13.7 (SD = 9.4) in Group A, 20.5 (10.0) in Group B, and 26.2 (12.6) in Group C. Group B was associated with the highest BMI z-score (p < 0.001) and the highest frequency of preterm births (p = 0.041). Mean length of stay was longer in Group A than in the other groups (p < 0.001) and decreased significantly by 9.8% (p = 0.024) in Group A and by 5% (p = 0.029) in Group B per 10 ng/mL increase in vitamin D level. We identified three subgroups of hospitalized children, defined according to ethnicity and discharge diagnosis, and characterized by increasing vitamin D levels. Vitamin D levels were associated with length of hospitalization.
... As general consensus, serum 25-hydroxyvitamin D (25(OH)D) level below 50 nmol/L considered as a cutoff point for vitamin D deficiency and if its serum level is less than 25 nmol/L, severe deficiency is diagnosed [3]. Vitamin D deficiency is associated with infection and increased autoimmunity [7]. Different studies among under five children shows that decreased level of 25(OH)D were more prevalent among under five children with respiratory tract infections (RTIs) and its deficiency was associated with increased risk of RTIs [8][9][10]. ...
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Background Studies show that 25 (OH) D status appears to have beneficial influence on the incidence and severity of some types of infections. However, studies with vitamin D supplementation on young children produced conflicting results. This study was conducted to assess and compare the pooled prevalence of vitamin D deficiency among healthy and sick children in sub-Saharan Africa. Method A systematic review of PubMed, CINAHL, Web of science, global health and Google scholar electronic databases was conducted. Both published and unpublished observational studies conducted among under-five children in the year 2010–2020 were included. STATA Version 14 was used for analysis. Heterogeneity of studies was assessed using I² test. A random-effects model was used to estimate the pooled prevalence among both healthy and sick children. Result A total of 1212 articles were retrieved from data bases of which 10papers were included. The pooled prevalence of vitamin D deficiency among healthy children was 50.06% with mean serum vitamin D level of 41.06 nm/L. The pooled prevalence among the sick children was 39.36% with 66.96 nm/L of mean concentration. The pooled prevalence among healthy children was significantly higher compared to those who have common medical illnesses and the pooled mean concentration among the sick was also much higher than the mean concentration among healthy children. Conclusion The pooled prevalence among both groups of population was significantly high and a concerning public health problem. The prevalence among healthy children was much higher as compared to sick children.
... 3 Vitamin D plays an important role in the regulation of calcium level and bone metabolism in the body, its active metabolite 1,25(OH)2D (calcitriol) facilitate the innate and adaptive immune systems and triggers effective antimicrobial pathways against bacterial, viral, and fungal pathogens in the cells of the innate immune system. 4 Moreover, it helps for brain development and function, including neuronal differentiation, proliferation, and apoptosis, regulating synaptic plasticity, the ontogeny of the dopaminergic system, immunomodulation, reduces the risk of asthma and reducing oxidative burden. 5 Over 40% of infants'/adults' skin should be exposed to sunshine daily for twenty minutes in order to synthesize a sufficient amount of 25(OH)D3 or to prevent its deficiency. ...
Full-text available
Background Exposure to sunlight is vital for the synthesis of vitamin-D and vitamin D plays an important role in growth and bones strength. Therefore, this study aimed to assess the knowledge and practice of infants exposure to sunlight among lactating women. Methods A cross-sectional study was conducted from May 01 to 30, 2019 among 327 infant coupled lactating mothers attended at Yirgalem General Hospital. An interviewer-administered questionnaire was used to collect relevant data through a convenient sampling technique. Results A total of 84.7% of respondents exposed infants to sunlight. More than 94% knew the benefit of exposing infants to sunlight. About 20.9%, 25.6%, and 19.9% of mothers exposed infants to sunlight within 15, 16 to 30, and 31 to 45 days of birth, respectively. In addition, 59.9% of respondents exposed infants to sunshine daily and 72.2% exposed without clothing the infants’ body. Moreover, 63.5% of mothers have applied lubricants and overall 54.5% of mothers exposed infants to sunlight in good practice. Unemployed women were 4.7 times more likely (aOR; 95%CI: 4.7; 2.0-11.4) to expose infants to sunlight when compared to those employed, while women whose husbands have at least secondary education level were 5.1 times more likely (aOR; 95%CI: 5.1; 1.6-16.1) to expose infants to sunlight when compared to those unable to read and write. Conclusion More than 45% and more than one-third of lactating mothers had poor practice and exposed infants to sunlight for inadequate time, respectively. Therefore, the finding indicates a need for awareness creation to increase women’s knowledge and practice toward the exposure of infants to sunlight.
... Primarily involved in calcium homeostasis, recent evidence suggests a multifunctional activity of Vitamin D. It has been found to serve important roles in glucose metabolism, cardiovascular function, neuroprotection, endocrine control and immune regulation [10]. Vitamin D mediates immunity via a multitude of mechanisms including inhibition of the production of interleukins by T-cells and immunoglobulins by B-cells [11]. Vitamin D exerts immunomodulatory effects on allergen-induced hypersensitivity via activation of vitamin D receptor (VDR), which is expressed on B cells, T cells, regulatory T cells (Tregs), dendritic cells and macrophages [1]. ...
Full-text available
Aim: Allergic disorders constitute a major health problem in the modern world. Hypersensitivity to various allergens mediated by immunoglobulin E (IgE) forms the pathologic basis of allergies. The emerging role of vitamin D in immunity makes it a potential preventative and therapeutic agent against allergies. The present study explored the link between serum vitamin D and IgE levels in local patients with known allergies. Material and Methods: Eighty subjects were recruited for this cross-sectional study and segregated into Group 1 (non-allergic control subjects, n=41)) and Group 2 (allergic subjects, n=39). Complete blood count (CBC), serum IgE and serum vitamin D with its associated biochemical markers, including parathyroid hormone (PTH), calcium and phosphate were determined for comparison between the two groups. Basic demographic data, medical history and sun exposure duration were also recorded. Results: IgE levels (Group 1, 87.13 IU/L ± 57.66 vs. Group 2, 1542.54 IU/L ± 1239.79; p=0.000) and eosinophil count (Group 1, 2.80% ± 1.83 vs. Group 2, 4.61% ± 4.19; p=0.014) were significantly higher in patients with allergies. No difference was observed between the groups in serum vitamin D levels and other markers. In patients with allergies, serum vitamin D was inversely related to serum IgE (r=-0.374, p= 0.019). Discussion: High serum vitamin D is associated with low IgE levels in patients suffering from allergic conditions, suggesting a potential interplay between allergic mechanisms and vitamin D. Further studies are warranted to clarify the role of vitamin D in the pathogenesis and clinical management of allergic disorders.
... However, to our knowledge, no previous study has provided evidence about such an inverse relationship in children so far. Vitamin D is thought to play a relevant role in reducing inflammation and in improving immune function; indeed, it has been reported to mediate the innate and adaptive immune responses and trigger effective antimicrobial pathways against pathogens [28]. Thus, future larger-scale and longitudinal studies (also in other environmental contexts) would be useful to confirm the current study findings. ...
Full-text available
Seasonal variations in UV-B radiation may influence vitamin D status, and this, in turn, may influence the risk of bronchiolitis hospitalization. The aim of this study was using a causal inference approach to investigate, simultaneously, the interrelationships between personal and environmental risk factors at birth/hospital admission (RFBH), serum vitamin D levels and bronchiolitis hospitalization. A total of 63 children (<2 years old) hospitalized for bronchiolitis (34 RSV-positive) and 63 controls were consecutively enrolled (2014–2016). Vitamin D levels and some RFBH (birth season, birth weight, gestational age, gender, age, weight, hospitalization season) were recorded. The discovered RFBH effects on the risk ok bronchiolitis hospitalization were decomposed into direct and vitamin-D mediated ones through Mediation Analysis. Winter-spring season (vs. summer-autumn) was significantly associated with lower vitamin D levels (mean difference −11.14 nmol/L). Increasing serum vitamin D levels were significantly associated with a lower risk of bronchiolitis hospitalization (OR = 0.84 for a 10-nmol/L increase). Winter-spring season and gestational age (one-week increase) were significantly and directly associated with bronchiolitis hospitalization (OR = 6.37 and OR = 0.78 respectively), while vitamin D-mediated effects were negligible (1.21 and 1.02 respectively). Using a comprehensive causal approach may enhance the understanding of the complex interrelationships among RFBH, vitamin D and bronchiolitis hospitalization.
... As general consensus, serum 25-hydroxyvitamin D (25(OH)D) level below 50 nmol/L considered as a cutoff point for vitamin D deficiency and if its serum level is less than 25 nmol/L, severe deficiency is diagnosed [3]. Vitamin D deficiency is associated with infection and increased autoimmunity [5]. Different studies among under five children shows that decreased level of 25(OH)D were more prevalent among under five children with RTIs and its deficiency was associated with increased risk of RTIs. ...
Full-text available
Background: Studies shows that 25(OH)D status appears to have some beneficial influence on the incidence and severity of some types of infections. However, studies with vitamin D supplementation on young children produced conflicting results. Method: A systematic review of PubMed, CINAHL, Web of science, global health and Google scholar electronic databases was conducted. STATA Version 14 was used for analysis. Heterogeneity of studies was assessed using I 2 test. A random-effects model was used to estimate the pooled prevalence among both healthy and sick children. Result: A total of 1212 articles were retrieved from data bases of which 13 papers were included. The pooled prevalence of vitamin D deficiency among healthy children was 50.06% with mean serum vitamin D level of 41.06 nm/L. The pooled prevalence among the sick children was 39.36% with 66.96nm/L of mean concentration. The pooled prevalence among healthy children was significantly higher compared to those who have common medical illnesses and the pooled mean concentration among the sick was also much higher than the mean concentration among healthy children. Conclusion: The pooled prevalence among both group of population was significantly of public health concern and the prevalence among healthy children was much higher among sick children.
... In the adaptive immune system, vitamin D promotes the shifting of pro-inflammatory Th1 phenotype to a fairly balanced phenotype with an increment of T reg cells. Vitamin D also suppresses dendritic cells, resulting in decreased T-lymphocyte activation and associated immune response [8,15]. ...
Vitamin D exerts multiple immune-regulatory functions on the innate and adaptive immune systems. However, there is conflicting evidence concerning the contribution of vitamin D to the progression of allergies. The goal of this study was to investigate the connection between vitamin D and the prevalence of allergic disorders and serum IgE levels among young adults. The study samples included 272 students (120 males and 152 females) from Birjand University of Medical Sciences in Birjand, Iran. The allergic disorders studied, comprising allergic rhinitis (AR), asthma and atopic dermatitis (AD), were confirmed by an expert allergist. Commercial Elisa kits were used to measure serum levels of vitamin D and total IgE for all participants. The median (IQR) serum vitamin D value was 10.0 (6.0–17.0) ng/mL and the prevalence of vitamin D deficiency among the target population was 81.5%. Vitamin D levels were notably higher in males than in females [12.0 (8.0–18.0) vs. 8.0 (4.0–15.0); P < 0.001]. The prevalence of AR, asthma and AD were 35.7%, 3.7% and 5.1%, respectively. There was no notable difference in serum vitamin D status between allergic and non-allergic students. The results of this study did not support any correlation between vitamin D status and allergy status among students.
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Low 25(OH)D levels are common in chronic kidney disease (CKD) patients and are implicated in all-cause mortality and morbidity risks. Furthermore, the progression of CKD is accompanied by a gradual decline in 25(OH)D production. Vitamin D deficiency in CKD causes skeletal disorders, such as osteoblast or osteoclast cell defects, bone turnover imbalance, and deterioration of bone quality, and nonskeletal disorders, such as metabolic syndrome, hypertension, immune dysfunction, hyperlipidemia, diabetes, and anemia. Extra-renal organs possess the enzymatic machinery for converting 25(OH)D to 1,25(OH)2D, which may play considerable biological roles beyond the traditional roles of vitamin D. Pharmacological 1,25(OH)2D dose causes hypercalcemia and hyperphosphatemia as well as adynamic bone disorder, which intensifies vascular calcification. Conversely, native vitamin D supplementation reduces the risk of hypercalcemia and hyperphosphatemia, which may play a role in managing bone and cardio-renal health and ultimately reducing mortality in CKD patients. Nevertheless, the combination of native vitamin D and active vitamin D can enhance therapy benefits of secondary hyperparathyroidism because of extra-renal 1α-hydroxylase activity in parathyroid gland. This article emphasizes the role of native vitamin D replacements in CKD, reviews vitamin D biology, and summarizes the present literature regarding native vitamin D replacement in the CKD population.
Objective: Both, anemia and vitamin D deficiency are prevalent in heart failure patients. Evidence is accumulating that vitamin D may stimulate erythropoiesis in addition to its well known effects on mineral metabolism. Methods: We studied the association of the components of the vitamin D axis with the risk of anemia in heart failure. We measured circulating 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2D) and hemoglobin in a cross sectional study of 364 end-stage heart failure patients awaiting cardiac transplantation, of whom 52.6% met the criteria for anemia (Hb <13g/dl in males and <12g/dl in females). None of the patients were on erythrocyte stimulating agents. Results: The mean hemoglobin concentration significantly decreased with decreasing tertile of 25(OH)D and 1,25(OH)2D (p<0.001). In multivariable-adjusted logistic regression analyses (age, gender, diagnosis, diabetes, kidney function, parathyroid hormone, VAD implantation, medication), the odds ratio for anemia of the lowest tertile of 25(OH)D (<50 nmol/l) and 1,25(OH)2D (<25pmol/l) were 4.69 (95%CI: 2.48–8.89) and 2.11 (95% CI: 1.17–3.78) compared with their respective highest tertile (>75 nmol/l and >37.5pmol/l). Patients with severe dual deficiency of 25(OH)D and 1,25(OH)2D had an odds ratio for anemia of 13.21 (95% CI: 4.61–38.28) compared with patients who were in the highest tertile of both vitamin D metabolites. Conclusions: Our data demonstrate that vitamin D deficiency is independently associated with low hemoglobin levels and anemia in end-stage heart failure. Prospective randomized studies have to demonstrate whether this association is causal.
Background: Numerous observational studies have found supplemental calcium and vitamin D to be associated with reduced risk of common cancers. However, interventional studies to test this effect are lacking. Objective: The purpose of this analysis was to determine the efficacy of calcium alone and calcium plus vitamin D in reducing incident cancer risk of all types. Design: This was a 4-y, population-based, double-blind, randomized placebo-controlled trial. The primary outcome was fracture incidence, and the principal secondary outcome was cancer incidence. The subjects were 1179 community-dwelling women randomly selected from the population of healthy postmenopausal women aged >55 y in a 9-county rural area of Nebraska centered at latitude 41.4°N. Subjects were randomly assigned to receive 1400–1500 mg supplemental calcium/d alone (Ca-only), supplemental calcium plus 1100 IU vitamin D3/d (Ca + D), or placebo. Results: When analyzed by intention to treat, cancer incidence was lower in the Ca + D women than in the placebo control subjects (P < 0.03). With the use of logistic regression, the unadjusted relative risks (RR) of incident cancer in the Ca + D and Ca-only groups were 0.402 (P = 0.01) and 0.532 (P = 0.06), respectively. When analysis was confined to cancers diagnosed after the first 12 mo, RR for the Ca + D group fell to 0.232 (CI: 0.09, 0.60; P < 0.005) but did not change significantly for the Ca-only group. In multiple logistic regression models, both treatment and serum 25-hydroxyvitamin D concentrations were significant, independent predictors of cancer risk. Conclusions: Improving calcium and vitamin D nutritional status substantially reduces all-cancer risk in postmenopausal women. This trial was registered at as NCT00352170.
Environmental disorders associated with vitamin D deficiency include musculoskeletal disorders (childhood rickets, osteomalacia, and fractures), and may include extraskeletal disorders (diabetes, cardiovascular disease, risk of falls, and cancer). There is high interindividual variability in the occurrence of both musculoskeletal and extraskeletal disorders. Previous twin and family studies suggested that genetic factors play a significant role in this variability. Little data exist on the possible effects of common genetic variation on vitamin D status; the available studies have been small and only small numbers of variants were examined. The SUNLIGHT consortium (study of underlying genetic determinants of vitamin D and highly related traits) was a multicenter genome-wide association study designed to identify common genetic variants that affect vitamin D concentrations and increase the risk of vitamin D insufficiency. Concentrations of vitamin D were determined in 33,996 individuals of European descent from 15 epidemiologic cohorts. Of these cohorts, 5 were designated as discovery cohorts (n = 16,125), 5 as in-silico replication cohorts (n = 9367), and 5 as de novo replication cohorts (n = 8504). Genome-wide analyses were conducted in all cohorts. Methods used to measure 25-hydroxyvitamin D concentrations varied between cohorts and included radioimmunoassay, chemiluminescent assay, enzyme-linked immunosorbent assay, or mass spectrometry. Concentrations lower than 75 nmol/L or 50 nmol/L were the defined threshold for vitamin D insufficiency. Combined effect estimates from the logistic regression analysis across cohorts were calculated by meta-analysis using a weighted Z-score-based approach. A genotype score was constructed by taking a weighted average of the confirmed variants. Genome-wide significance for association with 25-hydroxyvitamin D concentration was reached in variants at 3 loci in discovery cohorts, and was confirmed in replication cohorts: the first locus was 4p12 within or near the GC gene (overall P = 1.9 × 10−109 for rs2282679); the second was 11q12 near DHCR7 (P = 2.1 × 10−27 for rs12785878; and the third was11p15 near CYP2R1 (P = 3.3 × 10−20 for rs10741657). The first locus encoded an enzyme involved in cholesterol synthesis, the second encoded an enzyme implicated in 25-hydroxylation of vitamin D in the liver, and the third was involved in synthesis of a liver protein involved in transport of vitamin D and its metabolites. Genome-wide significance in the pooled sample was reached for variants at a fourth locus, 20q13, near CYP24A1 (P = 6.0 × 10−10 for rs6013897). A high genotype score in the highest quartile for the 3 confirmed variants in comparison with a score in the lowest quartile was associated with a substantial increase in the risk of vitamin D insufficiency (25-hydroxyvitamin D concentrations <75 nmol/L or <50 nmol/L; the odds ratio for <75 nmol/L was 2.47, with a 95% confidence interval of 2.20–2.78 (P = 2.3 × 10−48) and the odds ratio for <50 nmol/L was 1.92, with a 95% confidence interval of 1.70–2.16 (P = 1.0 × 10−26). These findings identify genetic variants at 3 confirmed loci involved in regulation of circulating 25-hydroxyvitamin D concentrations that substantially increase the risk of vitamin D insufficiency.
Vitamin D is a 9,10-secosteroid and is treated as such in the numbering of its carbon skeleton. Vitamin D occurs in two distinct forms-vitamin D2 and vitamin D3. Metabolic activation of vitamin D is achieved through hydroxylation reactions at both carbon 25 of the side chain and, subsequently, carbon 1 of the A ring. Metabolic inactivation of vitamin D takes place primarily through a series of oxidative reactions at carbons 23, 24, and 26 of the side chain of the molecule. These metabolic activations and inactivations are well characterized and result in a plethora of vitamin D metabolites. Of all the compounds, only four, vitamin D, 25-hydroxyvitamin D (25(OH)D), 24,25-dihydroxyvitamin D (24,25(OH)2D), and 1,25- dihydroxyvitamin D (1,25(OH)2D) have been extensively quantitated, and to date only two of those, namely, 25(OH)D and 1,25(OH)2D, provide any clinically relevant information. However, the quantitation of vitamin D and 24,25(OH)2D can provide important information in a research environment. This calls for further research.