Vitamin D and Immune System | OMICS International
As similar socioeconomic and sociocultural habits of mother, infant and environment The incorrect marketing of complementary foods that could impede are ingredients for maturation of innate and adaptive immunity[25, 26]. . The establishment of infection would require parasite attachment to the gut. Innate immunity is our first defense against invaders. The epithelial and mucosal linings of our respiratory and GI tracts, as well as our skin are major. The interaction between innate and adaptive immunity is mediated by a type of phagocyte called a dendritic cell. These cells are multifunctional; they can detect .
Breastfeeding duration or initiation rates can be much more variable within the other populations. Although nearly all Filipino women in Cebu initiate breastfeeding and many continue to breastfeed for at least 18 months, the median duration is around 12 months [ 6263 ].
Similarly, Polish women living in the Mogielica Human Ecology Study Site area typically breastfeed for around 12 months [ 64 ]; unpublished data.
To control for diurnal changes in milk composition, all samples were collected in the morning. Mothers were asked to nurse their infants from the sample breast 2 h prior to the sample collection and only nurse from the non-sample breast to allow for a standardized pooling period for milk in the breast. Participants provided mid-feed milk samples following Neville and colleagues [ 66 ].
Briefly, infants suckled from the sample breast for 2—2. Mothers then manually expressed up to 20 ml of milk before resuming normal feeding. Mid-feed sampling was selected because it allows researchers to collect a smaller volume of milk, yet produces a sample with mean constituent concentrations that are not significantly different from a pooled, pumped content of an entire mammary gland [ 66—68 ]. Mothers were asked to refrain from nursing from either breast for 1 h, instead of 2 hours, prior to a morning sampling.
The sample breast was then fully evacuated with a manual breast pump [ 69 ]. Milk protein content is not significantly affected by time since last feed or sample expression mode, so differences in collection procedure for these samples are not expected to impact the results of this study [ 70 ]. All procedures were conducted with approval from respective institutional review boards and local advisory boards, where available. Details of all ethical approvals are provided in the Supplementary Material S1.
Written or oral informed consent was obtained from all participants. Whole milk samples were prepared and analyzed according to the protocol described by Huang et al.
Statistical analysis Two individuals were excluded from the dataset before statistical analysis. One individual from Argentina was excluded from analysis due to improbably low values of all immune proteins, likely due to a technical error during laboratory analysis.
All statistical analyses were performed in R version 3. The VDR gene contains 11 exons and spans approximately 75 kb. The 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 are involved in binding to Vitamin D [ 35 - 37 ]. Their 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 ]. Their distribution and frequency vary among ethnic groups. The 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.
The most evident effects of the D-hormone on the immune system seem to be in the down-regulation of the Th1-driven autoimmunity. Low serum levels of Vitamin D might be partially related, among other factors, to prolonged daily darkness reduced activation of the previtamin D by the ultra violet B sunlightdifferent genetic background i. 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.
The 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 significant clinical improvement was strongly correlated with the immunomodulating potential in Vitamin D-treated RA patients [ 4042 ].
In immune cells, activation of VDR leads to production of downstream gene products. These proteins have potent antiproliferative, pro-differentiative, and immunomodulatory effects [ 43 ]. This inhibition has been observed in T cells, monocytes or macrophages  and subsequently may influence the expression of various essential secreted molecules on the cell surface.
Vitamin D and innate immune system The innate immune system is the immediate, non-specific first line of the defense against pathogens and includes complement, antimicrobial peptides produced by neutrophils and macrophages, in addition to antigen presentation [ 45 ].
Interaction between innate and adaptive immunity
It is important to review the levels of innate defense to understand the role of Vitamin D in innate immune response. The epithelial cells of the skin, gut, respiratory and urinary tract is the first line of defense which protects against invasion by organisms. The active Vitamin D is important in up-regulating genes of the proteins required for the tight, gap and adheres junctions [ 46 ]. The Vitamin D is a potent stimulator of antimicrobial peptides in innate immunity and sufficient 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. It is now clear that the transcription of cathelicidin is dependent on sufficient Vitamin D and transcription of beta defensin 4 requires binding of NFkB to appropriate response elements on the beta defensin 4 RNA [ 2950 ]. Also, Vitamin D has a role in the attraction of other immune cells to promote wound healing or fight infection and is essential in activating antigen specific T-cell [ 5253 ].
Vitamin D prevents inflammatory response overreaction and prevents further cell or tissue damage by inflammation . As mentioned above, engagement of TLRs leads to a cascade of events that produce peptides with potent bactericidal activity e. These 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 has a potent antiendotoxin and some direct antimicrobial activity [ 57 ].
In critically ill patients, correlation was reported between low levels of Vitamin D and those of LL and there was an evidence for the regulation of LL levels by vitamin D status [ 56 ]. Also, the LL is known to be effective against Methicillin-resistant S. The effects 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-cellsmacrophages and their monocyte precursors play a central role in initial non-specific immune responses to pathogenic organisms or tissue damage-so called cell-mediated immunity.
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Their 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 Tlymphocytes T-cells [ 28 ].
Macrophages possess both enzymes essential to produce active Vitamin D leading to intracrine and paracrine effects. The high expression of VDR by monocytes ensures sensitivity of these cells to the differentiating effects of active Vitamin D. In the same time, the active Vitamin D down-regulates the expression of granulocytemacrophage colony-stimulating factor GM-CSFstimulates production of immunosuppressant prostaglandin E2 from macrophages and modulates macrophage responses, thus, inhibiting the release of more inflammatory cytokines and chemokines [ 42 ].
Therefore, Vitamin D deficiency will impair the antimicrobial function of macrophages due to decreased capacity to mature, to produce lysosomal enzymes, to secrete H2O2 and to produce specific surface antigens by down-regulating the expression of HLA-II [ 6465 ]. The presence of CYP27B1 in macrophages is important for the physiological action of active Vitamin D in immune-regulation.
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. This is may be a negative feedback mechanism, preventing excessive TLR activation and inflammation at a later stage of infection [ 70 ]. Therefore, the downregulation of pattern recognition receptors by active Vitamin D in APCs may contribute to its ability to attenuate abnormal Th1-driven inflammatory responses and potential autoimmunity [ 71 ].
This pattern recognition receptor detects muramyl dipeptide MDPa lysosomal breakdown product of bacterial peptidoglycan common to Gram-negative and Gram-positive bacteria. One pathway, concerns the inactivation of active Vitamin D by the enzyme hydroxylase CYP24mitochondrial enzyme that initiates active Vitamin D catabolism.
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 ]. This 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 human monocytes, neutrophils and other human cell lines, the active Vitamin D induces genetic expression of antimicrobial peptides AMPssuch as defensins and cathelicidin hCAP. The AMPs display a broad-spectrum of antimicrobial and antiviral activities including the influenza virus and these endogenous antibiotics destroy invading microorganisms [ 2877 ].
DCs are heterogeneous in their location, phenotype and function and per their origin, they are divided into two groups: The mDCs are professional APCs [ 78 ] and the pDCs are more closely associated with immune tolerance [ 7980 ] 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 ].
In the same time, the active Vitamin D and its analogs can inhibit DCs differentiation and maturation, therefore, impairing normal turnover of DCs in tissues and locking them in an immature-like state. On the other hand, active Vitamin D up-regulate; inhibitory molecules e. Additionally, Vitamin Dmodulated DCs produce more anti-inflammatory cytokine IL and less pro-inflammatory cytokines IL Th1 driving and IL Th driving and this might dampen Th1 and Th17 responses, render T cells anergic and recruit and differentiate Treg subsets [ 28457880 ].
The ability of Vitamin D to influence the differentiation 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 effects on cells that interact with APCs, namely cells from the adaptive immune system [ 9091 ].
Vitamin D and adaptive immune system The 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 influence 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 ]. There are four possible mechanisms explaining how the serum Vitamin D can influence T-cell function: The VDR expression is undetectable in quiescent T lymphocytes and upon T cell activation, it increases five times [ 94 ].
The active Vitamin D regulates T-cell development and migratory function and Th1 and Th2 cells are direct targets for the active Vitamin D. Direct actions on T cells represent a different 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 [ 2893 ].
Activation of the VDR by active Vitamin D changes the cytokine secretion patterns, suppresses effector T-cell activation and induces Tregs [ 9596 ]. The active Vitamin D inhibits the migration of T cells to lymph nodes . In contrast, in the gastrointestinal tract GITthe Vitamin D has a negative effect on chemokines and chemokine receptors [ 96 ] and Vitamin D promotes a T-cell shift from Th1 to Th2 and may limit the potential tissue damage associated with Th1 cellular immune responses [ 4299 ].
The initial studies evaluating the effects 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 influences the phenotype of T-cells by inhibiting Th1 cells i. By switching the immune response from Th1 to Th2, the Vitamin D may help to limit the tissue damage associated with excessive Th1 immune responses.
However, studies using VDR gene knockout mice showed reduced Th1 levels [ ], therefore, the in vivo effects of Vitamin D on T cells are more complex [ 28 ]. Th17 cells is a third group of Th cells and is named so because of their capacity to secrete IL [ ].
Th17 cells are important for promoting immune responses to some pathogens and have been linked to inflammatory tissue damage [ ]. In vitro treatment of T-cells with active Vitamin D suppresses Th17 development and inhibits production of IL [ ].
T regulatory or suppressor T cells Tregs is a fourth group of CD4 T cells and exert suppressor functions. The active Vitamin D modulates the T-cell phenotype and promotes the development of Tregs [ ]. Topical application of active Vitamin D affects the differentiation and functions of Tregs, increases the suppressive activity and the in vivo expansion of antigen-specific Tregs [ ].
The explanation for this may be the death of activated T cells due to intake of active Vitamin D especially with the absence of Thpolarizing conditions or regulation of Th17 cell recruitment via chemokine and chemokine receptors [28,]. In the same time, the combination of active Vitamin D and dexamethasone increase the frequency of generation of ILproducing Tregs [ ]. The regulation of VDR expression by active Vitamin D in B cells suggests that the effects of active Vitamin D may differ according to its serum level in individuals and the state of B cells i.
The 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 effect to be apparent [ ]. Therefore, the activity of Vitamin D on B cells may be affected by VDR expression and the ability to degrade the active molecule. Also, the increased susceptibility of activated B cells to many of the effects 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 [ ].
The 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 and anti-CD40 with or without Bcell receptor cross linking, the active Vitamin D inhibits also the plasma cell differentiation and immunoglobulin production.
However, if B cell were treated with active Vitamin D after 5 days of culture, the inhibition was not evident. This indicates that the Vitamin D inhibits the generation of plasma cells but not their subsequent persistence and is responsible for decreased immunoglobulin secretion [ - ].
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Thus, it inhibits the B cell proliferation by inhibiting the previous cycling B cells from entering the cell cycle. These results suggest that the effect of active Vitamin D on plasma and memory cell differentiation may be due to suppression of ongoing B-cell proliferation [ ]. Vitamin D and kidney disease The 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.
The progression of chronic kidney disease CKD and many of the cardiovascular complications may be linked to Vitamin D deficiency [ ]. First, Low Vitamin D in a substrate-product relationship [ ]. In addition, proteinuria will damage the proximal tubular cells and limits the number of megalin receptors and Vitamin D binding to the megalin receptor [ ].
Therefore, there will be marked reduction in endogenous Vitamin D and active Vitamin D with increased decay [ ]. Third, Elevated FGF which is a phosphaturic hormone i. 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 deficiency [ ].
RAAS have multiple effects on CVS; it regulates blood pressure, electrolytes, volume homeostasis, endothelial function, vascular remodeling and fibro genesis . 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 [ - ].
The level of Vitamin D showed an inverse relationship with the degree of albuminuria in CKD suggesting its anti-proteinuric effects which may be mediated through RAS-angiotensin II mechanism [ ]. 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 effect in CKD patients. Vitamin D has antiinflammatory actions which will reduce the state of chronic inflammation associated with the progression in CKD, therefore, Vitamin D will limit infiltration of renal tissues with immune cells and inflammation-related cardiovascular complications.
In addition, Vitamin D has potent antimicrobial actions and thereby will improve the ability of those patients to combat infectious pathogens [ ]. Active Vitamin D Reno protective effect is mediated via suppression of RAAS, reduction of proteinuria, protection of structural and functional integrity of podocytes [ ].
Active Vitamin D anti-inflammatory properties may be due to suppression of NF-B pathway which via regulation of many inflammatory cytokine enhances both inflammation and fibro genesis . Active Vitamin D has immune modulatory effects in CKD patients which will ameliorate renal fibrosis and slow-down proteinuria development.
This can be done by enhancing Th2 cell differentiation, decreasing IL-6 expression, decreasing inflammatory and oxidative stress, altering T cell behavior, thus favoring tolerance development and reduce proinflammatory activity- ]. However, Vitamin D attenuates inflammation and acquired immunity via its potent tolerogenic effects 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 deficiency and increased risk of various infectious diseases [ ].
The relationship between Vitamin D and infection was suggested about more than years ago, and before the advent of effective antibiotics, Vitamin D has been used to treat infections such as tuberculosis [ ]. Several studies have been associated between Vitamin D deficiency and increased risk for infection. Military recruits from Finland with low Vitamin D lost more days from active duty i.
Also, other studies reported association between low level of Vitamin D and increased rate of infection with influenza [ ], bacterial vaginosis [ ] and HIV [ ]. VDR is an important element in host immune response to different infection. Some organisms either down-regulate or even block its activity which lead to impairment of innate immune response such as TB [ ], Mycobacterium leprae [ ], Epstein-Barr virus EBV [ ], Aspergillus fumigatus [ ] and HIV infection that completely inhibits VDR activity [ ].
Genetic polymorphisms of VDR were linked to TB susceptibility, extent infection, response to treatment and time of microbiological resolution by different studies [ - ].
The potential role of Vitamin D in host resistance to infections was based on the following four findings: Increased TLR2 expression by about two folds after stimulation with Vitamin D in human keratinocytes. Microarray analysis of VDREs genes showed active Vitamin D increased CD 14 by more than fold in well-differentiated human squamous carcinoma cells . The CAMP and defensins act as chemo-attractant for immune cells such as neutrophil and monocytes and other components of immune response [ ].
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In Human, both innate immune mechanism i. In addition, cathelicidin promotes autophagy, which enhances auto-phagolysosomal fusion and antimicrobial activity. Regarding infections, effect of Vitamin D on proinflammatory cytokines remains controversial i. However, these suppressive effects are attributed to vitamin D feedback mechanisms to reduce tissue damage [ ]. Thus, it seems that first, the Vitamin D triggers antimicrobial host defense and enhances early inflammatory reactions needed for cell recruitment and efficient coordination of immune responses, later, after a while, Vitamin D by negative feedback mechanism, prevents extensive inflammation and tissue destruction [ ].
The 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. Therefore, low Vitamin D may be a consequence and not a cause of the inflammatory process [ ].
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 ]. Vitamin D supplement in AID animal models prevented or ameliorated autoimmunity. In the same time, Vitamin D deficiency 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 [ ]. Epstein-Barr virus EBVis one of the most inducing infectious risk factor for autoimmunity. Therefore, the availability of sufficient level of Vitamin D represents an exogenous and endogenous player in AIDs [ ].
The Vitamin D has multiple effects on various cell lineages of immune system and its anti-inflammatory and immune-modulatory roles were suggested to explain the association between Vitamin D and autoimmunity. Vitamin D inhibits activity of Th1 and secretion of proinflammatory cytokines e.
On the other hand, Vitamin D enhances Th2 immune response and secretion of anti-inflammatory cytokines e. Vitamin D may increase activity of Tregs and inhibits activity of IL Low serum level of Vitamin D was associated with increased incidence, severity and seasonality i. Also, infants with regular Vitamin D intake had a reduced incidence of developing T1D [ ].
However, Mahon et al. The increased level of this anti-inflammatory cytokine was associated with inhibition of harmful auto-reactive T-cell functions . The observed wide variation may be due to age of the patients, disease duration, ethnicity, seasonality, medications, geographic causes and method of assay [ - ].
Also, Vitamin D deficiency was noted in European American female patients with SLE and in obese healthy controls with positive anti-nuclear antibodies indicating that Vitamin D deficiency may play a role in initiating autoimmunity [ ]. On the other hand, no associations were found between SLE development and Vitamin D dietary intake . However, these studies were dependent on questionnaire for dietary Vitamin D intake and the serum levels of Vitamin D were not reported [ ].
There are several causes that can explain the vulnerability of SLE patients to Vitamin D deficiency; those patients always advised to avoid exposure to sunlight due to photosensitivity [ ]; renal involvement with subsequent defect in the 1-hydroxylation of Vitamin D [ ]; 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 [ ] and the genetic variation [ ].
This 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 deficiency; skin melanin pigmentation, clothing as a barrier to Vitamin D photosynthesis, pollution as a block for some ultraviolet radiation, ageing of the skin, inflammatory process and latitude that dramatically influences the amount of solar radiation available to synthesize vitamin D3 [ ].