Vitamins
Many vitamins are key catalyst in multiple cellular/metabolic functions. They are critical components of evelotinary conserved processes and molecular pathways. Our bodies are capable of synthesizing some of them, but supplementation is requires for most. They are an important contributing factor to developing an effective AIR regimen with the goal of regressing your BASP.
► The nutritional benefits of vitamins and minerals depend on not only the amount of nutrients consumed, but also on how readily they are absorbed into the body. For this, food processing is one of the most important factors affecting bioavailability since it may either increase or decrease the bioaccessibility of nutrients and bioactive compounds [32]. In fact, processing methods are getting more sophisticated and diversified to meet the growing demands for high-quality foods, with nonthermal processing emerging as a good method for extending shelf-life and product quality while also preserving functional and nutritional properties. Therefore, efforts should be made during processing to mitigate the influence of applied technology on vitamins and minerals, and to be more favorable if nutritional quality is measured in terms of both stability and bioaccessibility [33].
For optimum physiological functioning to occur, adequate nutrition must be provided in a balanced manner in order to avoid potentially harmful interactions, particularly when medications are supplied at pharmacological concentrations. In this respect, several nutrients work together to enhance digestive function and absorption by complementing one another. In contrast, some may obstruct these processes and compete for absorption, while others may be needed to work in tandem to facilitate metabolism, potentially affecting a variety of biochemical processes [34]. The human body has a lot of synergistic and antagonistic functionalities that need to be taken into account, especially in the health and research fields, and where nutrient-related confounding factors also need to be taken into consideration [35]. Below are the key roles played by vitamins and minerals as immunomodulators. ◀︎ [1]
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► Vitamin A
► The recommended daily allowance of vitamin A is 900 micrograms (μg) for women and 700 μg for men. The richest food sources of vitamin A include dairy products, fish, liver, and fortified cereals; the top sources of provitamin A include broccoli, carrots, squash, and cantaloupe [36]. Vitamin A and β-carotene are structurally interrelated, and the liver converts β-carotene to vitamin A. One molecule of β-carotene yields two molecules of vitamin A. When we look at the two molecules side by side, we can see that vitamin A is remarkably similar to half of the β-carotene molecule. β-Carotene is a plant pigment that is responsible for the vibrant colors of red, orange, and yellow vegetables. B-Carotene is classified as a provitamin A carotenoid, which means that it can be converted by the body into vitamin A [37].
Vitamin A deficiency causes illnesses and deaths worldwide, particularly among women, children, and infants in low-income countries. Approximately 253 million children are at high risk of experiencing immunodeficiency due to vitamin A deficiencies [38]. On the other hand, vitamin A supplementation in individuals with hypovitaminosis A decreases morbidity and mortality rates due to diarrheal and measles diseases [39,40]. Similarly, regular supplementation with high-dose vitamin A could decrease both morbidity and mortality among infants delivered by HIV-positive mothers [41], in addition to reducing diarrhea-associated morbidity among HIV-positive children following hospital release for acute lower respiratory tract infections [42].
Vitamin A exists in three main forms: retinoic acid (RA), retinol, and retinal, and RA has demonstrated remarkable biological activities [43]. Experimental work by Rampal et al. [44] explored the role of RA in human dendritic cells (hDCs) and CD4+ T cell re- sponses. DCs primed with RA (RA monocyte-derived DCs) increased the expression of C-C motif chemokine receptor 9 (CCR9)+ T cells, which express large amounts of IFN-γ under Th1/Th17 circumstances and also promote the production of IL-17+ T cells. In addition, RA monocyte-derived DCs suppress IL-9 production and increase IFN expression in T cells when stimulated with transforming growth factor (TGF)-1 or IL-4. RA treatment reduces the T cell production of IFN and IL-17 in experiments with naive CD4+ T cells stimulated under Th1/Th17 conditions in the absence of DCs. These findings indicated that RA, instead of acting as an anti-inflammatory agent, may sustain or worsen intestinal inflammation under inflammatory conditions [45]. RA significantly affects macrophage activity by regulating cytokine release, including IL-1, IL-6, IL-12, tumor necrosis factor (TNF)-α, and nitric oxide (NO). Moreover, T cell–macrophage co-cultures treated with RA show reduced IFN-γ production and increased IL-4 secretion by T cells, demonstrating that RA can influence Th1/Th2 differentiation pathways. RA also inhibits the expression of IL-12, which is thought to stimulate IFN production by T cells [46].
RA inhibits intestinal DC inflammation by targeting nuclear factor kappa B (NF- κB), which can induce both anti- and pro-inflammatory actions. RA combined with IL-4 promotes the release of suppressor of cytokine signaling 3 (SOCS3), which suppresses the production of pro-inflammatory cytokines, such as TNF-α and IL-12p70 [47]. When RA is combined with IL-15, the c-Jun N-terminal kinase (JNK) pathway becomes activated, increasing the production of pro-inflammatory cytokines by DCs, including IL-12p70 and IL-23 [48]. ◀︎
Source: [2021] Exploring the Immune-Boosting Functions of Vitamins and Minerals as Nutritional Food Bioactive Compounds: A Comprehensive Review
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NIH Fact Sheet Thiamin (Vitamin B1)
► Vitamin B1, also known as thiamin or thiamine, is a water-soluble vitamin that may be obtained from foods, dietary supplements, and medications. The recommended daily amount of vitamin B1 is 1.1 mg for women and 1.2 mg for adult men. The release of intracellular adhesion molecules (ICAMs) by thiamine–immune cell interactions is medi- ated by hemin-dependent oxygenases. ICAMS bind to cells expressing different integrins, regulating immune cell localization. Thiamine exerts antioxidant actions to protect cell surface sulfhydryl groups found on neutrophils from oxidative damage. In this regard, thiamine inhibits the oxidative-stress-mediated stimulation of NF-κB and the formation of pro-inflammatory cytokines in macrophages [49].
Thiamine deficiency has been associated with neuroinflammation, T cell infiltration, and the overexpression of pro-inflammatory cytokines (IL-1, IL-6, and TNF-α). Additionally, thiamine deficiencies upregulate the expression of CD40 and CD40L by microglial cells and astrocytes, inducing neuronal death [50]. Within this context, Bozic and coworkers reported that benfotiamine (synthetic thiamine) significantly reduces the inflammatory response in lipopolysaccharide (LPS)-induced BV-2 microglia. LPS stimulation activates pro-inflammatory functions in microglial cells in vitro. Moreover, benfotiamine decreases the expression of inducible NO synthases (iNOS) and NO while increasing the expression of cyclooxygenase-2 (COX-2), heat shock protein 70, IL-6, TNF-α, and NF-κB [51]. Thiamine also suppresses the pro-oxidative activity of microglial cells, suggesting that thiamine may be used to treat neurodegenerative diseases. Similarly, LPS increases the production of thromboxane 2, leukotrienes, prostacyclin, prostaglandin E2, NF-κB, COX-2, and iNOS and induces macrophage cell death in the RAW264.7 murine macrophage cell line, and these effects could all be suppressed by the presence of benfotiamine [52]. ◀︎
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NIH Fact Sheet Riboflavin (Vitamin B2)
► Vitamin B2
Vitamin B2, also known as riboflavin, serves as a vital cofactor for several enzymes involved in energy metabolism [53]. For men aged 19 and over, the recommended daily amount (RDA) of vitamin B2 is 1.3 mg per day, while for women, it is 1.1 mg per day. Women should consume 1.4 mg per day throughout pregnancy and 1.6 mg per day during breastfeeding. Bacterial metabolites of vitamin B2, when combined with the non-classical major histocompatibility complex (MHC) class I-related protein (MR1), activate innate mucosal-associated invariant T (MAIT) cells [54], which produce IFN-γ and IL-17 and play pivotal roles in mucosal defense and inflammation in the gut [55]. Riboflavin is a potent anti-inflammatory modulator with antioxidant and anti-tumor properties that increases the phagocytic activity of macrophages [56]. Riboflavin affects numerous metabolic processes in a roundabout way and is essential for the appropriate functioning of a number of systems, including the immune system. The effects of riboflavin at doses from 3 to 531 nM have been examined against the activity and proliferation of RAW 264.7 murine macrophages, which are a type of immune-competent cell. Riboflavin deficiency impairs macrophage activity and survival, reducing their capacity to mount an immunological response. Within 4 days of growth in media with low riboflavin contents, RAW 264.7 cells showed signs of riboflavin deficiency, including slowed cell growth and the induction of apoptosis, which released lactate dehydrogenase. Riboflavin starvation prevented respiratory bursts and significantly hindered phagocytosis, suggesting that riboflavin deficiency may impact the immune system, decreasing the body’s ability to mount an adequate host immunological response [57]. ◀︎
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NIH Fact Sheet Niacin (Vitamin B3)
► Vitamin B3 (Niacin, Nicotinic Acid, and Nicotinamide)
The recommended daily amount of vitamin B3 is 14 mg for women and 16 mg for adult men. Vitamin B3 can activate the innate immune system by up to 1000-fold the normal level, making it an effective initial line of defense against pathogens. At large dosages, nicotinamide can protect the body against Staphylococcus aureus infections. Nicotinic acid supplementation has been found to reduce inflammation via monocytes in models of atherosclerosis [58,59].
To explore how niacin affects blood vessel inflammation in vivo and in vitro and identify the niacin-associated lipid regulatory mechanism, niacin was administered to guinea pigs fed a high-fat diet, resulting in reduced levels of inflammatory factors (IL-6 and TNF-α) in plasma, decreased CD68 and NF-κB p65 protein expression in the arterial wall, and reduced oxidative stress. In oxidized low-density lipoprotein (oxLDL)-stimulated human umbilical vein epithelial cells (HUVECs) and THP-1 macrophages, niacin reduced IL-6 and TNF-α secretion, suppressed NF-κB p65 and notch 1 protein production, and reduced HUVEC apoptosis. Furthermore, niacin reduced lipid deposition in the artery wall, raised high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A (ApoA) levels in plasma while decreasing triglycerides (TG) and non-HDL-C levels, and elevated the mRNA expression level of cholesterol 7-hydroxylase A1 in the guinea pig liver. The findings indicate that niacin reduces vascular inflammation in vivo and in vitro via NF-κB signaling pathway inhibition [60]. Another experimental study reported that niacin decreased the levels of IL-1α, IL-6, and TNF-α in alveolar macrophages exposed to LPS. NF-κB activation was also reduced by niacin through the inhibition of NF-κB p65 phosphorylation and nuclear factor-1 B (NFIB) phosphorylation. In addition, the inhibition of hydroxycarboxylic acid receptor 2 (HCA2) prevented the niacin-induced production of pro-inflammatory cytokines. These results indicated that niacin inhibited the production of pro-inflammatory cytokines by LPS-mediated alveolar macrophages, which may have been mediated by HCA2 [61]. ◀︎
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NIH Fact Sheet Pantothenic Acid (Vitamin B5)
► Vitamin B5 (Pantothenic Acid)
The recommended amount of pantothenic acid for adults is 5 mg per day. Vitamin B5, also known as pantothenic acid, is found in both animals and plants and is available in a variety of foods such as vegetables, meat, cereal grains, eggs, legumes, and milk. Examination of the antibacterial and pro-inflammatory effects of pantothenic acid in macrophages infected with the Mycobacterium tuberculosis strain H37Rv revealed the in vivo therapeutic value of pantothenic acid for patients with tuberculosis. Vitamin B5 (VB5) was used to treat H37Rv-infected mice to determine whether VB5 promotes H37Rv clearance from the lungs and whether VB5 regulates inflammatory cells. VB5 increased phagocytosis and upregulated the inflammatory response in macrophages infected with H37Rv. Research findings indicated that oral administration of VB5 to mice 1, 2, and 4 weeks after an infection caused a reduction in the H37Rv colony-forming units detected in the lungs. The proportion. of macrophages was also regulated, and CD4+ T cells were stimulated to produce IFN-γ and IL-17; however, the percentages of polymorphic nuclear neutrophils and CD4+ and CD8+ T cells were unaffected by VB5 administration. VB5 substantially suppressed the development of M. tuberculosis b modulating both innate and adaptive immunity [62].
Dexpanthenol (a vitamin B5 derivative) substantially alleviates pulmonary edema in mice, preventing neutrophil accumulation in the lungs and enhancing superoxide dis- mutase (SOD) levels [63]. Dexpanthenol also decreased TNF-α levels, reduced the total oxidant status, and reduced the oxidative stress index in endometriosis patients [64]. After inducing necrotizing enterocolitis, dexpanthenol decreased intestinal damage, increased antioxidant enzyme (SOD) and glutathione (GSH) activity, and induced the production of pro-inflammatory cytokines (IL-1 and TNF-α) [65].◀︎
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► Vitamin B6 (Pyridoxine)
► The recommended daily allowance of vitamin B6 for adults 50 and younger is 1.3 mg. Deficiency in vitamin B6, also known as pyridoxine, results in decreased antibody pro-duction and increased IL-4 levels. Mice fed a pyridoxine-deficient diet exhibit altered T cell responses, including the suppression of T cell proliferation, decreased IL-2 levels, increased IL-4 levels, and the altered expression of transcription factors, including T-bet and SOCS-1 [66]. Vitamin B6 deficiencies in young grass carp (Ctenopharyngodon idella) results in decreased anti-inflammatory cytokine production (TGF-β, IL-4, IL-10, IL-11, and IL-13) and increased pro-inflammatory cytokine production (IL-1, IL-6, IL-8, IL-12, IL-15, and IL-17) [67]. Weaned Rex rabbits fed with a vitamin B6 supplemented diet revealed significantly increased levels of IL-6 and IFN mRNA expression in the spleen (p < 0.05). Furthermore, vitamin B6 significantly enhanced the number of M cells in the appendix (p < 0.05).
Vitamin B6 was found to affect the immunological performance of rabbits, and vitamin B6 supplementation was recommended in weaning three-month-old developing Rex rabbits at a dose of 10–20 mg/kg [68]. Another study by Zhang et al. found that vitamin B6 inhibits NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation, which in turn prevents the production of IL-1. Both pyridoxal (PL) and pyridoxal 5′-phosphate (PLP) suppressed the expression of cytokine genes and inhibited the processing of caspase-1 and the subsequent production of mature IL-1 and IL-18 in LPS- primed macrophages, indicating that they were inhibiting NLRP3-dependent processing. When administered to peritoneal macrophages, PLP but not PL significantly decreased the generation of mitochondrial reactive oxygen species (ROS) (Figure 1). Importantly, PL and PLP decreased IL-1 production in mice when LPS and ATP were combined or when LPS was used alone. In addition, both PL and PLP administration protected mice against fatal endotoxins. Taken together, these results indicate the unexplored anti-inflammatory properties of vitamin B6, which might be useful for the prevention of inflammation-related illnesses caused by the NLRP3 inflammasome [69]. ◀︎
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NIH Fact Sheet Biotin (Vitamin B7}
► Ttamin B7 (Biotin)
Vitamin B7 (BiotinVitamin B7, also known as biotin, is a water-soluble B complex vitamin that plays a pivotal role in the development of chronic inflammatory conditions [70]. The recommended amount of biotin for adults is 30 mg per day. Kuroishi et al explored the effects of biotin mended amount of biotin for adults is 30 mg per day. Kuroishi et al. explored the status of the effect on nickel (Ni) allergies in mice by assessing the modulation of IL-1 production of biotin status on nickel (Ni) allergies in mice by assessing the modulation of IL-1 production, and the in vivo addition of biotin to drinking water resulted in a dose-dependent reduction in ear edema in both biotin-sufficient and biotin-deficient mice. These reductions of IL-1 production, and the in vivo addition of biotin to drinking water resulted in a dose-dependent reduction in ear edema in both biotin-sufficient and biotin-deficient mice. These findings indicated that biotin deficiency impacts Ni allergy in mice during therapeutic benefits for the treatment of human metal allergies [71]. ◀︎
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NIH Fact Sheet Folate (Vitamin B9)
► Vitamin B9 (Folate)
Vitamin B9, also known as folate, is a water-soluble vitamin that can be obtained in two forms: dietary folate, which is naturally available in juices and citrus fruits, among other foods; and folic acid, which is used as a dietary fortification and delivered via supplements. The recommended daily amount of folate is 400 μg for adults, whereas women who are considering pregnancy or may be pregnant should take 400 to 1000 μg of folic acid per day. In vitro, in vivo, and human studies suggest that folate supplementation is correlated with lower infection rates, positive effects on blastogenic responses and T lymphocyte proliferation, delayed hypersensitivity responses, increased phagocytosis, and upregulated immunoglobulin production. However, folate does not appear to affect the function of NK cells. The negative consequences of folate deficiencies on immunological function are likely mediated by abnormalities in DNA and RNA synthesis or methyl metabolism, which are both affected substantially by folate availability [72]. Researchers observed that folate plays an integral role in Treg maintenance, both in vitro and in vivo. Treg cells that express high levels of folate receptor 4 show improved survival in response to folate administration. In an in vitro study, Treg cells could be distinguished from naive T cells under conditions of low folate levels, but they were unable to survive in this environment. The reduced expression of the anti-apoptotic protein Bcl2 was associated with poor Treg cell survival under folate-deficient conditions, independent of IL-2 (Figure 1). Dietary folate deficiency is associated with decreased Treg cells in the small intestine, which is an important location for dietary folate absorption. These results establish a novel connection between food and the immune system, which may have implications for the maintenance of immunological homeostasis in the gastrointestinal tract [71]. ◀︎
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► Vitamin B12 (Cobalamin)
The recommended amount of cobalamin for adults is 2.4 μg per day. Vitamin B12 deficiency results in the downregulation of lymphocytes and affects the functionalities of NK cells, which are instrumental in abolishing cancer cells [73]. More precisely, patients with vitamin B12-deficient anemia have a smaller proportion of CD8+ T cells than the general population. Compared with healthy individuals, the proportions of CD4+ lymphocytes were significantly higher in patients with vitamin B12 deficiency, resulting in an abnormally high CD4+/CD8+ ratio. In people with vitamin B12 deficiency, NK cell activity is significantly reduced, and splenic NK activity is also reduced in rats fed a vitamin B12-deficient diet; however, no significant impacts on NK activity were observed in the axillary nodes or thymus [73,74].
Intramuscular administration of vitamin B12 (in the form of methylcobalamin) to patients who have recently been diagnosed with vitamin B12 deficiency completely restores production of CD8+ T lymphocytes, returns the CD4+/CD8+ ratio back to normal levels, and restores CD3CD16+ and CD3CD57+ counts (both of which have high NK cell activity) (Figure 1), which results in restored NK cell activity [73]. Conversely, vitamin B12 deficiency or supplementation had no effects on immunoglobulin levels in the blood [73]. These findings suggest that CD8+ T cells can be upregulated, and the CD4+/CD8+ ratio can be normalized by intramuscular cyanocobalamin injections in patients with pernicious anemia and low vitamin B12 levels (three to ten times lower than the reference level) [75].
Similarly, findings showed that TNF-α production has increased in the spinal cords vitamin B12-deficient rats, whereas TNF-α synthesis was elevated in the macrophages of vitamin B12-deficient mice [76]. Furthermore, due to glycoprotein 130 (gp130) dysregulation, vitamin B12-deficient animals demonstrated reduced IL-6 production [76].. ◀︎
Key Role of Vitamin B’s as Immune Modulators
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► Vitamin C
The daily dose of vitamin C recommended for adults is 65 to 90 mg. Vitamin C is a water-soluble antioxidant found in plasma and cells. In addition to roles in metabolic functions, vitamin C appears to contribute to the maintenance of immune homeostasis. Recent in vitro experiments examined the inhibitory effects of vitamin C on the expression of pro-inflammatory mediators, including IL-6 and TNF-α, in adult blood cells. Vitamin C has been proposed to act as a potential modulator that prevents an overexuberant immune response, such as in patient groups at risk of developing systemic inflammatory response syndrome, including newborns [72]. Vitamin C may also influence LPS-induced gene ex- pression in human macrophages via NF-κB [77]. In an in vitro study, vitamin-C-pretreated murine IgM/CD40-activated B cells showed a low level of apoptosis induction in a dose- dependent manner, whereas lower vitamin C concentrations supported the antioxidant properties of activated B cells, without affecting cell proliferation or the expression of distinct surface molecules, such as CD80 and CD86 [78]. In a clinical study involving healthy male university students, vitamin C resulted in substantial increases in IgA and IgM levels in blood [79].
Research findings showed that platelet aggregation inhibits tumor cell migration, and the in vitro administration of vitamin C enhanced the capacity of NK cells to kill tumor cells [80]. In addition, leukocytes, including lymphocytes, actively accumulate vitamin C in the presence of a concentration gradient, highlighting the vitamin-C-dependent functional and developmental characteristics of immune cells. Vitamin C is an antioxidant with notable effects on both the innate and adaptive immune responses and is required for the metabolism of microorganisms. Furthermore, vitamin C has been shown to limit the development of several bacterial species. However, the presence of this vitamin can induce oxidative stress in other bacterial species, which may result in the inhibition of bacterial growth [79].◀︎
VITAMIN C / ASCORBIC ACID PATHWAY
Gene Set: BIOCARTA_VITCB_PATHWAYClick [√] to Enlarge Source: [3]
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Vitamin D is a significant pro-hormone for optimal intestinal calcium absorption for the mineralization of bone [77]. Recently, many studies have revealed numerous positive effects of vitamin D use in the elderly population. Vitamin D deficiency in the elderly is associated with decreased cognitive function, a higher risk of Alzheimer’s disease [78], loss of muscle mass and function [79], and osteoporosis. Cross-sectional studies have demonstrated that a low level of vitamin D is related to a higher risk of cardiovascular diseases such as hypertension, heart failure, and ischemic heart disease [80,81]. However, the effects of vitamin D as a supplement are still controversial. One study demonstrated that a high serum vitamin D concentration is associated with high atherosclerosis cardiovascular disease risk scores [82].
Since vitamin D production is usually stimulated by adequate sun exposure, vitamin D levels tend to be lower in elderly people with reduced outside activity. Vitamin D therapy in the elderly was shown to improve muscle mass and performance, and to a reduced the rate of falls [79]. Furthermore, a recent study reported that vitamin D also has an anti-cancer effect by inhibiting cancer cell growth in several types of cancer [83]. In this regard, numerous agencies and scientific organizations have developed recommendations for vitamin D therapy and also provide guidance on optimal serum 25-hydroxyvitamin D (25[OH]D) concentrations. The general target for the 25(OH)D concentration is above 30 ng/mL, and the replacement dose can vary, ranging from between 400 and 2,000 IU/d depending on age, body weight, disease status, and ethnicity [84]. Vitamin D intake through natural food sources such as milk, beverages made from soy, almonds, and coconuts is also important in elderly people with low vitamin D levels [84].
► Vitamin D intake should be 400 international units (IU) for children under the age of 1 year, 600 IU for persons between the ages of 1 to 70, and 800 IU for those beyond 70. Vitamin D was postulated to play multifunctional roles in the immune system following the identification of the vitamin D receptor (VDR) in macrophages, DCs, and activated Tand B lymphocytes, in addition to the report that these cells produce 25-hydroxyvitamin D1-alpha-hydroxylase (encoded by CYP27B1) [81]. ◀︎
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► The phagocytic activity of macrophages and NK cell functionalities are stimulated by treatment with VDR ligands whereas the stimulatory abilities of monocytes and macrophages are decreased, as indicated by the reduced surface expression of MHC-II and co-stimulatory molecules [82]. Vitamin D modulates immune functions via the regulation of nuclear transcription factors, including nuclear factor of activated T cells (NFAT) and NF-κB,or through the direct binding to vitamin-D-responsive sites on cytokine gene promoters [83]. Intracellular IL-1, IL-6, TNF-α, IL-8, and IL-12 expression in monocytes is inhibited by vitamin D [84]. The TNF-α gene promotor contains VDR-responsive regions, whereas the IFN-γ gene promoter contains a negative transcriptional regulatory element that binds vitamin D. VDR monomers to bind to the repressive complex in the IFN-γ promoter, competing with the nuclear factor angiotensin type 1 (AT1) to control granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, vitamin D inhibits NF-κB activation by boosting inhibitor of NF-κB (IκBα) expression and interfering with the binding of NF-κB-regulated genes (IL-8, IL-12, etc.) [85]. Studies have focused on the impacts of vitamin D on the maturation, differentiation, and migration of antigen-presenting DCs, revealing that the increased expression of MHC class II, CD40, CD80, and CD86 in DCs inhibits differentiation, maturation, and immunostimulatory abilities [86]. The active form of vitamin D, 1,25(OH)2 D3, suppresses DC maturation by downregulating IL-12, upregulating IL-10, and reducing the antigen-presenting capabilities of DCs, decreasing the stimulation of T cell proliferation and generation, and promoting a Th2 response [4]. Furthermore, the active form of vitamin D promotes the production of various endogenous antimicrobial peptides with a wide range of activities against viruses, bacteria, and fungi [87]. The activation of TLR ligands in response to innate immunity results in a direct antimicrobial infection response by polymorphic nuclear cells, monocytes, and macrophages [88]. ROS and antimicrobial peptides such as cathelicidins are produced by the immunological response. Functional vitamin-D-responsive regions are found in the gene promoter of human antimicrobial cathelicidin peptides, which are transcribed in response to the vitamin D treatment of human keratinocytes, monocytes, and neutrophils. Moreover, upregulation of VDR and CYP27B1 expression by TLRs leads to the intracrine, vitamin-D-dependent production of cathelicidins, and enhanced macrophage microbicidal activity. Cathelicidins also promote the release of IL-6, IL-10, and IL-18, in addition to the expression of the epidermal growth factor receptor, and enhanced neutrophil, monocyte, macrophage, and T cell chemotaxis, along with the proliferation and migration of keratinocytes [82]. Research findings showed that vitamin D activates autophagy and facilitates the co-localization of mycobacteria and antimicrobial peptides inside autophagosomes, resulting in an increase in bacterial elimination rate. In addition, vitamin D suppresses the expression of TLR2 and TLR4 on monocytes, resulting in a PAMPhyporesponsive state [89]. ◀︎
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► Vitamin D exerts immunomodulatory effects on the adaptive immune system through its direct influence on T lymphocytes, particularly Th cells, and B lymphocyte proliferation, differentiation, and apoptosis [84]. Several lines of evidence suggest that vitamin D can inhibit the effects of the adaptive immune system [90], including suppression of Th1 cell formation and reducing IFN-γ, IL-2, and IL-12 production, which are essential for Th cell development [91,92]. Vitamin D also suppresses the growth and activity of Th17 cells, including the production of IL-17 and IL-21, mediated by the reduced secretion of IL-23 andIL-6. In this respect, reduced IFN-γ levels suppress T cell recruitment, whereas reduced-2 levels suppress T cell growth. Additionally, inhibition of IL-12 production supportsTh2 cell growth, increasing IL-4, IL-5, and IL-10 production and further suppressing Th1cells, thus shifting the balance toward a Th2 phenotypic profile [93,94]. Furthermore, the theTh17 cell line produces IL-17, and has been implicated in the development of severe autoimmune diseases; however, several experimental studies suggest that vitamin D3suppresses Th17 formation and activity by blocking NFAT and runt-related transcription factor 1 (RUNX1), binding to the IL-17 promoter, and inducing FOXP3, in addition, to inhibiting RAR-related orphan receptor γ2 (RORt), which is the transcription factor that regulates IL-17 [95]. The active form of vitamin D suppresses B cell growth, plasma cell differentiation, immunoglobulin production (IgG, IgM, and IgE), and memory B cell formation and causes B cell death [93]. ◀︎ [1]
Incidence of Autoimmune Disease with Vitamin D/Omega 3 Supplementation over 5 years
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► The daily dose of vitamin E recommended for adults is 15 mg. Many dietary fats and oils, particularly those high in polyunsaturated fatty acids (PUFAs), contain vitamin E; therefore, the dietary consumption of vitamin E is closely associated with the consumption of PUFAs [96]. Vitamin E is the most potent lipid-soluble chain-breaking antioxidant found in cell membranes and is thought to contribute to membrane integrity by reducing lipid peroxidation by ROS [97].
Several experimental studies performed in animals and humans have shown that vitamin E improves immunity by inhibiting COX2 activity, improving effective immune synapses in naive T cells, initiating T cell activation signals, and modulating the Th1/Th2 balance. These changes are primarily due to the reduced production of prostaglandin E2 (PGE2) because of inhibition of COX2 activity and decreased NO production [98]. In addition, vitamin E inhibits NF-κB activity, which is necessary for the maximum transcription of several proteins involved in inflammatory responses, including numerous cytokines, such as IL-1β, IL-2, and TNF-α that affect various inflammatory processes by decreasing vitamin E function [99]. The redistribution of key membrane-associated signaling molecules such as linker for activation of T cells family member 1 (LAT), the tyrosine-protein kinase ZAP70 (ZAP70), phospholipase C, and the Vav proteins, have also been proposed as a mechanism through which vitamin E enhances naive T cell function [100]. In addition to the suppression of PGE2, vitamin E supplementation among older adults has been found to decrease the production of other pro-inflammatory markers such as TNF-α and IL-6, especially in response to infections [101,102]. Vitamin E supplementation decreases the inflammatory response in LPS-stimulated peripheral blood mononuclear cells (PBMCs) by decreasing pro-inflammatory cytokine production, such as TNF-α, IL-1, and IL-6, by monocytes [103].. ◀︎
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► Vitamin K is a fat-soluble vitamin available in two natural forms, phylloquinone (K1) and menaquinone (K2), and a synthetic form, menadione (K3) [104]. An adult requires around 1 mg/kg body weight of vitamin K daily. Vitamin K derivatives (vitamin K3 and vitamin K5) decrease the proliferative response and cytokine release by activated T cells [105,106], and vitamin K derivatives suppress the production of IL-4, IL-6, IL-10, and TNF-α. Vitamin K supplementation also increases the numbers of CD4+, CD25+, and FOXP3+ Tregs [105].
According to the results of a mass spectrometric study, K3 may directly interact with the thiol antioxidant GSH and inhibit the activities of the extracellular signal-regulated kinase (ERK), JNK, and NF-κB in lymphocytes [106]. Due to the antioxidant effects of vitamin K3, NF-κB expression may be inhibited. NF-κB regulates the production of sev- eral cytokines and enzymes involved in immune responses [106]. In a meta-analysis, a synthetic analog of vitamin K2 was found to inhibit the development of secondary liver tumors, increasing the survival rate among patients with hepatocellular carcinoma; acti- vation of apoptotic pathways and the suppression of NF-κB were proposed as possible mechanisms [107]. The key immunomodulatory roles played by vitamins are shown in Table 1. ◀︎
Source: [2021] Exploring the Immune-Boosting Functions of Vitamins and Minerals as Nutritional Food Bioactive Compounds: A Comprehensive Review
Click [√] to Enlarge Source [6]