For background knowledge I used course textbooks on anatomy and physiology to reinforce what I already knew about immunity and immune response. Following this I used 'metalib' and 'Google Scholar' to find all my research papers and articles. I started by using search terms such as 'Nutrition and Immunity' then I used more specific search prompts i.e. 'effects of vitamin A on immune response.
It is well documented that vitamins are essential for the normal growth and development of the human body. Vitamins carry out a diverse range of intra and extracellular biochemical functions from having powerful antioxidant qualities to being able act as precursors for enzyme function. This review will be focussing in particular on the affect vitamins can have on immune response and immunoregulation. The vitamins that will be analysed in detail are vitamins A, D and E as they have been shown to have the most significant effects on the body's immunological response. The review will start however with the definition, effects and functions of vitamins in general.
What are Vitamins?
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Vitamins are organic compounds required as nutrients in small quantities by the human body. An organic compound is a vitamin when it cannot be manufactured in the body in sufficient quantities and therefore must be acquired through its diet. Vitamins are not classified by their molecular structure because a vitamin is actually a group of vitamer compounds that all share the same biological and chemical activity for example: Folic acid, folinic acid and 5-Methyltetrahydrofolate can all be referred to as vitamin B9 even though they are not structurally identical. As mentioned at the beginning of the paper, as well as playing a fundamental role in immunity, vitamins also have many other biochemical functions within the body: some are powerful antioxidants e.g. vitamins C and E. Whereas vitamin D is involved heavily in the regulation of mineral metabolism. Some vitamins aid in the regulation of tissue and cell growth and differentiation. Others are able to act as precursors for enzyme cofactors and also as coenzymes, these functions are carried out mainly by the B complex vitamins. There are a total of 13 vitamins required by the human body but I will be looking in particular at vitamins A, E and D due to their unique effects on the immune system, starting with retinol.
Vitamin A and its role in immunoregulation:
Vitamin A is comprised of a group of compounds that play an important role in vision, bone growth, reproduction, cell division, cell differentiation and immunity. When converted to the retinal (retinaldehyde) form, vitamin A is essential for vision, and when converted to retinoic acid, is essential for skin health and bone growth. Retinoic acid is also the compound that can have an effect on some aspects of the adaptive immune response, the details of which will be discussed shortly. Vitamin A can be acquired from various fruits, vegetables and dairy products but is found in especially high quantities in liver, carrots and broccoli leaf.
Retinoic acid can enhance T-cell proliferation and cytotoxicity. This is thought to be mediated due to the up-regulation of inter-leukin 2 (IL-2) secretion and signalling in T-cells and IL-2 is a cytokine that mediates the proliferation of T-helper and cytotoxic T cells as well as the activation of natural killer cells. Studies have shown that vitamin A deficiency can cause a reduction in T helper cell activity. The mechanism for this effect may have a connection with vitamin D. In a vitamin A deficient environment it is speculated that 1,25(OH) 2VD3 (calcitriol) does not have to compete with retinoic acid for RXR (retinoic acid receptor), their common nuclear binding partner and this causes the inhibitory effects of calcitriol on T-cell function i.e. reduced TH-cell activity to be expressed. Vitamin A is also known to enhance B cell activation as well as inhibit B cell apoptosis and these effects are thought to be mediated through the binding of vitamin A metabolites to RAR (retinoic acid receptors), which is retinoic acid's nuclear receptor which acts as a transcription factor. There are also a set of vitamin A metabolites called retro-retinoids and they too can affect general lymphocyte functions such as B-cell proliferation and T-cell activation and proliferation. For example 14-hydroxy-retroretinol can cause an increase in B cell proliferation, whereas anhydroretinol inhibits B-cell proliferation and induces apoptosis in T cells. By being able to control antigen presentation on Dendritic cells, retinoic acid is able to increase the migration of tumour-infiltrating Dendritic cells to the draining lymph nodes and this in turn results in an increase in tumour-specific T-cell responses, retinoic acid is able to initiate this mechanism by increasing the expression of matrix metalloproteinases (zinc-dependent endopeptidases which are thought to be involved with cell dispersion and adhesion as well as playing a role in modulating other cell behaviours).
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Vitman A is also able to regulate more specific aspects of the immunological response, such as the TH1-TH2 cell balance and in addition Treg and TH17 cell differentiation. TH1-TH2 cell balance hypothesis is said to involve homeostasis between TH1 and TH2 activity. This theory of immunoregulation states that different immune response pathways are directed by either TH1 or TH2 cells. TH1 cells drive the 'cell mediated immunity' pathway which fights intracellular pathogens and stimulates prolonged delayed type hypersensitivity skin reactions. TH2 cells drive the 'humoral immunity' pathway and therefore have the ability to increase antibody production to fight extracellular pathogens. Either pathway is able to down regulate the other and overstimulation of either pathway can cause disease.
Studies have shown that vitamin A deficiency caused decreased TH2 cell response whereas vitamin A supplementation inhibits the production of TH1 cell cytokines. Retinoic acid has this effect as it is able to induce inter-leukin 4 (IL-4) expression which causes up-regulation of TH2 cell differentiation. Alongside being able to increase IL-4 expression retinoic acid can also inhibit the expression of T-bet (A TH1 cell master regulator) and induce "TH2 cell promoting transcription factors, such as GATA3 (GATAbinding protein 3), macrophage-activating factor (MAF) and signal transducer and activator of transcription 6 (STAT6)".
In addition to its regulatory effects on the TH1-TH2 cell balance, retinoic acid also moderates the differentiation of Treg and TH17 cells. Studies have shown that retinoic acids aids transforming growth factor beta (TGFÎ²) to the drive the generation of induced Treg cells which displays the fact that retinoic acid plays a role in oral and mucosal tolerance as well. In addition Vitamin A can aid dendritic cells from the gut associated lymphoid tissue (GALT) to enhance Treg differentiation. Retinoic acid has also shown to have a direct affect on Treg cells themselves as it can enhance the expression of gut homing receptors on Treg cells targeting these cells to the gut mucosa. Retinoic acid is able to control inflammation by inhibiting TH17 differentiation. This is achieved when CD4+ T cells are exposed to retinoic acid with TGFÎ² and IL-6 which causes a proliferation of Treg cells and inhibiting the induction of RORÎ³T which is a transcription factor for TÂH17 cell differentiation.
Vitamin E, just an antioxidant?
Vitamin E is made up of 8 fat soluble compounds, 4 tocopherols and 4 tocotrienols. It is a powerful antioxidant that works against free radicals and lipid peroxidation. Vitamin E is heavily involved in the maintenance of healthy skin and can be found in high quantities in nuts, seeds and cereal germs.
Vitamin E can reduce the release of reactive oxygen species (ROS) by monocytes and the expression of CD11b (also known as integrin alpha M, a receptor that mediates inflammation by regulating leukocyte adhesion and migration) and VLA4 (very late antigen 4) which results in reduced monocyte adhesion to the endothelium. Vitamin E is able to inhibit the release of pro-inflammatory cytokines by macrophages and monocytes such as IL-1, IL-6, IL-8 and TNF. Vitamin E can also repress the upregulation of VCAM1 (vascular cell adhesion molecule 1) and ICAM1 (Inter-Cellular Adhesion Molecule 1) on the endothelium induced by IL-1Î² and oxidised LDL. The upregulation of E-selectin and various chemokines is also decreased due to vitamin E. E-selectin plays an important part in recruiting leukocytes during inflammation. Vitamin E can decrease IFNÎ³ production and CD95L (a transmembrane protein that induces apoptosis) expression on T-cells. This results in reduced inflammation and immune mediated tissue damage.
Vitamin D and its role in immunoregulation:
The physiologically relevant forms of vitamin D are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D3 (VD3) can be converted from 7-dehydrositosterol in the skin or obtained through the diet where it occurs naturally in high quantities in fatty fish, eggs and meat. VD3 is converted to 25(OH)VD3 in the liver which is then metabolised to 1,25(OH)2VD3 (calcitriol) in the kidneys. It is in this form that vitamin D can regulate the concentration of calcium and phosphate in the blood and in turn promote mineralisation, growth and remodelling of bone.
Calcitriol also has numerous inhibitory effects, mainly on T-cells, for example the following are all inhibited by calcitriol: T-cell proliferation, expression of IL-2, IFNÎ³ mRNA and protein in T-cells and CD8 T-cell mediated cytotoxicity. IL-2 mediates T-cell proliferation and INFÎ³ causes activation of natural killer cells as well as neutrophils and macrophages, VD3 can decrease their production by activating VDR (vitamin D receptor) which then binds to RXR forming the VDR-RXR complex. This then binds to VDRE (vitamin D response element) which results in the inhibition of the promoter genes encoding IL-2 and INFÎ³. Calcitriol also has a direct affect on non-specific T-cells and can cause them to suppress primary mixed lymphocyte reactions and cytotoxic T-cell responses. It seems that calcitriol has the overall affect of blocking the induction of TH1 cell cytokines, in particular IFNÎ³, whilst promoting TH2 cell responses. This effect is thought to be mediated indirectly by the reduced IFNÎ³ production and directly by increasing IL-4 production, a cytokine that stimulates B-cell proliferation therefore activating a Humoral response. Calcitriol suppresses the synthesis of IL-12 by antigen presenting dendritic cells, a cytokine that promotes T helper cell differentiation. Furthermore calcitriol can inhibit TH17 cell responses due to its ability to inhibit iIL-23 and IL-6 production.
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Calcitriol does not only have inhibitory effects on T-cells. B-cell proliferation, plasma-cell
differentiation and IgG secretion can all be decreased by calcitriol. The vitamin can also suppress the differentiation of dendritic cells by decreasing the expression of MHC II (major histocompatibility complex) molecules and cluster of differentiation proteins: CD80, CD86 and CD40 which are involved in providing signals for T cell activation. Calcitriol also has some stimulatory effects on innate immune cells. For example, it can increase monocyte proliferation and also stimulate the production of IL-1 and cathelicidin which is a bacterial peptide produced by monocytes and macrophages.
It is clear that the vitamins reviewed in this paper have an integral role to play in both cell mediated and humoral immunity. Not only do these vitamins have an effect on immune response and immunomodulatory activity but they also facilitate in the acquisition of mucosal and oral immune tolerance. It appears that retinoic acid and calcitriol are closely linked when considering the TH1-TH2 cell balance and they seem to have antagonistic effects on each other. A research avenue that could be further investigated is the use of these vitamins, perhaps Vitamin D3, to therapeutically treat auto-immune diseases and also rejection in transplant recipients.