Vitamins: Key Role Players in Boosting Up Immune Response-A Mini Review

Vitamins perform different functions in our body and to boost up immune response towards pathogens is one of them. Immunity provides protection to life by its three main such as skin, cellular response, and humoral immune response. Both vitamins quality and quantity within the body promote systematic immune processes by regulating Tlymphocytes, antibodies, and cytokines formation. In this review, we will summarize the role of water soluble and fat soluble vitamins to boost up immunity functions. Vitamins A, C, and E mainly aid in enhancing the skin epithelium barrier function. With the exception of vitamin C, all the vitamins are claimed to be essential for antibody production. Most of the vitamins are applied in our body to produce a cell-mediated response with the production of cytokines and T-lymphocytes. Supplementation of the diet with vitamins in specifically selected appropriate quantities routinely can support body’s natural defence mechanism by enhancing the immune response.


Introduction
Vitamins are vital organic nutrients in our meal that are utilized by the cells of our body for proper growth, development, disease prevention like deficiency disorders, and to improve immune system efficacy. Vitamins are taken routinely along with diet and are required in proper trace amounts so that all the barriers of the immune system such as skin, cell-mediated and humoral immune response etc. could be sustained. The immune system helps in preventing the active tissues of the body from the agents that lead to diseases [1]. Bioavailability of vitamins varies with age, sex, and physiological conditions. Their quantities within the body are mostly regulated by the type of dietary intakes and eating habits. Vitamin supply can also be affected by drugs, tea or caffeine, smoking, alcohol abuse, dietary fibers (phytates) etc., This review focuses on almost all vitamins either water/fat-soluble vitamins, in context with the human immune system. Vitamin deficiency suppresses overall immunity by affecting cell-mediated and adaptive immune response, leading to impaired regulation of the balanced immune response with increased morbidity, malnutrition, and mortality. Vitamins A, C, and E mainly aid in enhancing the skin epithelium barrier function. With the exception of vitamin C, all the vitamins are claimed to be essential for antibody production [2]. Vitamins are also vital for developing innate immunity and adaptive immunity in the body [3]. Most of the vitamins like, B 6 , B 9 , B 12 , A and D are also applied in our body to boost-up the cell-mediated immune response with the production of cytokines and T-lymphocytes. Overall, inadequate intake and lowered nutritional status of these vitamins and trace elements may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition. Therefore, the intake of appropriate amounts of all such essential vitamins in our daily diet can help in supporting the cognitive power of the body leading to wellbeing of health [4].

Bioavailability
Bioavailability means availability of vitamins in blood circulation and their effect in our body as we understand it commonly. In broader spectrum, bioavailability is defined as the proper absorptivity and uptake of various nutrients by the cells [5,6]. Factors that affect bioavailability vary by age, sex, and physiological conditions, like pregnancy [7]. Vitamin deficiency occurs more commonly either due to insufficient intake of the vitamins or due to disturbances in absorption and utilization of these vitamins from the gut. Malnutrition results in weakened immunity and hence people are attacked by chronic infections due to weak immune response. Many types of eating disorders like anorexic/bulimic condition and binge eating and problems in ingestion or engulfing food reduce total dietary intake of vitamins. Vitamin bioavailability also depends on the type and amount of nutrients digested along with the body, such as phytates present in beans and veggies, and caffeine in tea/coffee reduces vitamin and mineral absorption. Sometimes increase or decrease of one vitamin may also affect vitamin absorption, for example, vitamin B 6 , B 9 , and B 12 work together to enhance its absorption but if any vitamin is reduced then it may affect others. Some drugs like antibiotics, antiinflammatory, histamine, anti-seizures etc. decrease vitamin B complex, vitamin D and C levels within the body cells. Few wellknown diseases like as "celiac disease" and "lactose intolerance" lessens the vitamin absorption by affecting the digestive processes, like incomplete digestion.
β-carotenes and retinol (a precursor of vitamin A) are the major precursors of vitamin A [8], (Figure 1) Vitamin A occurs naturally in food stuffs like fish, beef liver, eggs, and dairy products which are the animal sources for vitamin A precursors such as retinol and palmitate, whereas green leafy vegetables and fruits serve as plant sources for carotenoids that can be converted into retinol. Vitamin A plays a key role in enhancing eye sight, growth, reproduction, blood cells formation and it also improves body's immune response [9]. βcarotenes function as an antioxidant when it comes to the enhancement of immune response [10], like, for example, in an experiment, when dairy cows were given 300 mg-600 mg β-carotene/ day, this supplementation resulted in the reduction of the incidence of retained placenta and metritis as compared to control cows [11]. Retinoic acid which acts as vitamin A metabolite, derived from retinol enhances the lymphocyte proliferation [12] and mitogen stimulation. In the case of innate immunity vitamin A is essential for maintaining and recovery of epithelial structures at the skin, urinary tract and lungs epithelium. According to Villamor and coworkers [13], vitamin A supplementation shows no effect on the concentration of immune factors in cervicovaginal fluids of HIV-infected pregnant women. However, Vitamin A supplementation imparts beneficial effects on intestinal integrity among children suffering from severe infections or to those who are malnourished [13]. It has also been known that vitamin A derivative called retinoic acid also plays an important function of allowing the proper migration of T-cells to the site of inflammation or infection in the gut [14] and this dispatching of immune cells to the proper sites in the gut is referred as gut homing, which is brought about by the presence of certain codes present on the receptors of T-cells [15]. Derivative of retinol (retinoic acid) is involved in the proper migration of the, cytotoxic killer cells (CD8 or Tlymphocytes), CD4 (helper T cells), and immunoglobulins involved in the immune response through mucous membrane (IgA) antibody producing cells.

Anti-HCV Role of Retinol (Vitamin A)
Slow deterioration of liver and hepatic cancer due to the hepatitis C virus is one of the leading causes of final phase of hepatic disease called hepatitis C [16]. Recent studies have shown that the derivative of vitamin A called retinoic acid has the role of viral inhibition [17]. Liver is the main site of detoxification of alcoholic compounds and poisons. Cho [16] hypothesized that in the people who abuse alcohol in their diets suffer from liver cancer or their liver undergoes cirrhotic conditions due to the impairment of vitamin A in their hepatic cells, thus providing the evidence of relationship between vitamin A reduction and HCV attack. In such people or patients, liver starts to deteriorate slowly due to reduced or suppressed retinol conversion to retinoic acid. In the liver cells, the alcohol in the form ethanol is converted into acetate through the activity of certain enzymes that convert the alcohol in the form that can be easily flushed out from the body, the enzymes that play such role are, the alcohol dehydrogenase and aldehyde dehydrogenase; the process starts by the metabolization of alcohol into acetaldehyde in the presence of alcohol dehydrogenase enzyme, which is further converted into acetate by the activity of aldehyde dehydrogenase [18]. Besides this ethanol neutralizing activity, both of these enzymes also play vital role in the conversion of retinol to retinoic acid. In the liver cells of people who use alcohol routinely beyond their optimum requirements, the concentration of ethanol often increases beyond the concentration of alcohol dehydrogenase being produced in their hepatic cells and this increase in ethanol also causes the decreased retinoic acid production leading to vitamin deficiency in hepatic cells [19]. During hepatitis C virus (HCV) attack the host cells start producing interferons which are the natural viral replication inhibitors and these interferons also lead to the activation of the interferon genes of the nearby cells which are called as interferon stimulated genes [20]. It has also been found that some of these genes activated by interferons also include certain genes that are activated or expressed in the presence of retinoic acid or they can be said to be the genes whose transcription is induced by retinoic acid [21]. All these studies provide evidence that improper vitamin A (retinol) conversion to retinoic acid by the alcohol dehydrogenase and aldehyde dehydrogenase leads to the decreased interferon production due to the inactivation of interferon producing genes which causes the liver cells to become susceptible to alcohol dependent HCV attack.
According to WHO, the vitamin A deficiency is a serious public health problem that affects 127 million preschool children and in recent results, it leads to the deaths of approximately 20 million people in the low income countries which is estimated to be the 2.4% of the total deaths due to vitamin A deficiency worldwide. In children, vitamin A deficiency results in increased risks of mortality and morbidity from measles and diarrheal infections, night blindness, and anemia, and among women it is likely to be associated with high mortality related to pregnancy. So, its consumption in daily diet should be increased according to Dietary Reference Intake's (DRI) recommended values. Table 1 is the USDA National Nutrient Database for vitamin A intake recommended for different age groups along with the natural sources of vitamin A.

Vitamin B Complex and Immunity
Vitamin B complex was historically supposed to be the single vitamin but later it was found that it consists of several different compounds that can be grouped into different categories according to their functional distinctions [22], members of B complex include thiamine (B 1 ), riboflavin (B 2 ), niacin (B 3 ), pantothenic acid (B 5 ), pyridoxine (B 6 ), biotin (B 7 ), folic acid (B 9 ) and cobalamins (B 12 ) [23]. Several members of vitamin B complex are used in our body to promote the defensive role for better health and prevention of diseases by boosting-up the immune system. Types of vitamins that fall in this category of vitamin B complex play a key role by acting as antioxidants in the body thus enhancing the efficiency of the immune response [24]. Members of vitamin B complex that have such roles in immune response efficacy include vitamin B 6 , B 9 and B 12 .

Vitamin B 6
Vitamin B 6 actually acts as co-factor for certain enzymes that helps the in carrying out their respective functions [22]. B 6 contains 3 pyridine derivatives therefore it is named as pyridoxine. Vitamin B 6 helps control levels of homocysteine in the blood. Homocysteine is a common amino acid [25]. Higher level of homocysteine (hyperhomosysteinaemia) is associated with heart diseases like Acute Coronary Syndrome (ACS) and cardiovascular death, collectively called athero-thrombosis [26,27]. The body needs B 6 in order to absorb vitamin B 12 and to make red blood cells and cells of the immune system. Vitamin B 6 helps the body to make several neurotransmitters like serotonin, chemicals that carry signals from one nerve cell to another. Serotonin is only synthesized by the tryptophan and this conversion of tryptophan to serotonin occurs in the presence of pyridoxal phosphate which is a vitamin B 6 derivative [28]. Vitamin B 6 is needed for normal brain development and function, and helps the body to make nor-epinephrine, which influences the mood, and melatonin, that helps in regulating the body clock. Symptoms of serious deficiency included muscle weakness, nervousness, irritability, depression, difficulty concentrating and sometimes short-term memory loss. According to National Institute of Health in USA, the Recommended Dietary Allowance of vitamin B 6 for adults should be 2 mg per day [22]. Vitamin B 6 helps to improve immune response to the increase in production of antibodies and also helps in communicative interactions between cytokines and chemokines [29]. Vitamin B 6 deficiency reduces the lymphocyte growth and proliferation, antibody formation and T-cell activity [30].   Table 2 shows the USDA National Nutrient Database for vitamin B 6 intake recommended for different age groups along with the natural sources.

Vitamin B 9
Vitamin B 9 or Folic acid (folate) also plays a role in immunity enhancement. It is commonly a key role player in the biosynthesis of nucleic acids, proteins [31] blood cells and nervous tissues [25]. Rich sources of folic acid include, poultry, shellfish, salmon, tuna, dark leafy vegetables, whole grains, beans, orange juice, citrus fruits, cantaloupes, asparagus, milk etc. Folic acid is crucial for proper brain function and plays an important role in mental and emotional health. Its deficiency in central nervous tissue may lead to depression, insomnia, fatigue, anxiety etc., [32]. For adults, Reference Dietary Intake of folate is 400-600 mcg/day for pregnant and for lactating it is 500 mcg/day.

Vitamin B 12
They are also known as cobalamins because they contain cobalt [25]. Normally, 2.4-2.6 mcg for pregnant women and 2.8 mcg/day intake of vitamin B 12 for lactating women is recommended. It aids in the metabolism of every cell of the human body, especially affecting DNA synthesis, fatty acid, and amino acid metabolism. It is also involved in B-cell synthesis and T-cell multiplication [33]. According to Vellema [34], in animal models, when they were devoid of vitamin B 12 in their diets, as a result, deficiency of B 12 caused immune response reduction during viral and bacterial infections in those model animals. This experimentation gave the proof of importance of vitamin B 12 in boosting body's immunity. Vitamin B 12 cannot be synthesized naturally in humans and plants. Only bacteria have the enzymes needed for B 12 synthesis. Food sources of vitamin B 12 are animal products that include meat, fish, poultry and dairy products. In Table 4 is the USDA National Nutrient Database for vitamin B 12 intake recommended for different age groups along with the natural sources.

Vitamin C and Immunity
It is commonly known as the L-ascorbic or simply ascorbic acid found in almost every type of body tissue but in pituitary gland and in central nervous system, it is present in higher concentrations, approximately up to 400 mg/kg [25]. Ascorbic acid stimulates iron absorption from the intestine and modulates iron transport for storage and is also involved in cellular growth and differentiation and collagen formation, also helps in the formation of catecholamine and carnitine [35], in the brain it aids in natural synthesis of vital neurotransmitters like dopamine and noradrenalin [25]. Vitamin C boosts up human immunity towards infections and cold illnesses by increasing phagocytosis, lymphocyte proliferation and neutrophil chemotaxis against exogenous pathogens. It neutralizes reactive oxygen species (ROS) formed in immune cells, without vitamin C, reactive oxygen species couldn't have been removed from immune cells which would lead to the destruction of immune cells, these reactive oxygen species are necessary to kill foreign invaders but they may also damage the cell itself if not taken care of at the meantime, this essential role is played by antioxidants like vitamin C [2]. Vitamin C is found in higher concentrations within the leukocytes and it has been found that it also aids in chemotaxis of neutrophils and monocytes.
During any kind of infection vitamin C concentrations the immune cells (e.g., leukocytes) falls rapidly to lower concentrations due to its utilization and then after eradicating the cause of infection it again restores back to normal, this proves that vitamin C actively takes part in warding off the infectious agents during an infection [36]. Deficiency of ascorbic acid in the body leads to suppressed immune response, susceptibility to infections, weak collagen formation and in case of an injury wound healing process gets delayed [37]. It also acts as a reducing agent and thus reduces oxidase enzymes that play an important part in metabolizing various kinds of drugs, ascorbic acid deficiency leads to the lower drug metabolization and also the lowered activity of electron transporters like cytochrome P-450 occurs [38]. It is evident that ascorbic acid also has antiviral activity, as according to Siegel and Morton [39] when in lab, mouse cells were cultured with ascorbic acid they started producing interferons.
In Table 5 is the USDA National Nutrient Database for vitamin C intake recommended for different age groups along with the natural sources.

Vitamin D and Immunity
It is composed of two main groups that contain vitamin D 2 and vitamin D 3 [35]. Vitamin D 2 is commonly known as ergocalciferol and D 3 as cholecalciferol. They are found mainly in the bones and teeth and help in their maintenance [40]. Main food sources of vitamin D include, fish liver oils, eggs of hen but the common source of vitamin D present in nature is the sunlight [35]. Lower concentrations of this vitamin in the body have been found to be the cause of increase in infection rates and apart from rickets, and other bone and joint disorders, now the lack of this vitamin has lead to the increased death rates due to cancers, heart diseases and other microbial infections [40]. In humans both types of vitamins (D 2 and D 3 ) are utilized but vitamin D3 is naturally produced by the human cells in the presence of ultraviolet radiations from the sunlight whereas the ergocalciferol or vitamin D 2 is not synthesized in humans but it is synthesized in the plants and can also be utilized [41]. Vitamin D 3 (1, 25dihydroxyvitamin) plays an important part in regulating human immune response [3]. Vitamin D is also best known for its activity in the expression of those genes that produce proteins which are toxic to a number of foreign microbes. According to Maggini and Wintergerst [2], vitamin D receptors (VDRs) are present in the monocytes, macrophages and thymus tissues which indicates their role in immunoregulation. They can regulate the immune response as well and can also modulate the innate and adaptive immunity of the human body [42]. Conversion of vitamin D, synthesized in the skin cells by the absorption of ultraviolet rays from sunlight, to vitamin D 2 (25hydroxyvitamin) takes place inside the liver cells as a result of the action of certain enzymes, such as, CYP27A1 in mitochondria and another is the microsomal enzyme CYP2R1, this hydroxylated form of vitamin D 2 then circulates to the kidneys where it gets converted to vitamin D 3 (1, 25-dihydroxyvitamin) via the action of mitochondrial CYP27B1 also known as 1-α-hydroxylase, and microsomal CYP2R1 enzymes [43]. Cholecalciferol/D 3 is the steroidal form of vitamin D and it starts circulating in the body and is transported via certain D3binding proteins to the specific tissues or cells where required [44], such as to the VDRs of macrophages and dendritic cells in order to activate various immune responsive actions [43], refer to Figure 2. It also has positive effects on the synthesis of immunoglobulins and cytokines and also has proved its activity against multiple sclerosis, arthritis rheumatoid arthritis etc., [1]. It also enhances the regulation of T-lymphocytes lipopolysaccharide surface receptors and also down-regulates expression of immunoglobulin E (IgE) initiated by vitamin A [45]. Ergocalciferol (D 3 ) provides protection against inflammation of adipose tissues [46]. Role of vitamin D against the tuberculosis bacteria has also been of importance and was reported in 1980s. Monocytes encounter the Mycobacterium tuberculosis by the activation of Vitamin D 3 [47]. It is also essential in overcoming inflammation and other chronic diseases like diabetes that are caused due to inflammation. Obesity is the mainly due to the inflammation and so is the diabetes, common of which is type II diabetes [48]. Vitamin D also acts and modulates the inflammations that may lead to chronic disease development [49,50]. Given below in Table 6 is the USDA National Nutrient Database for vitamin D intake recommended for different age groups along with the natural sources.

Vitamin E and Immunity
Regarded as the derivative of tocol or tocotrienol and among them α-tocopherol is best known for its role in maintaining health in the humans. α-tocopherol, in the form of lipoproteins is secreted by the liver and plays its part as the protector of certain proteins and fatty acids present in the membrane from free radicals by acting as an antioxidant [51]. Vitamin E molecules produced in plants are also of key importance to humans as there are approximately 8 different kinds of molecules in human body that are obtained from plant sources [52]. Niki and Traber [52] described that, at the start, the concentrate containing antioxidant molecules was referred to as the 'inhibitols' because it resembled to the inhibitols obtained from different plant sources like lettuce, wheat, palm oils etc. and these inhibitols were neutralized by the agents that destroy the hydroxyl (OH) groups. In 1940s, the α-tocopherols were known to be the key role players in neutralizing and destroying free radicals that form within the different cells of tissues and this role of vitamin E gained extreme importance and interest. α-tocopherols do not have any role in the signaling pathway rather it changes the chemical composition of the environment where the process of signaling needs to be carried out [51]. Vitamin E is also known to be the immunoregulator and plays an important role in enhancing immune response [53] by inactivating and inhibiting the free radicals as a result of antioxidant activity [2]. When the diet is supplemented with vitamin E intake, it results in the mitogen stimulated increased T-lymphocyte multiplication, increased cytotoxic cell activity and maximize the action of macrophages against the intruders thus providing the strong basis of action against infections [54,55]. An increase in vitamin E is also known for inhibiting the activation of protein kinase C (PKC) enzyme which in turn leads to the reduced platelets, nitric oxide and also the shows reduced superoxide accumulation in macrophage cells and neutrophils [56]. The deficiency of vitamin E in the body leads to the development of a disease called ataxia [57]. Table 7 is the USDA National Nutrient Database for vitamin E intake recommended for different age groups along with the natural sources.

Sources Deficiency Causes Recommended Dietary Intake of Vitamin E Per Day
Sunflower, safflower, wheat germ, peanuts, tomato, spinach, broccoli.

Conclusion
Adequate intake of micronutrients, especially vitamins are required and considered mandatory for healthy immune system and its optimal functionality. Immunity is the natural defense mechanism in biological systems to fight against infections, diseases or other unwanted biological invasions and autoimmune diseases. Immunity provides protection to life through three different kinds of barriers including, Skin/epithelial barrier, 2. Cellular response (T lymphocytes and cytokines) and last one are Humoral immune response (antibodies).
Vitamins are a group of substances that are needed for normal cell function, growth, and development. We can obtain them from fruits, vegetables, beans, lentils, whole grains and fortified dairy foods. Vitamins have the properties to help the body in fighting against a variety of illnesses and protect the body from damage to cells. Many foods contain vitamins that promote, enhance and regulate the immune system. Some vitamins have more immune protection power than others. Vitamins A, C, and E mainly aid in enhancing the epithelium/skin barrier function. With the exception of vitamin C, all the vitamins are claimed to be essential for antibody production. Most of the vitamins like (vitamin B 6 , B 9 , B 12 , A and D) are also applied in our body (orally) to produce a cell-mediated response with the production of cytokines and T-lymphocytes. Comprehensively, inadequate intake and lowered nutritional status of these vitamins and trace elements may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition. Therefore, supplementation with selected vitamins can support the body's natural defence system by enhancing all three levels of immunity.