Viruses do not kill us; our immune system does!
Invading pathogens may turn our immune system against our body. Thus, maintaining an optimal immune system is indispensable for healthy living.
Micronutrients are vital to regulate immune systems, even a minor deficiency may cause immune dysfunction.
Some specific micronutrients – vitamin A, B6, B12, B9 (folate), C, D, E, zinc, copper, iron, and selenium-are essential for immune health that often act synergistically at different stages of immune responses.
This article will discuss some of the necessary vitamins and minerals that is crucial for regulating immune system and overall health as well.
Micronutrients are essential regulator of immune components: the physical & biochemical barriers, antimicrobial substances, immune cells, and complement proteins
Role of vitamins on immune system regulation
Vitamin D3:
Vitamin D is immune specific, meaning that it can directly regulate the immune system via vitamin D receptor on immune cells. It is recognized as the most important vitamin for immune health.
Now a considerable research evidenced the lower levels of vitamin D (<30ng/ml) and high infection rate, as well as increased morbidity and mortality. Several studies show significant correlation between vitamin D3 deficiency and COVID-19 associated deaths and complications.
Ninety percent (90%) of total vitamin D3 required to make the body function properly comes from direct sunlight. The sun’s ultraviolet B (UVB) ray penetrates into the skin and makes vitamin D in presence of cholesterol under the skin. The liver than converts this vitamin D3 into 25-dihydroxyvitamin D3 (25(OH)VD3), which is then metabolized in the kidneys to form most physiologically active 1,25-dihydroxy vitamin D3 (1,25(OH)2VD3).
This synthesis occurs quickly under white skin, but very slowly in dark skin due to their high eumelanin (a type of melanin) content which absorbs most of the UVB, thereby inhibiting UVB rays to reach 7-dihydrocholesterol for vitamin D synthesis.
Vitamin D3 can also be processed by the cells of immune system.
The greater the body area exposed to the sun, the higher the level of vitamin D produced in the body. Daily sun exposure of 10-25 mins with UV index of 8 or onward is enough to make required amount of vitamin D3, however, the irony is, the same scenario also applies to photoaging and skin cancer. UV exposure causes oxidative stress and free radical release.
Therefore, foods rich in vitamin D3 or taking supplements is suggested to prevent photoaging.
Along with skin color, and age, some other factors may contribute to the lower absorption of vitamin D as well, including gut dysfunction, subcutaneous fat (the higher the fat the lower the absorption), body areas exposed to the sun, metabolic diseases (diabetes, arthritis, high blood pressure, cardiovascular disease), season, genetic variation, chronic infection (may lower the vitamin D level), autoimmune diseases (needs more vitamin D intake), sedentary lifestyle, and chronic stress may interfere with the absorption and may need higher doses of vitamin D intake.
Moreover, certain drugs, such as statin blocks vitamin D absorption by lowering cholesterol level.
However, high doses of vitamin D for a long period of time may cause hypercalcemia, since vitamin D absorbs the calcium in the intestine. For this reason, it’s recommended to avoid high consumption of calcium rich foods or calcium supplements (especially in the form of calcium carbonate); and at the same time taking vitamin K2 that would direct the calcium to the bone and not to the blood or other soft tissues. Shortly, vitamin D increases the blood calcium level and k2 directs the calcium where to settle in. Further, vitamin K can directly neutralize free radicals.
Immune-specific Functions of Vitamin D3
-Calcitriol regulates biochemical barrier proteins, i.e., antimicrobial cathelicidin and beta-defensin.
-Support gut barrier, modify intestinal microbiota composition to a healthier state.
-Chronic Vitamin D3 deficiency accelerates (intestinal) inflammation, leading to autoimmune diseases.
-Protect against lung infection.
-Protect gut lining from disruption by inducing the expression of cell-to-cell tight junction proteins.
-Maintains renal and corneal epithelial barrier function.
-Vitamin D receptors are expressed by almost all types of cells; white blood cells need vitamin D desperately for their immunomodulatory function.
-Antimicrobial protein expression.
Vitamin A
Vitamin A exists in three forms: retinol, retinal, and retinoic acid. Most biological functions come from retinoic acid. Endothelial cells as well as immune cells has receptors for retinoic acid.
Vitamin A deficiency has long been known to associate with infectious diseases in children, particularly caused by respiratory and intestinal infections.
A recent study showed a strong correlation between vitamin A deficiency and risk of tuberculosis disease among group of household contacts of pulmonary tuberculosis patients. The study suggested that vitamin A supplementation may prevent tuberculosis disease among high-risk individuals for tuberculosis.
Retinol (Vitamin A1) is found in animal-sourced foods. Liver is the richest source of vitamin A, which absorbs in the small intestine. Carotenoids such as β-carotene is found in many plant sources, such as broccoli, dark-leafy greens, and dark-yellow vegetables (carrots, sweet potato, pumpkin, butternut squash). Carotenoids are provitamins that converts into retinol within the intestinal mucosa via carotenoid oxygenases.
Retinol is the precursor of retinal, and retinoic acid, two active metabolites that acts to regulate vision and transcription of many genes, respectively.
In our body, liver stores retinol as retinyl esters; in the gut-associated immune cells and other tissues retinol is oxidized to retinal, which then oxidized to form retinoic acid. Retinoic acid serves to regulate immune cell function through binding retinoic acid receptors on them.
Like vitamin D, the bioactive metabolites of vitamin A, i.e., retinoic acid shows hormone like properties; 1,25(OH)2VD3 and retinoic acid has some overlapping functions on regulating immune system.
Both are fat-soluble vitamins and taking supplements after eating some fats will increase their absorption.
Immune-specific Functions of Vitamin A
-Formation of epithelial tissue: epithelial cell differentiation, maturation, stratification, and keratinization, thereby maintaining the physical barrier to protect against pathogen invasion.
-Maintains the formation and integrity of mucous membrane that lines the various body cavities and covers the internal organs, including eyelids, nose, mouth, trachea (windpipe), respiratory tract, intestines, urethra, ureters, urinary bladder.
-Regulates gut/mucosal homing of cytotoxic T cells to protect against viral infections.
-Successfully used to treat psoriasis, and promising results with several other autoimmune diseases.
-Due to physiological regulation of IgE, vitamin A is promising to treat IgE-mediated type I hypersensitivity disease or allergic reactions.
-Direct role in maintaining T-cell mediated and antibody-mediated immune responses.
-Retinoic acid is essential for intestinal immune responses; drive B and T cells to mobilize into intestinal tissue.
-Carotenoids regulate membrane fluidity, cell to cell communication via gap junction, and reduces toxicity from reactive oxygen species (ROS).
Vitamin E
Vitamin E is a fat-soluble antioxidant, that regulates immune function indirectly.
Vitamin E can be found in eight forms, among which alpha-tocopherol is particularly important because the liver metabolizes vitamin E only in the form of alpha-tocopherol.
The recommended daily intake of vitamin E is 15mg for adults. Enough vitamin E can be found in diets. There are controversies on taking Vitamin E supplements. The benefits are observed in people only with deficiency.
The deficiency is usually observed in people with digestive issues (e.g., Crohn’s disease), liver disease, hepatobiliary disease, some genetic conditions, and some other diseases may impair vitamin E absorption in the small intestine.
Patients with cystic fibrosis may have reduced absorption of vitamin E as well, along with vitamin D, K, and A due to inability to produce sufficient pancreatic enzymes for digestion.
Immune-specific Functions of Vitamin E
-Disrupts free radical induced chain reaction, thus protect against cell damage
-Epithelial barrier integrity
-Regulates NK cell-mediated toxicity to kill intracellular pathogens
-Indirectly promotes T cell function
Vitamin B6 (pyridoxine), B12 (cobalamin), and B9 (folate)
All B vitamins are water-soluble, that means, body cannot store them and excrete as urine.
Vitamin B6 is a reactive oxygen species (ROS) scavenger. Free radical formation and oxidative stress is a common scenario in diabetic mellitus and vitamin B6 supplementation has been evidenced to suppress oxidative stress in a diabetic rat model.
Vitamin B12 and folate work together to form S-adenosylmethionine (SAMe), which is a substance that play important role in immune function, depression, liver disease, and some other conditions.
Body cannot make B vitamins on its own, thus it should have to be received from foods or supplements.
Immune-specific Functions of Vitamin B6, B12, & B9
-Important regulator of intestinal immune function and gut barrier function.
-B6 directs lymphocytes localization to the intestine
-Folate ensures survivability of regulatory T cells in the small intestine
-Gut microbiome uses B12 as a cofactor for metabolism
-Deficiency may impair immune responses via reducing certain serum antibody production (IgG, and IgM)
-B6 increases the production of interleukin 2, an important regulator of white blood cells.
-Regulates natural killer cell (NK cell) activity to fight against viral infection.
Vitamin C (Ascorbic acid)
vitamin C is a potent antioxidant and a water-soluble nutrient. However, it has some overlapping function with vitamin E.
Vitamin C and E are relatively non-specific (indirect) in their functions on immune system.
Large doses of intravenous vitamin C infusion has shown to be beneficial for moderate to severe COVID19 patients in China.
Recommended daily allowance of vitamin C for adults is 65-90 mg.
Immune-specific Functions of Vitamin C
-Protects cell damage by free radicals.
-Maintaining the integrity of epithelial barriers.
-Enhances collagen synthesis, thereby shortening the wound healing time.
-Promotes healthy skin by regulating keratinocytes, fibroblasts, and lipid synthesis.
-Proliferation, function, or movement of phagocytes.
-Clearance of dead cells.
-Reduces tissue damage due to infection.
-High level of vitamin C has antimicrobial activity.
Role of minerals on immune system regulation
Zinc
Zinc has been demonstrated to inhibit SARS-COV-2 viral replication inside the cells by inhibiting RNA-dependent RNA polymerase. Decrease in blood zinc levels was observed in COVID19 patients.
However, oral administration of zinc as a prophylaxis is probably not very beneficial, since without any external intervention (such as hydroxychloroquine which works as a zinc ionophore or zinc transporter through which zinc enters into the cells), it is hard to ensure substantial concentrations of zinc inside the cells for inhibiting viral replication.
The recommended daily allowance (RDA) of zinc is 8~11mg/day for adults. Animal products, legumes, nuts and seeds are all excellent sources of zinc.
Immune-specific Functions of Zinc
-Skin and mucosal membrane integrity.
- Promote wound healing.
-Regulates immune cell production and growth, particularly T cells.
-Closely linked to antibody production, primarily IgG.
-Enhances antibacterial activity against E. coli, and S. aureus.
-Bridges between innate and adaptive immune responses
-Antioxidant and anti-inflammatory; protect against reactive oxygen species and reactive nitrogen species as well
-Regulates cytokine release by suppressing the pro-inflammatory T helper cells (Th9 & Th17) development
Selenium
Dietary selenium shows its biological activity via incorporating into selenoproteins. In response to dietary selenium, the immune cells as well as other tissue cell types synthesize selenoprotins.
Selenoproteins plays important role in activating immune system, while at the same time suppresses excessive immune responses as well as chronic inflammation.
Selenium deficiency is linked to enhanced oxidative stress and immune cell dysfunction.
Selenium is required at trace amount, high level of selenium may cause toxicity.
The recommended dietary allowance (RDA) of selenium for adults is 55mcg.
Selenium is also required to offset mercury toxicity (high levels of mercury is found in large sea fish), because excess mercury blocks up selenium which involved in the antioxidant network, especially glutathione pathway, resulting in ROS accumulation. Study suggests that, consuming high amounts of fish with se: mercury ratio less than 1 may greatly increase the risk of mercury toxicity.
Immune-specific Functions of Selenium
-Certain selenoproteins detoxify hydrogen per oxide, hence they are called antioxidants
-The glutathione peroxidase enzymes are crucial antioxidants; they utilize Se to sense oxidative stress and neutralize ROS.
-Affects leukocyte, including NK cell function
Iron
Iron is an essential nutrient to promote healthy immune function.
Iron is absolutely necessary for virtually all pathogens infecting human, thus an important aspect of innate immune system (immediate response after pathogen invasion) is to reduce the availability of iron to invading pathogens; this process is named nutritional immunity.
Iron can exist in two oxidation states: ferrous, and ferric, which makes them ideal for redox (loss or gain of electron) catalysts that regulates diverse cellular processes. However, this redox potential also facilitates iron-mediated toxicity.
Extra iron buildup may cause by certain diseases, such as hereditary hemochromatosis and beta-thalassemia. Iron overload can damage liver, heart, and pancreas, among others. Therefore, careful consideration should be given while taking supplements.
Iron is available in many food sources, especially meat or seafood. The daily recommended iron intake depends on many factors, including age, sex, pre-existing disease conditions, and type of diet.
Immune-specific Functions of Iron
-Essential for epithelial tissue formation.
-Neutrophil, a white blood cell requires iron to generate ROS to kill pathogens
-By interacting with neutrophil-derived hypochlorous acid (which is basically a Clorox), iron produces hydroxyl radicals (۰OH) that causes severe cell damage than any other ROS can do; thereby promoting bacterial killing
-Promote anti-inflammatory and suppresses pro-inflammatory responses
-Antimicrobial activity
Copper
Copper is fundamental to maintain innate immune response.
Copper deficiency can cause abnormally low level of white blood cells that are responsible for innate immunity or immediate response against pathogens and increases viral virulence.
However, having copper deficiency is not very common. People with certain digestive issues, such as Celiac disease may have deficiency. Taking excessive zinc may also cause copper deficiency.
Too much copper is also toxic. Extra copper negatively modulates immune responses and may buildup in the brain, eyes, and kidneys. It may also interfere with the zinc and iron absorption.
Copper can be found in variety of food sources, including tap water. The RDA for copper for adults over 19 years of age is 900mcg.
Function
-Accumulates in phagocytic cells to fight off certain infectious pathogens.
-Enhances NK cell activity against viral infections
Magnesium
Magnesium has a strong role on innate immune regulation, both in direct and indirect manner.
Too little Mg enhances oxidative stress after intense exercise. Mg deficiency is strongly linked to excessive inflammation by inducing the pro-inflammatory cytokine release. The deficiency is particularly observed in athletes, and elderly people.
Clinical studies suggest that Mg is involved in asthma-associated pathological responses; and Intravenous infusion of Mg showed reduced symptoms in patients with acute or chronic asthma.
Magnesium is widely available in many plant or animal-derived foods; squash and pumpkin seeds are probably the richest source of magnesium on earth.
Immune-specific Functions of Magnesium
-Regulates innate immune cell function, activation, and antigen (e.g., pathogens) binding.
-Free radical scavenger and a part of copper/zinc-superoxide dismutase which is a key enzyme in defense against ROS
-Reduces superoxide anion production and DNA damage due to oxidative stress.
-Decreased immunity against recurrent bacterial infections, as well as fungal infections.
Summary
At adequate level, these micronutrients ensure healthy immune function and minimize the risk of infections, while overdosing may cause serious health risks. It is always advised to get most vitamins and minerals from natural food sources which would significantly reduce the risks of overdosing.
References
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