Different roles of zinc in immune responses

Zinc (Zn) is a micronutrient required for basic cellular activities such as cell growth, differentiation, and survival. Zinc deficiency impairs innate and adaptive immune responses. However, the exact physiological mechanism of zinc-mediated regulation of the immune system remains largely unclear. This article will highlight the different roles of zinc in immune responses and some measures to supplement zinc.

1. Why do we need zinc?

Zinc can help support:
DNA synthesis Carbohydrate metabolism Normal cognitive function Fertility Bone health Eye health Zinc boosts immunity Healthy hair, skin and nails

2. Different roles of zinc in immune responses

The human body contains 2-3g of zinc, most of which is bound to proteins. More than 300 enzymes have been shown to contain zinc, directly involved in catalysis, as a cofactor or for structural stabilization. Another large group of zinc-containing proteins are transcription factors, many of which contain zinc fingers and similar structural motors. From silico studies looking for known patterns of zinc binding, it is estimated that about 10% of the human genome encodes proteins that can bind zinc.
Severe zinc deficiency is characterized by growth retardation, skin lesions and poor wound healing, hypogonadism, anemia, diarrhea, anorexia, mental retardation, impaired immune function and vision . Notably, also in milder forms of zinc deficiency, immunostimulating effects were also observed.
At the cellular level, zinc is required for proliferation and differentiation, but zinc homeostasis is also involved in signaling and apoptosis. Cells depend on a constant supply of zinc and utilize complex homeostasis of many proteins, but the plasma pool, which is required for zinc distribution, accounts for less than 1% of total body content. Although it has an important function, the body has only a limited reserve of zinc, which is easily depleted and cannot compensate for a longer period of zinc deficiency. In addition, during infection, inflammatory cytokines mediate changes in liver zinc homeostasis, leading to zinc sequestration into hepatocytes and subsequently leading to hypokalemia. Changes in zinc absorption, storage or excretion can rapidly lead to zinc deficiency and affect zinc-dependent functions in virtually all tissues, especially in the immune system.
The trace element zinc is necessary for the growth and development of all organisms, and the high rate of proliferation and differentiation of immune cells requires a constant supply of zinc.
In a Beisel review, the impact of zinc deficiency on immunity in animal models is summarized. The effects are decreased production of lymphocytes and decreased T-helper cell counts, natural killer cell (NK) activity, antibody production, cell-mediated immunity, and immunity. cell. In humans, the most prominent example of the effects of zinc deficiency is acrodermatitis enteropathica, a rare autosomal recessive disease that causes atrophy of the thymus and is highly susceptible to bacterial, fungal and viral infections. This is a specific zinc malabsorption syndrome based on a mutation in the gene for the intestinal zinc transport protein hZip4. All symptoms can be reversed by zinc supplementation.
Zinc deficiency affects not only a single component of the immune system, but the effects are complex, occurring at multiple levels and involving the expression of hundreds of genes. Short-term effects include modulating thymulin bioactivity according to plasma zinc status, while long-term effects may lead to changes in immune cell populations. Even epigenetic effects were observed. Zinc deficiency during pregnancy in rats not only impaired the immune function of the offspring, but to a lesser extent, compromised immune function was still found in the second and third filial generations, although These mice were fed a zinc-enriched diet.
A major mechanism by which zinc affects immunity is its role as a signaling ion. The concentration of free zinc in the cell is regulated by three mechanisms. One is transport across the plasma membrane. Another mechanism involves storage and release from vesicles, known as zinc bodies, where zinc is stored as a complex with multiple ligands. Finally, zinc binds to metallothionein (MT). Through its 7 binding sites with different affinities, MT buffers zinc in the pico to nanoscale and can also be controlled by zinc release, oxidizing zinc-binding cysteine ​​thiol moieties.
Zinc deficiency in the elderly may decrease zinc-dependent signaling. In a recently published study, zinc-deficient elderly peripheral blood mononuclear cells (PBMCs) showed impaired NF-B activation and interleukin (IL)-2 production in response to with stimulation with PHA, corrected by zinc supplementation in vivo (45 mg/day as gluconate) for 6 months or ex vivo with zinc supplementation to PBMC, showed an association between zinc deficiency and effects of zinc on NF-κB signaling.
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2.1. Zinc and innate immunity

Zinc supplementation in vitro may trigger the events required to recruit leukocytes to the site of infection. For example, high zinc concentrations induce chemotaxis of polymorphonuclear leukemic cells, and zinc promotes the adhesion of myelomonocytic cells.
On the other hand, zinc deficiency in the body causes impaired phagocytosis, killing of parasites and oxidative burst of monocytes and neutrophils, and at the same time reduces cell activity. NK. Zinc is also required for recognition of HLA-C molecules by killer cell inhibitory receptors on NK cells, but notably, zinc is only required for inhibitory but not stimulatory effects. Through this mechanism, zinc deficiency can promote nonspecific killing of NK cells. However, this effect was counteracted by decreased NK cell lysis activity in zinc-deficient patients.

2.2. Zinc and adaptive immunity

The adaptive immune response is based on two groups of lymphocytes:
B cells, which differentiate into plasma cells that secrete immunoglobulins and thereby induce humoral immunity T cells, which mediate cytotoxic effects and the helper cell function of cell-mediated immunity. Both reactions depend on the clonal expansion of cells after recognition of their specific antigen. While B cells depend on zinc for proliferation, they do so to a lesser extent than T cells. In addition, elevated levels of apoptosis in pre-B and T cells were found in mice deficient zinc. Mature cells are resistant to zinc deficiency-induced apoptosis, possibly due to higher levels of the anti-apoptotic protein BCL-2 in these cells. Zinc deficiency not only affects B-lymphocyte proliferation but also leads to decreased antibody-mediated immunity.
The most prominent effect of zinc deficiency is impaired T-cell function from various causes. Thymulin, a hormone secreted by thymic epithelial cells, requires zinc as a cofactor and exists in plasma in two forms, an active form that binds to zinc and an inactive form, which does not contain zinc. zinc. It is required for T-cell differentiation and function, which may explain some of the effects of zinc deficiency on T-cell function.
In mice, zinc deficiency decreased levels of biological activity of thymulin in the circulation. This effect was observed in the absence of thymic atrophy and thymulin activity was restored following serum zinc supplementation in vitro, suggesting that thymulin activity is directly dependent on serum zinc .
In humans with mild zinc deficiency, thymulin activity is also reduced and a comparable effect of zinc supplementation in vitro, in vivo has been described.
Furthermore, the TH1/TH2 balance is affected by zinc. During zinc deficiency, the production of TH1 cytokines, especially IFN-γ, IL-2, and tumor necrosis factor (TNF)-α is decreased, while the levels of TH2 cytokines IL-4 are reduced. , IL-6 and human IL-10 were unaffected in cell culture models, in vivo. In addition to the immunomodulatory effects of zinc deficiency, zinc supplementation can modulate T-cell-dependent immune responses. Zinc addition to PBMCs leads to T-cell activation, an indirect effect that has been reported produced by other immune cells mediated by cytokine production, but higher concentrations of zinc may also directly suppress T-cell function. Here, zinc reduces IL-dependent T-cell stimulation -1 by inhibiting the kinase-1-linked interleukin-1 receptor. In vitro, zinc inhibited mixed lymphocyte cultures (MLCs) and a clear reduction in MLC was also shown in PBMCs from subjects supplemented with 80 mg of zinc daily for one week. Notably, the response to the recovered antigen, tetanus toxoid, was unaffected in these cells and zinc specifically inhibited the allergenic response.

2.3. Zinc and cytokine levels

Zinc has been characterized as a positive and negative regulator of proinflammatory cytokines, especially IL-1 and TNF-α. Several reports describe that zinc supplementation to human peripheral blood mononuclear cells leads to increased mRNA production, release of IL-6, IL-1β and TNF-α monokines. The combination of non-stimulatory concentrations of LPS and zinc resulted in the production of large amounts of monokines.
On the other hand, some reports indicate that zinc treatment suppresses the formation of inflammatory cytokines. This difference can be explained by the observation that the effect of zinc is concentration dependent and that zinc can be either excitatory or inhibitory in the same experimental system. While an increase in intracellular free zinc, which can be mimicked by moderate addition of zinc to cell culture, is a zinc signal involved in monocyte cytokine production in response to with LPS, higher concentrations may have an antagonistic effect by inhibiting nucleotide cycle phosphodiesterase and subsequent activation of protein kinase A. In T cells, cytokine secretion is only indirectly affected by zinc . The release of IFN-γ by zinc and soluble IL-2 receptors is dependent on the presence of monocytes as well as on direct cell-to-cell contact and production of IL-1 monokines, Zinc-mediated IL-6.

2.4. Zinc in health and disease

Severe zinc deficiency impairs immune system function. This may explain why a deficiency is associated with an increased risk of pneumonia and other infections.
Zinc helps maintain the integrity of the skin and mucous membranes. Therefore, clinicians often treat skin ulcers with topical zinc supplements.
Studies have shown that zinc supplements can be used to treat diarrhea in malnourished children. However, the effect of supplementation on diarrhea in children with adequate zinc, such as most children in the US and other Western countries, is unclear.
Age-related macular degeneration (AMD) is the leading cause of vision loss in people age 50 and older. The Age-Related Eye Disease Study (AREDS) found that people at high risk for AMD could slow the progression of advanced AMD by about 25% and vision loss by 19% by taking 40-80 mg. zinc/day, along with several antioxidants (vitamin C, vitamin E, copper, lutein, zeaxanthin).
Taking higher levels of zinc may interfere with copper absorption, which is why copper supplements are also included in AREDS.
Taking zinc improves symptoms of a genetic disorder known as Wilson's disease. Patients with Wilson's disease have too much copper in their bodies.
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2.5. Zinc for the common cold

It is thought that zinc can reduce the severity and duration of the common cold. However, clinical studies on this issue have shown conflicting results. There is evidence that zinc can reduce the binding of rhinovirus to the nasal mucosa, thereby suppressing the inflammatory response.
One study found that the use of zinc lozenges was associated with a reduction in the duration and severity of cold symptoms.
Another clinical trial showed that zinc gluconate lozenges significantly reduced the duration of symptoms in subjects with experimental rhinovirus colds. However, the severity of symptoms was not affected.
Neither zinc gluconate nor zinc acetate lozenges affect the duration or severity of cold symptoms in subjects with spontaneous colds.
A recent Cochrane review concluded that zinc (lozenges or syrup) taken within 24 hours of the onset of symptoms reduced the duration and severity of the common cold in healthy individuals .
The Cochrane review also indicates that zinc lozenges have the potential to produce side effects. Due to somewhat conflicting data, it is difficult to make firm recommendations regarding dosage, formulation, and duration of use.
The US Food and Drug Administration (FDA) has issued a public health advisory advising against the use of over-the-counter nasal products containing zinc (Zicam) because of numerous reports of permanent anosmia (absence or decreased sense of smell).
Zinc is also available in homeopathic preparations as zinc gluconate nasal for the treatment and prevention of colds. This formulation was also found to cause anosmia.

3. Potential impact of zinc on antiviral immunity against SARS-CoV-2

A study by a team of researchers in the US published on December 9, 2020, said that the multifunctional essential trace element zinc has long been considered a potential antiviral agent in the fields of infections, through direct antiviral activity that can be enhanced by ionophores such as chloroquine or by enhancing virus-specific immune responses. Zinc deficiency is associated with higher rates of infection with various viruses, including the common cold virus, HSV, HCV and HIV. Therapeutic zinc supplementation has been shown to compensate for zinc deficiency and reduce infection rates. However, mechanistic studies demonstrating the antiviral activity of zinc in vitro, including effects on viral enzyme activity, are often based on the use of zinc concentrations that are significantly in excess of those of zinc. with concentrations observed under physiological conditions.
Based on these observations, controlled zinc supplementation to achieve zinc homeostasis has been suggested as a possible component in the method of prevention and healing of viral infections, including SARS-CoV-2.
However, there are some considerations that should be considered when administering zinc supplements to patients. Zinc functions as a trace element essential for immunity as well as resistance to many pathogens. Therefore, zinc can influence immune responses and infections in several ways.
It should be noted that some patients infected with SARS-CoV-2/ COVID-19 disease may present with a decreased total white blood cell count. Furthermore, reports indicate that lymphopenia is present in the majority of patients. Importantly, zinc supplementation has the potential to suppress immune responses and should only be taken in a controlled manner.
Although the use of zinc in zinc-deficient conditions is well supported, the potential effects of zinc homeostasis and supplementation in viral infections such as COVID-19 should be carefully considered. renal function and studied further in controlled clinical trials.
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4. Reasonable zinc supplement

Zinc is available as a dietary supplement. It is also present in many cold lozenges and some over-the-counter medicines sold as cold remedies.
Most people will not benefit from oral zinc supplements if their zinc status is normal. However, there is great potential for reducing the burden of zinc deficiency with targeted supplementation in both developed and developing countries.
Zinc supplements are most likely to be helpful if other potentially limited micronutrients are used concurrently.
Zinc toxicity can occur in both acute and chronic forms. Gastrointestinal symptoms such as nausea, vomiting, loss of appetite, and diarrhea may occur. Headaches are also common.
Large doses of zinc can cause copper deficiency, so if taking supplements, the amount of zinc and copper should be proportional.
Zinc comes in two standard dosages. Low dosages are between 5-10 mg per day, which work well as a daily preventative measure. High dosages are between 25-45mg, which should only be taken by people at risk of zinc deficiency or if there is a proven medical benefit.
Several supplement forms are available:
Zinc citrate is about 34% zinc by weight (146 mg zinc citrate contains 50 mg elemental zinc) Zinc sulfate is about 22% zinc by weight (220 mg zinc sulfate contains 50 mg elemental zinc) Zinc gluconate contains approximately 13% zinc by weight (385 mg zinc gluconate contains 50 mg elemental zinc) Zinc monomethionine approximately 21% zinc by weight (238 mg zinc monomethionine contains 50 mg elemental zinc) Summary In contrast, zinc is a micronutrient required for basic cellular activities such as cell growth, differentiation, and survival. Zinc deficiency impairs innate and adaptive immune responses. However, the exact physiological mechanism of zinc-mediated regulation of the immune system remains largely unclear.
To have more knowledge about taking care of children according to age, please visit the website (vinmec.com) regularly and make an appointment with the leading doctors, Pediatricians - Nutrition experts when you need advice.
References: ncbi.nlm.nih.gov, docsopinion.com immunityageing.biomedcentral.com

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