Zinc is the second most abundant trace element in the human body (after iron), and it is the essential cofactor for over 300 enzymes and for the DNA-binding zinc finger proteins that regulate gene expression across the entire genome. The immune system is particularly dependent on adequate zinc status — zinc is required for the normal development and the function of all of the immune cells, including the neutrophils, the natural killer (NK) cells, the monocytes, the macrophages, the dendritic cells, the T lymphocytes, and the B lymphocytes, and its deficiency produces a characteristic immunodeficiency syndrome that includes the lymphocyte depletion, the thymic atrophy, the lymphopenia, the impaired cell-mediated immunity, and the increased susceptibility to the infections that are the hallmark of zinc deficiency. This zinc-dependent vulnerability of the immune system is one of the most important and least appreciated aspects of nutritional immunology, and it explains why zinc supplementation has been shown to reduce the incidence and the severity of the infections in children, in the elderly, and in people with the chronic diseases that are associated with the zinc deficiency.
Zinc and the Innate Immune Function
The innate immune system is the first line of defence against the invading pathogens — it includes the physical barriers (the skin and the mucous membranes), the chemical barriers (the gastric acid, the lysozyme, the defensins), the cellular barriers (the neutrophils, the monocytes, the macrophages, the NK cells), and the humoral factors (the complement proteins, the cytokines, the acute-phase proteins). Zinc is required for the normal development and the function of all of the cellular components of the innate immune system — it is a cofactor for the zinc-dependent metalloenzymes that are essential for the respiratory burst in neutrophils (including the superoxide dismutase, which protects the neutrophils from the oxidative damage of their own reactive oxygen species), it is required for the normal development and the bactericidal activity of the macrophages, and it is essential for the cytotoxic function of the NK cells, which kill the virus-infected cells and the tumour cells by releasing the perforin and the granzyme granules. The impairment of these innate immune functions by zinc deficiency explains why zinc-deficient individuals are more susceptible to the bacterial, the viral, and the fungal infections that are the clinical hallmark of the zinc deficiency syndrome.
The neutrophil is one of the most important cellular components of the innate immune system, and it is particularly sensitive to zinc status — zinc deficiency impairs the chemotaxis, the phagocytosis, the respiratory burst, and the microbicidal activity of the neutrophils, reducing their ability to migrate to the site of the infection, to engulf and to kill the pathogens, and to generate the reactive oxygen species that are essential for the intracellular killing of the ingested microorganisms. The zinc-dependent impairment of the neutrophil function in zinc deficiency is one of the primary mechanisms of the increased susceptibility to the bacterial infections that is the hallmark of zinc deficiency, and it explains why zinc supplementation reduces the incidence and the severity of the pneumonia and of the other lower respiratory infections in zinc-deficient children.
Zinc and the Adaptive Immune Function
The adaptive immune system is the antigen-specific, memory-enabled system that provides the long-lasting protection against the re-infection with the same pathogen. It includes the cell-mediated immunity (which is mediated by the T lymphocytes, including the CD4+ helper T cells and the CD8+ cytotoxic T cells) and the humoral immunity (which is mediated by the B lymphocytes and by the antibodies that they produce). Zinc is required for the normal development and the function of both the T and the B lymphocytes — it is a cofactor for the zinc-dependent enzymes that are essential for the lymphocyte proliferation, for the cytokine production, and for the cytotoxic activity, and it is required for the normal development of the thymus (the primary organ of T cell maturation, which undergoes a dramatic atrophy in zinc deficiency). The thymic atrophy of zinc deficiency produces a severe depletion of the circulating T lymphocytes (particularly the CD4+ helper T cells), which impairs the cell-mediated immunity and produces the characteristic lymphopenia and the inverted CD4+/CD8+ ratio that is the hallmark of the zinc deficiency immunodeficiency.
The clinical importance of zinc for the T cell function is underscored by the observation that zinc deficiency produces a shift in the Th1/Th2 balance — it reduces the production of the Th1 cytokines (IL-2, IFN-gamma) that are required for the cell-mediated immune responses and increases the production of the Th2 cytokines (IL-4, IL-5, IL-10) that promote the humoral immune responses. This Th1/Th2 shift in zinc deficiency impairs the cell-mediated immunity (which is primarily Th1-driven) and predisposes to the intracellular pathogens (including the mycobacteria, the viruses, and the fungi) that are controlled by the cell-mediated immune responses. The correction of the zinc deficiency restores the normal Th1/Th2 balance and reverses the immunodeficiency — zinc supplementation in zinc-deficient individuals has been shown to increase the CD4+ T cell counts, to restore the normal Th1 cytokine production, and to reduce the incidence of the opportunistic infections that are the hallmark of the T cell immunodeficiency.
Practical Application
For general zinc supplementation, the evidence-based approach is to supplement with 15-30mg of zinc daily (as zinc citrate, zinc picolinate, or zinc gluconate — the forms that are well absorbed and well tolerated). The RDA of zinc is 8mg daily for women and 11mg daily for men, and the tolerable upper intake level is 40mg daily for adults (above which the zinc can interfere with the copper absorption and produce the copper deficiency anaemia). For the treatment of the zinc deficiency, higher doses of 30-60mg daily may be used for a limited period (2-3 months), followed by a maintenance dose of 15-30mg daily. For comprehensive immune support, zinc pairs well with vitamin C (which has antiviral and immunomodulatory effects), with vitamin D (which has immunomodulatory effects and which is particularly important for the T cell function), with the elderberry extract (which has antiviral effects and which is particularly useful for the prevention and the treatment of the respiratory infections), and with the selenium (which is required for the glutathione peroxidase enzyme and which works synergistically with zinc for the support of the immune function).
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