Zinc is a divalent cation (Zn2+) that is essential for the function of over 300 enzymes in the body and that is required for the development and the function of every component of the immune system — including the neutrophils, the natural killer (NK) cells, the macrophages, the T lymphocytes, the B lymphocytes, and the cytokines and chemokines that coordinate the immune response. Zinc is the most important trace element for immune function, and its deficiency is the most common cause of immunodeficiency worldwide (it affects approximately 2 billion people, primarily in the developing world where zinc-deficient soils produce zinc-deficient crops and where the diet is low in animal source foods that are rich in bioavailable zinc). The clinical manifestations of zinc deficiency are devastating — it causes growth retardation, hypogonadism, dermatitis, alopecia, diarrhoea, and profound immunodeficiency (with thymic atrophy, lymphopenia, and the recurrent infections that are characteristic of cell-mediated immunodeficiency). The reversal of zinc deficiency with zinc supplementation is one of the most cost-effective public health interventions available, and it has been estimated that zinc supplementation in the developing world could prevent approximately 400,000 deaths annually in children under 5 years of age.
Zinc and Innate Immunity
Zinc is essential for the development and the function of every component of the innate immune system — the neutrophils, the natural killer (NK) cells, and the macrophages. In neutrophils, zinc is required for the NADPH oxidase activity that generates the superoxide radical that kills pathogens, for the myeloperoxidase activity that generates the hypochlorous acid that is one of the most potent antimicrobial compounds in the immune arsenal, and for the activity of the proteolytic enzymes that degrade the pathogens that are engulfed by phagocytosis. In NK cells, zinc is required for the expression of the NK cell receptors (the killer immunoglobulin-like receptors, KIRs, and the NKG2 receptors) that recognise and kill virus-infected cells and tumour cells, and for the perforin-granzyme pathway that is the primary mechanism by which NK cells kill their targets. In macrophages, zinc is required for the phagocytosis of pathogens, for the generation of the inflammatory cytokines that coordinate the early immune response, and for the intracellular killing of pathogens that have been engulfed by phagocytosis.
The clinical importance of zinc for innate immunity is most clearly demonstrated by the effect of zinc deficiency on the innate immune system. In zinc deficiency, the number and the function of neutrophils, NK cells, and macrophages are all reduced, and the innate immune response to infection is correspondingly impaired. The susceptibility to infection in zinc deficiency is particularly marked for the infections that are handled primarily by the innate immune system — including the bacterial infections that are handled by neutrophils (particularly the Staphylococcus aureus and Streptococcus pneumoniae skin and respiratory infections that are common in zinc-deficient individuals), the viral infections that are handled by NK cells (particularly the herpes family viruses, including CMV, which is a major cause of morbidity in zinc-deficient individuals with impaired NK cell function), and the parasitic infections that are handled by macrophages (including malaria, which is more severe in zinc-deficient individuals).
Zinc and Adaptive Immunity
Zinc is also essential for the development and the function of the adaptive immune system — the T lymphocytes and the B lymphocytes. In T lymphocytes, zinc is required for the activity of the thymulin enzyme (which is produced by the thymic epithelial cells and which is essential for the maturation and the function of T lymphocytes), for the function of the zinc-dependent transcription factors (including NF-kappaB, which regulates the expression of the cytokine genes that are activated during the immune response), and for the activity of the cytokine receptors (including the IL-2 receptor, which requires zinc for its assembly and its function). In B lymphocytes, zinc is required for the activity of the zinc-dependent enzymes that are involved in antibody synthesis and for the function of the plasma cells that secrete antibodies. The importance of zinc for the adaptive immune system is most clearly demonstrated by the thymic atrophy and the lymphopenia that characterise zinc deficiency, and by the restoration of thymic size and of lymphocyte numbers following zinc supplementation.
Practical Application
For general zinc supplementation, the evidence-based dose is 15-30mg of elemental zinc daily (as zinc citrate, zinc gluconate, or zinc picolinate, the better-absorbed forms), taken with a meal to minimise the GI upset that can occur when zinc is taken on an empty stomach. The RDA for zinc is 8mg daily for women and 11mg daily for men, and most people achieve this from a varied diet that includes meat, fish, poultry, shellfish, and the zinc-fortified cereals that are common in the developed world. Zinc supplementation above 40mg daily should not be sustained for more than 2-3 weeks because it interferes with copper absorption and can produce copper deficiency. For comprehensive immune support, zinc pairs well with the other immune nutrients (including vitamin D, which has direct effects on the expression of the cathelicidin and beta-defensin antimicrobial peptides; vitamin C, which supports neutrophil function and which is an antioxidant that protects immune cells from oxidative damage; and the omega-3 fatty acids, which have anti-inflammatory effects that reduce the demand for immune activation), with the probiotics (which support the gut immune system and which complement the systemic immune effects of zinc), and with the Mediterranean dietary pattern (which is associated with better immune function and with reduced risk of infection).
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