Zinc and Immune Function

Effects of fetal zinc deficiency on immunological development

Gestational Zn deficiency in mice and non-human primates has short- and long-term deleterious effects on the offspring. Substantial reductions are seen in lymphoid organ size and circulating immunoglobulin (Ig) levels in pups born to marginally Zn-deficient mice (Beach et al., 1982). Additional murine studies showed that many of the immunodeficiencies seen at birth persisted into adulthood, despite the pups having been raised on a normal Zn diet after weaning (Beach et al., 1983). Indirect evidence for such effects in humans is also available. Intrauterine growth retardation, which has been linked to maternal Zn deficiency (Dutz et al., 1976), results in depressed cell-mediated immunity, which can persist for years (Dutz et al., 1976; Ferguson, 1978).

Effects of zinc deficiency on barrier function

Zn deficiency damages epidermal cells, resulting in the characteristic skin lesions of AE or severe Zn deficiency (see Shankar and Prasad, 1998). Damage to the linings of the gastrointestinal and pulmonary tracts is also observed during Zn deficiency (see Shankar and Prasad, 1998).

Effects of zinc on immune-cell numbers

Lymphopenia is common in Zn-deficient humans and animals and occurs in both the central and peripheral lymphoid tissues (Walsh et al., 1994). B-cell development in the bone marrow is adversely affected by Zn-deficiency (see Walsh et al., 1994; Shankar and Prasad, 1998). When mice were fed a marginally Zn deficient diet for 30 days, the number of nucleated bone-marrow cells was reduced by one-third, with a preferential reduction in small non-granular cells. The numbers of B-cells and their precursors were reduced by nearly 75%.

Losses were predominantly in pre-B and immature B-cells, which declined by about 50% and 25%, respectively. Thus, Zn deficiency blocks development of B-cells in the marrow, resulting in fewer B-cells in the spleen.

Studies of Zn deficiency in bovine, porcine, rat and murine models and in severely Zn-deficient children describe substantial reductions in the size of the thymus (see Shankar and Prasad, 1998; Prasad, 2000a). Mice maintained on a Zn-deficient diet for as little as 2 weeks showed moderate thymic involution. After 4 weeks, the thymus retained only 25% of its original size and, at 6 weeks, only a few thymocytes remained in the thymic capsule. Thymic atrophy exceeded that of other organs and overall weight loss, which declined only 20% by 6 weeks. The reduction in thymic size and cellularity was seen mostly in the thymic cortex, where immature thymocytes develop. Such changes were not observed in control animals, confirming that Zn was responsible for the effect. Following only 1 week of normal Zn intake, thymic size increased and cellular repopulation of the cortex was seen.

Adult mice maintained for 2 weeks on a Zn-deficient diet had reduced numbers of T and B lymphocytes in peripheral blood, lymph nodes and spleen; numbers of peripheral-blood lymphocytes (and macrophages) were eventually reduced by more than 50% (see Good, 1981; Shankar and Prasad, 1998). Even marginal Zn deficiency substantially suppresses the numbers of peripheral blood immune cells in mice and in humans (Moulder and Steward, 1989; Zalewski, 1996). Zn-deficient children with AE have reduced numbers of lymphocytes, particularly T-cells, in the blood and peripheral lymphoid tissues. Decreased CD4+/ CD8+ cell ratios are also seen. Recent studies in an experimental human model show that the percentage of CD8+CD73+ T lymphocytes (these are precursors to cytotoxic T lymphocytes (CTL)) is decreased in Zn deficiency (see Prasad, 2000a). This and the other effects described are reversed with Zn supplementation.

Effects of zinc deficiency and repletion on immune-cell functions

Neutrophil functions

Neutrophil chemotaxis and function are impaired in Zn-deficient animals and patients with AE and other types of Zn deficiency (see Walsh et al., 1994; Shankar and Prasad, 1998). These impairments are reversible by in vitro addition of Zn to the cells. In addition, in vitro addition of Zn improved the neutrophil response against Staphylococcus. One study observed that exercise-induced potentiation of superoxide formation by neutrophils was attenuated by Zn supplementation (Singh et al., 1994); this might be due to the role of Zn in superoxide dismutase.

Monocyte/macrophage functions

Effects on monocyte/macrophage function are also seen during Zn deficiency. In humans, the chemotactic response of monocytes from AE patients is suppressed and can be restored following addition of Zn to cells in vitro (see Walsh et al., 1994; Shankar and Prasad, 1998). Monocytes from Zn-deficient mice have impaired killing of intracellular parasites, which is rapidly corrected in vitro by addition of Zn. Reduced macrophage phagocytosis of Candida has also been observed in deficient animals. In other studies, however, the ability of macrophages from Zn-deficient rodents to phagocytose particles either was enhanced and accompanied by greater numbers of Fc- and C3b-bearing cells or remained unchanged. High concentrations of Zn in vitro inhibited macrophage activation, mobility, phagocytosis and oxygen consumption. When marasmic children were rehabilitated with a Zn-containing regimen, monocyte phagocytic and fungicidal activity was suppressed (Schlesinger et al., 1993). Since elevated Zn levels can inhibit complement activation (Montgomery et al., 1979), complement-mediated phagocytosis may be adversely affected by high Zn levels. Additional studies are clearly needed to understand more fully the conditions under which Zn affects monocyte/ macrophage phagocytosis.

Natural killer cell function

Human and animal studies showed decreased natural killer (NK)-cell activity in Zn deficiency (see Walsh et al., 1994; Shankar and Prasad, 1998; Prasad, 2000a). NK-cell function was depressed following treatment of cells with 1,10-phenanthroline, a Zn chelator, and was reversed by readdition of Zn but not Ca or Mg. Exogenous Zn also stimulated production of interferon (IFN)-7 by human peripheral-blood NK cells (Salas and Kirchner, 1987). However, exposure of NK cells to high levels of Zn in vitro inhibited cytotoxicity by rendering target cells more resistant to damage. This and other reports of Zn-mediated inhibition of NK activity may be partially explained by the demonstration that the NK-cell-inhibitory receptor requires Zn (Rajagopalan et al., 1995).

T- and B-cell functions

T-cell responses, such as proliferation in response to mitogens, cytotoxicity and delayed-type hypersensitivity (DTH), are suppressed during Zn deficiency and reversed by Zn supplementation (Good et al., 1976; Cunningham-Rundles et al., 1981; Moulder and Steward, 1989; see also Shankar and Prasad, 1998; Prasad, 2000a). Suppressed DTH responses in malnourished children are also restored following Zn supplementation (e.g. Golden et al., 1978). Patients receiving total parenteral nutrition devoid of Zn had reduced T-cell responses to mitogens, which returned to normal after 20 days of Zn supplementation (Allen et al., 1981). Mitogen-induced lymphocyte responses were greater after feeding rats for 14 days on a diet containing 0.1% by weight Zn than after feeding 0.004% Zn (see Chvapil et al., 1976; Shankar and Prasad, 1998). In an experimental human model of Zn deficiency, the production of IL-2 and IFN-7 was decreased, whereas the production of IL-4, IL-6 and IL-10 was not affected (Beck et al., 1997; Prasad et al., 1997, 1999; Prasad, 2000b). IL-2 production in patients with sickle-cell disease and Zn deficiency is decreased and Zn supplementation results in increased production of IL-2 (Prasad et al., 1999). Thus, Zn deficiency in humans appears to be accompanied by an imbalance of T-helper-1 and T-helper-2 function.

Since NFkB binds to the promoter enhancer area of the IL-2 and inter-leukin 2 receptor alpha (IL-2Ra) genes, we investigated the effect of Zn deficiency on activation of NFkB and its binding to DNA in HUT-78, a Th0 malignant human lymphoblastoid cell line (Prasad et al., 2001). We showed for the first time that in Zn-deficient HUT-78 cells, phosphorylation of the NFkB-inhibitory subunit (IkB) and of IkB kinase, ubiquitination of IkB and binding of NFkB to DNA were significantly decreased in comparison with Zn-sufficient cells. Zn increased the translocation of NFkB from cytosol to nucleus. We concluded that Zn plays an important role in the activation of NFkB in HUT-78 cells, which may regulate IL-2 gene expression.

B-cell proliferative and antibody responses are inhibited by Zn deficiency (see Moulder and Steward, 1989; Walsh et al., 1994; Shankar and Prasad, 1998). Interestingly, T-dependent antibody responses are more affected by Zn deficiency than T-independent ones: the plaque-forming colony responses to a T-dependent antigen (sheep red blood cells) and a T-independent antigen (dextran) were reduced 90% and 50%, respectively, in Zn-deficient mice (Fraker et al., 1977, 1978, 1984, 1986). Mice fed a high-Zn diet had increased numbers of splenic plaque-forming colonies in response to T-dependent antigens (Salvin et al., 1987).

Effects of high-dose zinc on immune cell functions

One study reported that 11 men receiving 300 mg Zn daily (20 times the US recommended intake) for 6 weeks experienced decreased proliferative responses of lymphocytes to mitogens and reductions in chemotaxis and phagocytosis of neutrophils (Chandra, 1984). Very high Zn intakes in adults and children can result in copper deficiency and this could be the cause of the immunosuppression (Porter et al., 1977; Prasad et al., 1978; Fosmire, 1990). Importantly, other larger and longer-term controlled trials of high-dose Zn supplementation in adults did not document deleterious effects on cellular immunity (Bogden et al., 1988, 1990). In one study, 103 apparently healthy elderly subjects age 60 to 89 years were randomly assigned to one of three treatments: placebo, 15 mg Zn day-1, or 100 mg Zn day-1 for 3 months (Bogden et al., 1988). None of the treatments significantly altered the DTH response to a panel of seven recall antigens or in vitro lymphocyte proliferative responses to mitogens and antigens. Bogden et al. (1990) administered 100 mg Zn daily to elderly subjects for 12 months and found no deleterious immunological effects. Moreover, deleterious immunological effects were not observed in trials where clinically healthy, and otherwise normal, children received daily Zn supplementation up to twice the US recommended intake (see Shankar and Prasad, 1998). Therefore, intake of Zn twofold above the recommended intake is considered well within the safety range for preschool children and adults. As for any nutritional supplement, caution must be exercised in taking excessive doses for prolonged periods of time.

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