Despite its important function, the body has only limited zinc stores that are easily depleted and can not compensate longer periods of zinc deficiency. Additionally, during infections pro-inflammatory cytokines mediate changes in hepatic zinc homeostasis, leading to sequestration of zinc into liver cells and subsequently to hypozincemia [9].
Zinc and innate immunity
Zinc supplementation in vitro can trigger events required for the recruitment of leukocytes to the site of infection. For example, high zinc concentrations induce chemotaxis of polymorphonuclear cells [34], and zinc promotes the adhesion of myelomonocytic cells [35]. On the other hand, zinc deficiency in vivo causes impaired phagocytosis, parasite killing, and oxidative burst of monocytes and neutrophil granulocytes, and a decrease in NK cell activity [36, 37, 38]. Zinc is also required for recognition of HLA-C molecules by the killer cell inhibitory receptors on NK cells, but, notably, zinc is only necessary for inhibitory, but not stimulatory effects [39]. Via this mechanism, zinc deficiency may promote nonspecific killing by NK cells. However, this effect is counteracted by a reduction of NK cell lytic activity in zinc deficient patients [40].
Zinc and adaptive immunity
The most prominent effect of zinc deficiency is a decline in T cell function, which results from multiple causes. Thymulin, a hormone secreted by thymic epithelial cells, requires zinc as a cofactor and exists in the plasma in two forms, a zinc-bound active one, and a zinc-free, inactive form. It is essential for differentiation and function of T cells, which could explain some of the effects of zinc deficiency on T cell function.
Furthermore, the TH1/TH2 balance is affected by zinc. During zinc deficiency, the production of TH1 cytokines, in particular IFN-γ, IL-2, and tumor necrosis factor (TNF)-α is reduced, whereas the levels of the TH2 cytokines IL-4, IL-6, and IL-10 were not affected in cell culture models [46] and in vivo [47, 48]. In addition to the immunomodulatory effects of zinc deprivation, zinc supplementation can modulate T cell dependent immune reactions.
Zinc and cytokine levels
Zinc has been characterized as a positive and negative regulator of pro-inflammatory cytokines, in particular IL-1 and TNF-α. Some reports describe that zinc supplementation to human peripheral blood mononuclear cells leads to an increased mRNA production and release of the monokines IL-6, IL-1β, and TNF-α, and a combination of nonstimulatory concentrations of LPS and zinc results in the production of large amounts of monokines [52]. On the other hand, several reports indicate that zinc treatment suppresses the formation of pro-inflammatory cytokines [46, 53]. This difference can be explained by the observation that the effect of zinc is concentration dependent, and that zinc can be stimulatory or inhibitory in the same experimental system.
Immunological changes during aging
Aging of the immune system, also referred to as immunosenescence, describes the age-related changes in immune function that lead to increased susceptibility of older people to infectious diseases, autoimmunity, and cancer. The capacity of the immune system to mount an adequate response decreases with age, starting around 60, but several factors such as lifestyle and underlying diseases can significantly affect the onset in each individual [54]. Interestingly, a comparison between alterations of the immune system during zinc deprivation and aging shows many similarities, indicating a possible relation between immunosenescence and zinc deficiency [55]. In both cases it comes to anergy, thymic atrophy, and reduced NK cell activity, cell mediated cytotoxicity, helper T cell activity and thymulin levels [56].
As it could be expected from the decline in immune function, aged patients suffer from an augmented incidence and mortality of infectious diseases such as pneumonia [57] and tuberculosis [58], and re-infections with herpes zoster increase [59]. The frequency of autoimmune diseases is augmented with age, too, accompanied by an increase in autoantibodies, which is, interestingly, not observed in centenarians [60, 61]. On the other hand, specific IgE production decreases, reducing the risk for allergies [62, 63].
Cancer is a disease that occurs over proportion in elderly as well. People ≥65 years have an eleven fold higher incidence of cancer and a fifteen fold higher mortality than younger subjects [64]. Although the immune system functions as a network in which nearly all elements interact with each other, some components can be identified that are especially affected by aging and whose functional impairment causes increased susceptibility for diseases like the examples mentioned above [65, 66].
The most severe changes during aging are found in the adaptive immune system. Aging leads to a shift in B cell populations and antibody production. B cell numbers decline with age and one would expect that this is accompanied by a decrease in immunoglobulins, but the opposite has been observed, showing an increase of IgA and several IgG subclasses [79]. The response to vaccination with several antigens is diminished, which may result from an impaired interaction with T helper cells (see below), but also a loss of antibody affinity was found. At the same time an increase in organ-specific and non-organ-specific autoantibodies was observed, but, whereas the latter increase with age, subjects over 90 years show lower levels of organ-specific autoantibodies than younger elderly [80]. Another change that occurs with age is increased clonal expansion of B cells, which may be connected to the increased incidence of lymphocyte malignancies with age [80]. The effects of aging on B cells and humoral immunity are summarized in figure 2.
Similar to the effects of zinc deficiency, the main changes of aging also affect the T cell system. T cells from elderly subjects show decreased proliferation in response to T cell receptor (TCR) stimulation or mitogens [81], an altered CD4/CD8 ratio, and higher expression of CD95 and the pro-apoptotic BAX combined with a decrease in BCL-2 and p53, which leads to increased apoptosis [82]. A prominent feature of immunosenescence is thymic involution. This leads to a decrease in the generation of new T cells, finally resulting in a lower number of naïve (CD45RA+) and a higher number of memory (CD45R0+) T cells [83]. Zinc deficiency can also cause thymic involution, regardless of age.
Decreased humoral immunity may not only result from changes in B cells, but in part be caused by a disturbance of T cell help and alterations of cytokine levels, because many cytokines that control B cell functions are affected by aging [90, 91]. As summarized in figure 3, a disturbed humoral response may be the result of a combination of an impaired interaction between antigen presenting cells (APC) and T helper cells and a shift in the TH1/TH2 balance, which both add to the immunological alterations that occur directly in B cells. It is noteworthy that zinc can antagonize all these effects.
Referência :
(1) Immun Ageing. 2009 Jun 12;6:9.