Effects of Iron Overload on Immunity

In contrast to the numerous studies conducted in humans and laboratory animals on the effects of iron deficiency on immune responses, less work has been conducted on the effects of iron overload on immune functions. Part of the reason for this is the fact that primary iron overload is not as common as iron deficiency. However, iron overload due to repeated blood transfusion in patients with haemoglobinopathies or renal disease is not rare.

Iron overload and T-cell functions

Patients with iron overload due to multiple transfusion (beta-thalassaemia, sickle-cell disease) generally have reduced proportions of T lymphocytes and

  1. 11.3. Protein kinase C translocation from the cytosol to the cell membrane of lymphocytes as a function of iron status. Values are mean ± standard error of the mean ratio of membrane-bound protein kinase C activity to cytosolic protein kinase C activity. C, control; PF, pair-fed; ID, iron-deficient; R3, R7 and R14, iron-deficient mice that received the control diet (repletion protocol) for 3 days (R3), 7 days (R7) and 14 days (R14); Con A, concanavalin A; PHA, phytohaemagglutinin. Bars with different letters are significantly different from each other (P < 0.05). (Reproduced with permission from John Wiley & Sons Inc., from Kuvibidila et al., 1999.)
  2. 11.3. Protein kinase C translocation from the cytosol to the cell membrane of lymphocytes as a function of iron status. Values are mean ± standard error of the mean ratio of membrane-bound protein kinase C activity to cytosolic protein kinase C activity. C, control; PF, pair-fed; ID, iron-deficient; R3, R7 and R14, iron-deficient mice that received the control diet (repletion protocol) for 3 days (R3), 7 days (R7) and 14 days (R14); Con A, concanavalin A; PHA, phytohaemagglutinin. Bars with different letters are significantly different from each other (P < 0.05). (Reproduced with permission from John Wiley & Sons Inc., from Kuvibidila et al., 1999.)

CD4+ T-cells and a reduced ratio of CD4+/CD8+ T-cells (Gugliemo et al., 1984; Kaplan et al., 1984; Dwyer et al., 1987; Table 11.1). Lymphocyte proliferative responses to mitogens and delayed-type hypersensitivity skin responses to antigens are also reduced in these patients (Hernandez et al., 1980; Munn et al., 1981; Escalona et al., 1987). However, it is not always certain whether the reduction in the proportion of T-cells is due to iron overload alone or to a combination with other factors, such as alloantigen sensitization or the coexistence of other nutrient deficiencies (protein-energy malnutrition, zinc, vitamin A, vitamin E), which are also known to impair cell-mediated and non-specific immunity (Kuvibidila et al., 1993). However, since iron chelation by desferrioxamine has been shown to improve lymphocyte proliferation, there is no doubt that iron overload plays some role in impaired immune responses in transfused patients. While there is no information on cytokine secretion, the percentages of CD3 + , CD4+ and CD8+ T-cells are slightly increased and lymphocyte proliferative responses to mitogens are reduced in untreated patients with hereditary haemochromatosis (Bryan et al., 1991). Following iron chelation, the

Incubation time (min)

Fig. 11.4. Hydrolysis of cell-membrane phosphatidyl inositol-4,5-bisphosphate in murine lymphocytes as a function of iron status. Data are mean + standard error of the mean IP3 generation in the presence of Con A/IP3 generation in the absence of Con A, expressed as a percentage of that ratio at zero time. C, control; PF, pair-fed; ID, iron-deficient; Con A, concanavalin A; IP3, inositol-1,3,5-trisphosphate; a,P < 0.01 vs. control and pair-fed mice. (Adapted, with permission from the American Society for Nutritional Sciences, from Kuvibidila et a., 1998.)

Incubation time (min)

Fig. 11.4. Hydrolysis of cell-membrane phosphatidyl inositol-4,5-bisphosphate in murine lymphocytes as a function of iron status. Data are mean + standard error of the mean IP3 generation in the presence of Con A/IP3 generation in the absence of Con A, expressed as a percentage of that ratio at zero time. C, control; PF, pair-fed; ID, iron-deficient; Con A, concanavalin A; IP3, inositol-1,3,5-trisphosphate; a,P < 0.01 vs. control and pair-fed mice. (Adapted, with permission from the American Society for Nutritional Sciences, from Kuvibidila et a., 1998.)

percentages of CD3 + and CD4+ T-cells returned to normal levels, while those of CD8+ decreased below normal levels.

Data on T-cell functions in laboratory animals with iron overload are inconsistent. While lymphocyte proliferation is impaired in mice (Omara and Blakley, 1994), it is increased in iron-overloaded rats (Wu et al., 1990). The secretion of IL-2 (Omara and Blakley, 1994) and IFN-7 (Mencacci et al., 1997) by mitogen-activated murine spleen cells is suppressed by iron overload. In contrast to this down-regulation of T-helper-1-type response, iron overload up-regulates the T-helper-2-type response: the secretion of IL-4 and IL-10 in response to Candida albicans is significantly increased when compared with spleen cells from mice with normal iron status (Mencacci et al., 1997).

Iron overload and B-cell functions

As is the case for T-cells, very little information is available on B-cell functions in non-transfusion patients with iron overload. However, it appears that the humoral immunity is not impaired by iron overload (Table 11.3). In fact, IgG,

IgA, IgM and total Ig secretion by non-activated and pokeweed mitogen-stimu-lated peripheral blood mononuclear cells obtained from patients with hereditary haemochromatosis is higher than that of cells from control individuals (Bryan et al., 1991). In patients with ß-thalassaemia and those with sickle-cell disease, B-cell numbers and Ig concentrations are elevated (Glassman et al., 1980; Escalona et al., 1987). Serum concentrations of IgE specific for C. albi-cans are increased several-fold in iron-overloaded mice compared with mice with normal iron status (Mencacci et al., 1997).

Iron overload and macrophage functions

While iron overload has no effects on the secretion of TNF-a by bacterial lipopolysaccharide-activated alveolar macrophages, it reduces the secretion of IL-1p (O'Brien-Ladner et al., 1998; Table 11.4). Further support for a negative effect of iron overload on IL-1 secretion is provided by increased levels following iron chelation by desferrioxamine. Macrophage phagocytosis and the secretion of nitric oxide and IL-12 are not affected by iron overload (Mencacci et al., 1997).

The role of iron in microbial killing by monocytes/macrophages is complex. Iron is required for the generation of hydroxyl radicals, which are more potent anti-microbial agents than hydrogen peroxide and superoxide anion, which are produced during the oxidative burst. The limited existing data suggest that macrophage killing capacity is either normal or slightly decreased in iron overload (Brock, 1992). However, when iron is added to the culture medium, macrophage killing capacity of certain microorganisms, such as Brucella abortus, Staphylococcus aureus and Mycobacterium tuberculosis, is increased (Jiang and Baldwin, 1993; Byrd, 1997).

Iron overload and neutrophil functions

Iron overload also has deleterious effects on neutrophil functions. Secondary iron overload due to multiple blood transfusions in patients with beta-thalas-saemia (Cantinieaux et al., 1987) and those with renal disease (Waterlot et al., 1985; Flament et al., 1986) is associated with reduced phagocytosis of various microorganisms (yeast, S. aureus, Escherichia coli) (Table 11.3). Nitroblue tetrazolium reduction, zymozan opsonization, myeloperoxidase activity and bactericidal capacity are also impaired in patients who are iron-overloaded due to transfusion (Waterlot et al., 1985; Cantinieaux et al., 1987). Although there are other factors that can contribute to impaired neu-trophil functions in transfused patients, the improved neutrophil phagocytosis and bactericidal capacity following decreased body iron stores by iron chela-tion or increased erythropoiesis provide good evidence for the negative effects of iron overload on neutrophil functions (Boelaert et al., 1990; Cantinieaux et al., 1999). The secretion of nitric oxide and IL-12 by neu-trophils obtained from uninfected and C. albicans-infected mice is abolished by iron overload when compared with cells obtained from mice with normal iron status (Mencacci et al., 1997).

Iron overload and NK cell function

Although NK activity is not depressed in patients with haemochromatosis (Chapman et al., 1988), it is severely reduced in transfused patients with beta-thalassaemia or sickle-cell disease (Kaplan et al., 1984). However, while in vitro incubation with desferrioxamine improved NK activity, in vivo administration of the same chelator to patients with beta-thalassaemia failed to correct it. This is most probably due to insufficient reduction of iron levels in NK cells or to the presence of some confounding variables that also impair NK activity. There is no information on NK activity in laboratory animals with iron overload.

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