Effects of Iron Deficiency on Immunity

Iron metabolism by T-cells and the effects of iron deficiency on T-cell functions

Resting T-cells do not express the transferrin receptor on their cell surface, and therefore either do not take up iron from their environment or take up very little (Tormey et al., 1972). Upon T-cell activation, T-cells express surface transferrin receptors in the G0/G1 phase of the cell cycle before the initiation of DNA synthesis, but after induction of interleukin (IL)-2 secretion (Neckers and Cossman, 1983). The increase in transferrin receptor concentrations is believed to be to ensure sufficient iron uptake to support the activity of ribonucleotide reductase for the biosynthesis of deoxyribonucleotides.

There are many cell-mediated immune responses that have been investigated in iron-deficient subjects and laboratory animals (Table 11.1). In children and adults, iron deficiency resulting from dietary restriction reduces the proportion of T lymphocytes in blood, although the absolute number of T-cells can be either reduced or unchanged (Chandra and Saraya, 1975; Srikantia et al., 1976; Bagchi et al., 1980; Prema et al., 1982; Swarup-Mitra and Sinha, 1984; Kemahli et al., 1988; Vydyborets, 2000). However, based on the report of Santos and Falcao (1990), it appears that iron deficiency resulting from blood loss does not reduce the proportion of T-cells in blood, but it does decrease total T-cell numbers. The discrepancy between these types of iron deficiency is probably related to the long period of time required for the development of iron deficiency by dietary restriction as compared with blood loss. The absolute numbers and proportions of CD4+ and CD8+ T-cells are either decreased or normal in iron deficiency.

In mice, iron deficiency reduces the proportion of total T-cells, helper T-cells, and cytotoxic/suppressor T-cells in the spleen (Kuvibidila et al., 1990;

Table 11.1. Iron and T-cell functions.

Immune function/response

Iron deficiency: before treatment

Iron deficiency: after treatment

Iron overload

Thymus weight

i or ^

T

Not determined

Spleen weight

T

4

Not determined

Total lymphocytes

i or ^

T

Total T-cell number (CD3+)

i or ^

T

Proportion of T-cells

i

T

4

(% CD3+)

Proportion of CD4 cells

i or ^

4

Total CD4 cells

i or ^

T

4

Proportion of CD8 cells

i or ^

T or ^ (4 iron chelation)

Total CD8 cells

i or ^

CD4/CD8 ratio

i or ^

4

Delayed-type

i

T

4

hypersensitivity

Antibody-dependent

i

cytotoxicity

Splenic T-cell cytotoxicity

i (mice)

Not determined

Not determined

Lymphocyte proliferation

i (in most studies)

T

4, T or ^

Interleukin-2 secretion

i or ^

4 or ^

4

Interleukin-4 secretion

Not determined

Not determined

T

Interleukin-10 secretion

Not determined

Not determined

T

Interferon-7 secretion

i

Not determined

4

Hydrolysis of PIP2

i

T

Not determined

Protein kinase C activity

i

T

Not determined

Protein kinase C

i

T

Not determined

translocation

Protein kinase C mRNA

i

Not determined

Not determined

PIP2, cell-membrane phosphatidylinositol-4,5-bisphosphate; T, increase; 4, decrease; no significant change from normal.

PIP2, cell-membrane phosphatidylinositol-4,5-bisphosphate; T, increase; 4, decrease; no significant change from normal.

Helyar and Sherman., 1992; Table 11.2). However, it does not alter the ratio of helper to cytotoxic T-cells (Table 11.2), which is also sometimes the case in humans. Iron deficiency induces thymus atrophy in mice, but does not affect the proportion of total T-cells, helper T-cells and cytotoxic/suppressor T-cells or the ratio of helper to cytotoxic T-cells in the thymus (Kuvibidila et al., 1990). The mechanisms of thymus atrophy are unclear but are probably multifactorial. Recent data suggest that iron deficiency decreases thymocyte proliferation in vivo but does not increase apoptosis (Kuvibidila et al., 2001). A defect in endocrine function of the thymus is not likely to be responsible for thymus atrophy, since plasma thymulin concentration is normal in iron-deficient mice (Kuvibidila et al., 1990).

Iron deficiency in humans and laboratory animals consistently induces anergy (Joynson et al., 1972; Bhaskaram and Reddy, 1975; Chandra and Saraya, 1975; MacDougall et al., 1975; Kuvibidila et al., 1981; Swarup-Mitra and Sinha, 1984; Kemahli et al., 1988). In most though not all studies, iron deficiency has been shown to decrease secretion of IL-2 (Galan et al., 1992; Kuvibidila et al., 1992; Latunde-Dada and Young, 1992; Thibault et al., 1993; Omara and Blakley, 1994), and interferon (IFN)-7 (Omara and Blaker, 1994), the lymphocyte proliferative responses to mitogens (Fig. 11.1) and antigens (Joynson et al., 1972; Bhaskaram and Reddy, 1975; Chandra and Saraya, 1975; MacDougall et al., 1975; Kuvibidila et al., 1983b, 1998, 1999; Swarup-Mitra and Sinha, 1984; Omara and Blakley, 1994) and antibody-dependent cytotoxicity (Bagchi et al., 1980). Most affected immune responses in humans are corrected within 1-3 months by iron therapy.

Iron metabolism by B-cells and the effects of iron deficiency on humoral immunity

In contrast to T-cells, resting B-cells express low levels of the transferrin receptor, which implies that they continuously take up small quantities of iron (Neckers et al., 1984). Upon activation with a mitogen, up to 80% of B-cells express surface transferrin receptor, and hence exhibit increased iron uptake.

Table 11.2. Distribution of B- and T-cell subsets in the spleen of iron-deficient and control mice (adapted, with permission from the American Society for Clinical Nutrition, from Kuvibidila et al., 1990).

Table 11.2. Distribution of B- and T-cell subsets in the spleen of iron-deficient and control mice (adapted, with permission from the American Society for Clinical Nutrition, from Kuvibidila et al., 1990).

B-cells

53.6

± 4.1

28.5

±

9.1a

50.8 ±

5.5

T-cells

29.3

± 3.6

11.4

±

6.9a

26.3 ±

6.2

Helper T-cells

17.4

± 2.6

6.5

±

4.1a

16.7 ±

4.0

Suppressor T-cells

11.1

± 1.6

4.1

±

2.7a

9.9 ±

2.7

Helper T-cells/suppressor T-cells

1.6

± 0.2

1.6

±

0.3

1.7 ±

1.2

aP < 0.001 versus control and pair-fed mice.

Values are mean ± standard error of mean. Sample sizes are 14 control, 16 iron-deficient, 16 pair-fed mice.

aP < 0.001 versus control and pair-fed mice.

Values are mean ± standard error of mean. Sample sizes are 14 control, 16 iron-deficient, 16 pair-fed mice.

  1. 11.1. Proliferation in response to concanavalin A of spleen cells and purified splenic T lymphocytes as a function of iron status. Values are mean ± standard error of the mean thymidine incorporation. C, control; PF, pair-fed; ID, iron-deficient; R, iron-replete; CPM, counts per minute. Bars with different letters are significantly different from each other (P < 0.05). (Adapted, with permission from the American Society for Clinical Nutrition, from Kuvibidila et al., 1983b.)
  2. 11.1. Proliferation in response to concanavalin A of spleen cells and purified splenic T lymphocytes as a function of iron status. Values are mean ± standard error of the mean thymidine incorporation. C, control; PF, pair-fed; ID, iron-deficient; R, iron-replete; CPM, counts per minute. Bars with different letters are significantly different from each other (P < 0.05). (Adapted, with permission from the American Society for Clinical Nutrition, from Kuvibidila et al., 1983b.)

This suggests that iron deprivation may also affect certain B-cell functions. Indeed, murine splenic B-cell proliferation in response to bacterial lipopolysac-charide is significantly reduced by iron deficiency (Kuvibidila et al., 1983a; Fig. 11.2). However, when parameters of humoral immunity are compared in iron-deficient and control individuals, it is noticed that, in general, humoral immunity is quite well preserved. The percentage and total number of B-cells and the concentration of immunoglobulins (Ig) are either unchanged or slightly increased, and antibody production in response to tetanus toxoid immunization is also normal (Table 11.3; Chandra and Saraya, 1975; Srikantia et al., 1976; Bagchi et al., 1980; Krantman et al., 1982; Prema et al., 1982). In contrast to humans, iron deficiency in laboratory animals decreases the percentage of B-cells in the spleen (Table 11.2; Kuvibidila et al., 1990; Helyar and Sherman, 1992), antibody production against tetanus toxoid (Nalder et al., 1972), secondary antibody response to influenza vaccine (Dhur et al., 1990), the number of plaque-forming cells (Kuvibidila et al., 1982) and Ig levels (Kochanowski and Sherman, 1985; Table 11.3). In addition, the number of intestinal cells containing IgM and secretory IgA (sIgA) in rats is reduced by iron deficiency, an alteration that may affect intestinal mucosal immunity (Perkkio et al., 1987). The discrepancy between humans and laboratory animals could be due to species differences.

  1. 11.2. Proliferation in response to lipopolysaccharide of spleen cells and enriched B-cell fractions as a function of iron status. Values are mean ± standard error of the mean (sem) thymidine incorporation.C, control; PF, pair-fed; ID, iron-deficient; R, iron-replete; CPM, counts per minute. Bars with different letters are significantly different from each other (P < 0.05). (Adapted, with permission from the American Society for Clinical Nutrition, from Kuvibidila et al., 1983b.)
  2. 11.2. Proliferation in response to lipopolysaccharide of spleen cells and enriched B-cell fractions as a function of iron status. Values are mean ± standard error of the mean (sem) thymidine incorporation.C, control; PF, pair-fed; ID, iron-deficient; R, iron-replete; CPM, counts per minute. Bars with different letters are significantly different from each other (P < 0.05). (Adapted, with permission from the American Society for Clinical Nutrition, from Kuvibidila et al., 1983b.)
Table 11.3. Iron and humoral immunity.

Iron deficiency:

Iron deficiency:

Immune function

before treatment

after treatment

Iron overload

% B-cells

i, T or o

i

T

Total B-cell number

i, T or o

o

T or o

Immunoglobulin levels

T or o

i

T

SIgA, IgM, IgG

i (rats)

Not determined

Ta

Antibody production

i (rats)

Not determined

Not determined

(influenza vaccine)

Antibody production

i in animals

Not determined

o

(tetanus toxoid)

o in humans

T

Plasma IgE after Candida

Not determined

Not determined

infection in mice

B-cell proliferation

i

T

I or o

aActivated cells from patients with hereditary haemochromatosis. i, decreased; T, increased; o, no significant change from normal.

aActivated cells from patients with hereditary haemochromatosis. i, decreased; T, increased; o, no significant change from normal.

Iron metabolism by monocytes and macrophages and the effects of iron deficiency on their functions

Although monocytes do not express transferrin receptor, macrophages do (Testa et al., 1991). Macrophages differ from lymphocytes or other cell types because they up-regulate the expression of surface transferrin receptor when cultured in an iron-rich medium. This makes sense because macrophages are involved in iron storage and require iron for cytotoxic activity (Jiang and Baldwin, 1993).

Although the production of macrophage migration inhibitory factor is reduced in iron-deficient adults (Joynson et al., 1972; Swarup-Mitra and Sinha, 1984), production of IL-1 is not, and macrophage cytotoxicity is only slightly reduced (Table 11.4; Bhaskaram et al., 1989). In vitro iron chelation by desfer-rioxamine led to reduced secretion of tumour necrosis factor (TNF)-a by alveolar macrophages from both healthy non-smokers and smokers, which implies that iron deficiency may reduce the production of this pro-inflammatory

Table 11.4. Iron and non-specific immunity.

Immune function

Iron deficiency: before treatment

Iron deficiency: after treatment

Iron overload

Macrophage/monocyte

i

Not determined

4 or ^

phagocytosis

Macrophage/monocyte killing

i

Not determined

4 or ^

capacity

Peritoneal macrophage

i

Not determined

Not determined

tumoricidal activity

Neutrophil phagocytosis

4

Neutrophil bactericidal activity

i

T

4

Myeloperoxidase activity

i

T

Not determined

Neutrophil migration to

i

Not determined

Not determined

inflammation site

Natural killer cell activity

i

Not determined

4

In vivo macrophage clearance

i (mice)

T

Not determined

of particles

Interleukin-1 secretion

i in rats

Not determined

4

^ in humans

Interleukin-12 secretion

Not determined

Not determined

4 for neutrophils

^ for macrophages

Interferon-a secretion

i

Not determined

Not determined

Tumour necrosis factor-a

i

Not determined

secretion

Nitroblue reduction

i or ^

Not determined

4

Zymosan opsonization

Not determined

Not determined

4

Nitric oxide production

Not determined

Not determined

4 for neutrophils

^ for macrophages

Complement C3

i

T

Not determined

Haemolytic activity CH50

i or ^

T

Not determined

4, decreased; Î, increased; no significant change from normal.

4, decreased; Î, increased; no significant change from normal.

cytokine (O'Brien-Ladner et al., 1998). Such an effect would be beneficial under circumstances associated with lung injury. In contrast to humans, macrophages from iron-deficient laboratory animals show reduced in vitro secretion of IL-1 (Helyar and Sherman, 1987) and IFN-7 (Omara and Blakley, 1994), decreased in vivo clearance of polyvinylpyrrolidone (Kuvibidila and Wade, 1987) and decreased tumoricidal activity (Kuvibidila et al., 1983b).

Iron metabolism by neutrophils and the effects of iron deficiency on their functions

Iron concentrations in neutrophils are affected by the iron status of the host: they can be low in iron deficiency and elevated in iron overload. Neutrophils can take up iron from iron-saturated transferrin (Brieland and Fantone, 1991), although transferrin receptors have never been demonstrated on the neutrophil surface (Parmley et al., 1983).

Several neutrophil responses have been assessed in both iron-deficient humans and laboratory animals (Table 11.4). Although neutrophil phagocytosis remains normal in iron deficiency, intracellular killing of bacteria is significantly impaired in both humans and laboratory animals (Yetgin et al., 1979; Walter et al., 1986; Murakawa et al., 1987; Chwang et al., 1988). In parallel with reduced bactericidal killing, the activity of myeloperoxidase, an iron-dependent enzyme involved in neutrophil killing of bacteria, is impaired. The impaired functions return to normal after a few weeks of iron repletion (Walter et al., 1986; Murakawa et al., 1987).

Iron deficiency and natural killer (NK)-cell activity

Similarly to T lymphocytes, resting NK cells do not express surface transferrin receptor, and they probably take up very little iron from the environment (Kemp, 1993). However, upon activation, they express the transferrin receptor on their surface. There is no information on the effects of iron deficiency on NK cell activity in human subjects. In rats, moderate, as well as severe, iron deficiency markedly reduces NK cytotoxicity against the YAC-1 target cell line (Spear and Sherman, 1992).

Mechanisms of impaired immunity in iron deficiency

The mechanisms by which iron deficiency impairs cell-mediated and non-specific immunity are not fully understood, but they are multifactorial (Table 11.5). They include, though are not limited to, reduced activity of iron-dependent enzymes (specifically ribonucleotide reductase), reduced cytokine secretion, a reduced number of immunocompetent T-cells and, very probably, altered signal transduc-tion. Specific steps of signal-transduction pathways that are potentially regulated by iron remain to be identified. However, protein kinase C activity and its translo-

Table 11.5. Possible mechanisms of impaired cell-mediated immunity.

Decreased Proportion and absolute numbers of immunocompetent T-cells Decreased Activity of ribonucleotide reductase Decreased Activity of other iron-dependent enzymes Altered Composition of cell-membrane phospholipids

Decreased Hydrolysis of cell-membrane phospholipids, hence reduced production of second messengers (e.g. diacylglycerol, inositol-1,3,5-trisphosphate) Defective Protein kinase C activation, hence reduced phosphorylation of various factors, including membrane receptors for interleukin-2 and transferrin Altered Activity of other protein kinases that phosphorylate various factors that regulate cell proliferation Altered Concentration of free cytoplasmic calcium, factor involved in signal transduction

Altered T-helper-1- and T-helper-2-type responses

Altered Concentrations of receptors on T-cells and antigen-presenting cells cation to the plasma membrane in murine spleen lymphocytes and human T-cell lines are impaired by iron deficiency (Alcantara et al., 1991, 1994; Kuvibidila et al., 1991, 1999; Fig. 11.3). Furthermore, iron chelation reduces production of mRNA for protein kinase C (Alcantara et al., 1991, 1994). One early event in T-cell activation pathways that is also reduced by iron deprivation is the hydrolysis of cell-membrane phosphatidylinositol-4,5-bisphosphate by phospholipase C (a zinc-dependent enzyme) (Fig. 11.4) (Kuvibidila et al., 1998). The end-products of this enzymatic reaction, inositol-1,3,5-trisphosphate and diacylglycerol, regulate protein kinase C activity. Both protein kinase C activation and the hydrolysis of cell-membrane phospholipids are crucial for signal transduction that leads to T-cell proliferation and many functions. The altered protein kinase C activation and hydrolysis of cell-membrane phospholipids may lead to impaired immune responses in iron-deficient humans and laboratory animals. However, a defect in the activity of other protein kinases involved in the regulation of the cell-cycle progression cannot be ruled out (Lucas et al., 1995).

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