Effects of Selenium on the Immune System

Studies over the past 30 years have demonstrated that an adequate Se intake is essential for both cell-mediated and humoral (antibody-mediated) immunity (for reviews, see Spallholz ei al., 1990; Kiremidjian-Schumacher and Roy, 1998; McKenzie ei al., 1998; Kiremidjian-Schumacher ei al., 2000; Rayman, 2000). The immunomodulatory effects of Se occur through three principal mechanisms: (i) anti-inflammatory effects of selenoproteins or selenocom-pounds; (ii) selenoenzymes or Se compounds altering the redox state of the cell by acting as antioxidants; and (iii) through the generation of cytostatic and anticancer compounds as products of Se metabolism.

Effects of selenium on respiratory burst and microbe killing

The respiratory burst is a microbicidal reaction that takes place in neutrophils and monocyte/macrophages. Using a partial reduction of oxygen, it produces superoxide (O2 ), hydrogen peroxide (H2O2) and other reactive oxygen species (ROS) that kill bacteria. As a defence mechanism, it is extremely effective, but the host must be able to remove the peroxides that are generated in the process; otherwise, host cell damage will result. Superoxide is converted by superoxide dismutase to H2O2, which can, if not removed, decompose to the extremely reactive hydroxyl radical (OH') (see Trenam et al., 1992).

In the 1970s, it was realized that Se deficiency led to decreased GPX activity and an inability to produce a respiratory-burst reaction that was effective at killing microbes (Spallholz et al., 1990). The reason for this is that the production of O2 • is sensitive to H2O2, which damages the O2 -generating enzyme. This loss of respiratory-burst reaction impairs effective killing of bacteria and results in granuloma formation (a mass of activated, but ineffective, leucocytes) and an inability of the host to eliminate microbes (references in Spallholz et al., 1990). Furthermore, nitric oxide (NO) is used by a variety of host cells to destroy bacteria and viruses. Reaction of NO with O2 • leads to the formation of peroxynitrite (ONOO-), which causes oxidative damage to lipids, proteins and DNA (references in McKenzie, 2000). In Se deficiency, there is an impaired capability to detoxify organic and inorganic peroxides, generated by oxidative stress or through general metabolism. As a consequence, damage to macro-molecules and cell membranes can occur.

Effects of selenium on eicosanoid metabolism

Potent lipid modulators of inflammation are synthesized from arachidonic acid cleaved from membrane phospholipids by the action of phospholipases A2 and C, followed by the action of cyclo-oxygenase (see Fig. 12.3; see also Calder and Field, Chapter 4, this volume). This family of metabolites of arachidonic acid, known collectively as eicosanoids (Gerritsen, 1996), has both pro-inflammatory and immunosuppressive properties (see Calder and Field, Chapter 4, this volume). Furthermore, the excessive generation of hydroperoxides formed by the lipoxygenase and cyclo-oxygenase enzymes in circulating leucocytes can lead to oxidative damage to endothelial cells.

The leucotrienes (LTs), such as LTB4, are pro-inflammatory compounds (see Calder and Field, Chapter 4, this volume). Some, like LTB4, are important chemoattractants for neutrophils, bringing them into the inflamed tissue. The LTB4 synthase enzyme requires reduction of 12-hydroperoxyeicosatetraenoic acid (12-HPETE) by the PHGPX or other GPX enzymes (reviewed in Parnham and Graf, 1987; Spallholz et al., 1990). Se deficiency results in decreased LTB4 synthesis and impaired neutrophil chemotaxis. Diminished peroxidase capacity in Se deficiency also leads to a decrease in the synthesis of prostacyclins (Cao et al., 2000). These mediators prevent arterial thrombosis and platelet aggregation. Instead, Se deficiency promotes the synthesis of thromboxanes, which cause platelet aggregation. Platelet degranulation results in the release of proinflammatory mediators, including vasoactive amines, eicosanoids and pro-inflammatory cytokines. Thromboxane synthesis and platelet aggregation and activation are decreased by Se (Zbikowska et al., 1999).

Lipoxins A4 and B4

15-HETE

15-Lipoxygenase

15-HETE

15-Lipoxygenase

5-HETE

5-HPETE

Membrane phospholipid

Phospholipase A2 and C

Y / 5-Lipoxygenase

Arachidonic acid '

Membrane phospholipid

TX synthase

Cyclo-oxygenase GPX -PGG2 and PGH2-y pgi2

Prostacyclin synthase

PGD2

PGF2

PGE2

Stimulated by Se Inhibited by Se

Fig. 12.3. The effects of selenium (Se) on the production of eicosanoids. The enzymes catalysing each step are indicated in italic. GPX indicates either a GPX or the phospholipid hydroperoxide GPX. Reactions stimulated or inhibited by Se are indicated. Cyclo-oxygenase is a key enzyme in eicosanoid synthesis. High levels of peroxides inactivate cyclo-oxygenase; these can be broken down by GPX - thus GPX is an activator of cyclo-oxygenase. PGG2 and PGH2 are unstable endoperoxides, which are converted to thromboxanes (TX), prostacyclins (PGI2) or prostaglandins (PG). 5-HETE, 5-hydroxyeicosatetraenoic acid. LT, lakotriene.

Effects of selenium on lymphocytes and killer cells

Se supplementation stimulates several activities of lymphocytes, natural killer (NK) cells and lymphokine-activated killer cells (summarized in Figs 12.4 and 12.5). Preservation of protein structure is partly Se-dependent, because of the role of thioredoxin reductases in maintaining proteins in their correctly folded configuration. For cell-mediated immunity to function, interaction between many immunologically active proteins and their receptors needs to occur. Interleukin (IL)-2 is a vitally important paracrine growth and activation cytokine for immune cells (see Devereux, Chapter 1, this volume). A major immunos-timulatory effect of Se is by Se-induced up-regulation of expression of the a and (3 subunits of the IL-2 receptor, which are expressed on many immune cells and notably on T and B lymphocytes. This increases the ability of these cells to respond to IL-2. Stimulation with IL-2 from activated CD4+ T-helper cells then potentiates the cytotoxicity of killer cells, increases numbers of lymphocytes, promotes antibody production by B lymphocytes and improves the responsiveness of immature bone-marrow cells to other cytokines in order to produce immune-cell precursors. The combination of IL-2 and interferon gamma binding to monocytes and macrophages boosts resistance to and killing of microbes (Kiremidjian-Schumacher et al., 1996).

Se also causes increases in the cytotoxicity of CD8+ cells, increases CD4+ cell numbers and responses to mitogens and greater survival of CD4+ cells in human immunodeficiency virus (HIV)-infected patients (for references, see Spallholz et al., 1990; Kiremidjian-Schumacher et al., 1996, 2000; Kiremidjian-Schumacher and Roy, 1998; McKenzie et al., 2002). The diminished prolifera-tive response of lymphocytes to mitogenic stimuli in aged mice can be reversed by dietary Se supplementation, acting by up-regulation of the IL-2 receptor (Roy et al., 1995). Se supplementation also appears to reverse the age-related decline in NK-cell function in elderly humans (Ravaglia et al., 2000). The loss of NK-cell activity is one means by which cancer cells may evade immunemediated destruction.

The thioredoxin reductases and the GPXs protect host cells from their own respiratory-burst reaction. The thioredoxin reductases also have the ability to inactivate NK lysin, a protein produced by cytotoxic cells to kill bacteria and tumour cells. In Se deficiency, it is possible that host cells are vulnerable to damage from both types of 'friendly fire'. Proof of the importance of this mechanism is that tumour cells often have elevated levels of thioredoxin reductase, which protects them from NK lysin. Thus, Se deficiency weakens the immune response at several key points.

In 1973, it was discovered that mice fed Se-enriched diets had increased titres for immunoglobulin G (IgG) and IgM antibodies and had higher levels of complement proteins. Most studies since then in various animals and in humans have confirmed that Se alone or in combination with vitamin E raises B-cell numbers and antibody production in response to vaccination. Studies showing that Se supplementation increases antibody production, complement responses and cell-mediated killing are catalogued in Spallholz et al. (1990) and McKenzie et al. (1998). Studies in farm animals have shown that Se

Se deficiency

Se supplemented

Se deficiency

ROS I

NEUTROPHILS

ROS I

But much inflammation and less microbe killing Chemotaxis I

More microbicidal, Chemotaxis Î Cell numbers Î

More microbicidal, Chemotaxis Î Cell numbers Î

MONONUCLEAR PHAGOCYTES

Chemotaxis I insufficient burst reaction for killing

Chemotaxis T

Phagocytosis T

Bacterial and parasite killing?

Complement-mediated phagocytosis

NATURAL AND LYMPHOKINE-ACTIVATED KILLER CELLS

,—J 1 virus-infected target-cell killing

CYTOKINE RELEASE AND ADHESION MOLECULE EXPRESSION

= Adhesion molecule Q = Leucocyte

BLOOD-VESSEL LUMEN

î Cytokine release î Expression of adhesion molecules t Infiltration of leucoctyes

Inflammation and tissue damage î Platelet aggregation and cytokine release

I Cytokine release I Adhesion molecule expression I Infiltration and tissue damage I Thrombosis and vessel damage

Fig. 12.4. Effects of selenium (Se) deficiency (left-hand column) or Se supplementation (right-hand column) on cells and molecules mediating innate immunity. T signifies an increase in activity or numbers and I denotes a decline in activity or numbers. Ros, reactive oxygen species. IL-X, various interleukins.

Se deficiency

Se supplemented

Se deficiency

i IgG and IgM titres

B-CELLS

Se supplemented

T B-cell numbers

T Increase in antibody titres

Better vaccine protection against bacteria i IgG and IgM titres

T B-cell numbers

T Increase in antibody titres

Better vaccine protection against bacteria

CD4+ CELLS

T CD4+ cell death in HIV infection

T Cell numbers T Response to mitogens T T-cell help to B-cells T IL-2 receptor expression T DTH response

CD8+ T-CELLS

i CD8+ cells

T Cytotoxicity against virus-infected cells i CD8+ cells

T Cytotoxicity against virus-infected cells

Fig. 12.5. Effects of selenium (Se) deficiency (left-hand column) or Se supplementation (right-hand column) on cells and molecules mediating acquired immunity. T signifies an increase in activity or numbers and i denotes a decline in activity or numbers. HIV, human immunodeficiency virus; IL-2, interleukin-2; DTH, delayed-type hypersensitivity; Ig, immunoglobulin.

deficiency increases the severity of and mortality from parasitic, viral, fungal and bacterial infections. It is now common farm practice to supplement animal feed with Se to boost growth and disease resistance. However, excessive amounts of Se (equivalent to > 400 ^g day-1 in humans) were found to lead to toxic effects and immune suppression (Spallholz et al., 1990).

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