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Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Canada
Correspondence: Dr. Catherine J. Field, Department of Agricultural, Food and Nutritional Science, 3-18e Agriculture Forestry Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2P5. E-mail: Catherine.Field{at}ualberta.ca
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONLONG-CHAIN POLYUNSATURATED FATTY...VITAMIN AVITAMIN CVITAMIN E AND SELENIUMIRON (Fe)ZINC (Zn)NUCLEOTIDESCONCLUSIONSREFERENCES |
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Key Words: arginine • glutamine • zinc • vitamin E • vitamin A • nucleotides • docosahexaenoic acid • eicosapentaenoic acid • ascorbic acid • iron
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONLONG-CHAIN POLYUNSATURATED FATTY...VITAMIN AVITAMIN CVITAMIN E AND SELENIUMIRON (Fe)ZINC (Zn)NUCLEOTIDESCONCLUSIONSREFERENCES |
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—Hippocrates c. 460—377 B.C.
It has long been accepted that immunity (or susceptibility to disease) depends to some extent on nutrition. The interdependency between the disciplines of nutrition and immunology was formally recognized in the 1970s when immunological measures were introduced as a component of assessing nutritional status [1 ]. Our understanding of the effect of nutrients on immune function has been refined as the field of immunology has grown from a descriptive science to one in which diverse immune phenomena can be tied together coherently and explained in quite precise structural and biochemical terms.
Today protein energy malnutrition (PEM) is cited as the major cause of immunodeficiency worldwide [2 ]. This is not surprising because immune cells have a high requirement for energy and amino acids for cell division and protein synthesis. The influence of PEM on immune function has been reviewed extensively [3 ]. Our knowledge of the effects of nutrition on immune function now extends beyond clinical nutrient deficiency. A growing body of literature demonstrates the immune benefits of increasing the intake of specific nutrients. This article will review our current understanding of the role of several nutrients in maintaining host immune defense. An inadequate status of some of these nutrients occurs in many populations in the world (vitamin A, iron, and zinc) where infectious diseases are a major health concern. We will also review nutrients that may specifically modulate host defense to pathogens (long-chain polyunsaturated n-3 fatty acids, vitamin C, vitamin E, selenium, and nucleotides). We begin with a review of the effect of long-chain polyunsaturated n-3 fatty acids on host defenses to illustrate how the two disciplines of nutrition and immunology have been combined to identify key mechanisms and propose nutrient-directed management of immune-related syndromes. Because we are unable to review all nutrients that are needed to maintain immune function, the reader is directed to some excellent reviews presented in Table 1 and to a recent book published on this topic [4 ].
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LONG-CHAIN POLYUNSATURATED FATTY ACIDS (PUFA) |
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TOPABSTRACTINTRODUCTIONLONG-CHAIN POLYUNSATURATED FATTY...VITAMIN AVITAMIN CVITAMIN E AND SELENIUMIRON (Fe)ZINC (Zn)NUCLEOTIDESCONCLUSIONSREFERENCES |
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-linolenic (n-3), cannot be synthesized by mammalian cells and so
must be obtained from the diet. Linoleic acid is found in most plant
oils (e.g., corn, safflower, and sunflower), margarines, and animal
fats, whereas -linolenic acid is found in flaxseed, soybean, and
canola oils. Long-chain n-3 PUFA, eicosapentaenoic acid (EPA), and
docosahexaenoic acid (DHA) can be synthesized from -linolenic acid
in humans but can be obtained preformed from marine fish oils. These
lipids are important in brain development, cardiovascular disease, and
cancer (see ref [5
]), and there is now convincing
evidence that dietary n-3 PUFA, particularly EPA and DHA, have a major
impact on the function of many components of the immune system.
Although various effects of dietary fat on immune functions have been
reviewed previously (see refs [6
7
8
9
]), in this review we
will summarize the well-documented effects of the long-chained PUFA EPA
and DHA on host resistance to infection and other diseases in which the
immune system is important.
Clinical studies of the effects of feeding fish oil on
immunological disorders
Fish oil administered in clinical trials and in animal models of
rheumatoid arthritis, ulcerative colitis, psoriasis, and organ
transplantation has resulted in measurable beneficial effects on the
immune system (see refs [9
, 10
]).
Similarly, feeding fish oil to animals reduces disease severity and
prolongs survival in animal models of lupus (see ref
[7
]), but human trials have not been as encouraging,
with studies showing positive [11
, 12
] or
no effects [13
]. These studies generally suggest that
feeding fish oil (a source of EPA and DHA) suppresses
inflammatory/autoimmune responses during conditions of partial immune
system activation. Thus, one might conclude that these lipids would
have a negative effect on the immune system of healthy humans or
animals. Indeed, feeding high amounts of EPA/DHA has been shown to
reduce survival or pathogen clearance in some animal models of
infection; however, other studies demonstrate no effect or even
protection against infection with EPA/DHA administration to infected
animals (see ref [7
]).
Feeding n-3 PUFA has been shown to decrease tumor growth, incidence,
and/or metastasis in a large number of animal studies (reviewed in refs
[5
, 14
]) and to prolong survival of cancer
patients in a human clinical trial [15
]. It is not clear
whether these effects involve n-3 PUFA modulation of immune function.
Although there are data to support an immune-independent mechanism
[16
], studies in our laboratory have shown that feeding
n-3 PUFA to tumor-bearing animals enhances natural killer (NK) cell
activity, CD8+ T-cell activation, and interferon-
(IFN-) and
tumor necrosis factor (TNF-) cytokine production after mitogen
stimulation [17
]. We and others [17
18
19
]
have demonstrated that tumor burden itself can modulate/suppress the
host’s NK activity and the ability of T cells to respond to various
stimuli, raising the possibility that the immune response to dietary
n-3 fatty acids may differ in immune-suppressed hosts (i.e.,
tumor-bearing) compared with normal, healthy hosts.
Dietary n-3 fatty acids (EPA and/or DHA or fish oil) and the immune
system
Feeding EPA and DHA has been shown to modulate specific functions
of innate and acquired immunity. In general, feeding high levels
(>10% of total fat) of n-3 PUFA (compared with diets high in n-6
PUFA) to healthy animals or human subjects results in suppression of
the ability of lymphocytes to respond to mitogen stimulation, NK cell
activity, and delayed-type hypersensitivity (DTH) reactions
[8
, 10
]. Suppression of these functions has
been demonstrated in studies supplementing as little as 180 mg EPA + DHA/day [20
] or up to 6 g DHA/day
[21
] to the diet of humans or by feeding animals from
1% w/w purified EPA or DHA [22
] up to 20% w/w fish oil
(approximately 3.5% w/w EPA+DHA; ref [23
]). Feeding
long-chain n-3 PUFA was shown to significantly decrease the production
of interleukin (IL)-1, IL-6, and TNF- by peripheral blood
mononuclear cells in humans and by peritoneal macrophages in animals
after mitogen stimulation (see ref [9
]). However, there
is some discrepancy with respect to TNF- production in animals,
because many studies document increases in TNF- production after
stimulation when EPA/DHA were fed [9
].
Conversely, a number of studies have shown that feeding more moderate
amounts of n-3 PUFA (i.e., fed at <10% of fat to animals and <1 g
EPA+DHA/day to humans) is not immunosuppressive [24
,
25
], and can even enhance immune functions such as
lymphocyte proliferation/activation [26
27
28
], NK cell
activity [26
, 29
], macrophage activation
[26
], and IL-1, IL-2, and TNF- production after
mitogen stimulation [27
, 28
]. Recently, we
have demonstrated that adding a small amount of DHA [and arachidonic
acid (AA)] to infant formula alters the maturation (expression of the
CD45RO+ antigen on CD4+ cells) of T cells in preterm infants to be more
similar to that of infants fed human milk [30
]. These
seemingly contradictory observations of the effect of n-3 fatty acids
on immune function in healthy humans and animals may be a result of the
overall content of polyunsaturated fat in the diet. We have found that
n-3 PUFA reduce splenocyte proliferation in healthy rats when fed in a
high polyunsaturated fat diet (unpublished results), but not when fed
in a diet with a low polyunsaturated fat level (which is more
representative of the diet consumed by most North Americans).
Mechanisms by which n-3 PUFA may modulate immune function
Several potential mechanisms have been proposed to explain the
immunomodulatory effects of dietary n-3 PUFA, including effects on
eicosanoid formation, signal transduction, gene expression, and lipid
peroxidation (reviewed in refs [6
, 31
,
32
]; Table 2
).
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Modulation of eicosanoid synthesis
Dietary fat composition influences eicosanoid synthesis by
affecting the supply of substrates (n-3 and n-6 fatty acids) for
eicosanoid production. Increasing the n-3 content of the diet produces
corresponding increases in the long-chain n-3 PUFA content of cell
membranes at the expense of n-6 PUFA, particularly AA. n-3 Fatty acids
compete with AA as substrates for cyclooxygenase (involved in
eicosanoid production) and also directly suppress the activity of
cyclooxygenase; thus, they inhibit AA metabolism to eicosanoids. Higher
levels of n-3 PUFA in cell membranes reduce the production of
proinflammatory eicosanoids (i.e., PGE2, LTB4,
TXA2) from n-6 PUFA and increase the production of
eicosanoids from n-3 PUFA (PGE3, LTB5). It is
important that eicosanoids formed from n-3 PUFA oppose or have weaker
effects than eicosanoids formed from n-6 PUFA [34
]
(Table 2) . The situation, however, is complicated because
PGE2 and LTB4 have somewhat opposing effects;
although both inhibit mitogen-stimulated lymphocyte proliferation,
LTB4 tends to enhance NK activity and T helper cell
(Th)1-type cytokine production (IL-1, IL-2, IL-6, TNF-, IFN-),
whereas PGE2 suppresses these functions. Thus, the outcome
of reducing PGE2 and LTB4 by n-3 fatty acids is
not clear and likely depends on the balance of the different mediators
produced, the timing of their production, and the sensitivities of
target cells to their actions. Because many studies indicate that
dietary n-3 PUFA reduce the ability of lymphocytes to proliferate in
vitro in response to mitogen stimulation [8
], a function
expected to increase with reductions in PGE2 and
LTB4, other mechanisms besides eicosanoid formation
probably are involved in n-3 PUFA immunomodulation.
Alteration of signal transduction
Evidence suggests that changes in membrane lipid composition can
alter the binding of ligands, such as cytokines, to their receptors
[35
, 36
]. Although support is limited, it
is possible that an increase in n-3 PUFA in immune cell membranes may
modify membrane properties and subsequently interfere with
ligand-receptor interactions, leading to changes in receptor signal
transduction. Another mechanism may involve the incorporation of n-3
PUFA into signaling molecules. Because all phospholipids and some of
their second messengers, such as diacylglycerol (DAG) and ceramide,
contain fatty acyl chains, it is possible that changing the fatty acid
composition of these molecules may alter their function
[32
]. Indeed, it has been demonstrated that EPA and DHA
are incorporated into signaling molecules such as DAG with the
administration of n-3 PUFA in the diet [37
,
38
], and there is some evidence that n-3 PUFA-enriched
DAG is less potent in activating protein kinase C (PKC) than n-6
PUFA-enriched DAG [39
]. Finally, many signaling
molecules, including some tyrosine kinases, are reversibly acylated
during signaling, which targets them to the cell membrane where they
interact with other signaling molecules. It has been suggested that
changing the fatty acid content of the diet (or the culture media) may
alter the acylation patterns of different signaling molecules
[31
, 40
, 41
], affecting their
ability to interact with the membrane. Alternatively, it is possible
that changes in membrane fatty acid composition induced by changes in
diet could alter the physical nature of the membrane regions to which
acylated signaling molecules bind [40
]. Changes in early
signal transduction events such as tyrosine kinase activation could be
responsible for changes in other downstream signaling events that have
been documented with n-3 PUFA administration (see Table 2
).
ii) Alteration of gene expression: An increasing number of
published studies indicate that n-3 fatty acids can modulate expression
of various immune genes (see Table 2
). Changes in gene expression
induced by n-3 fatty acids may be the result of direct or indirect
effects of fatty acids on the transcription factors that initiate gene
expression. Recent work demonstrated that long-chain PUFA, including
EPA, can bind to and activate the class of transcription factors known
as the peroxisome proliferator-activated receptor (PPAR; refs
[42
, 43
]), providing a mechanism by which
n-3 PUFA could regulate directly gene expression. Some evidence
indicates that PPARs are involved in immune cell function, because the
activation of PPAR with natural or synthetic PPAR agonists has been
shown to inhibit macrophage activation and the production of TNF-,
IL-1, and IL-6 as well as activation of nitric oxide synthase (NOS)
[31
, 44
]. It has also been shown that
long-chain n-3 PUFA can modulate the activity of transcription factors
such as nuclear factor 
-B (NF-B) and activated protein-1 (AP-1)
[45
, 46
]. In these studies, upstream signal
transduction events were modified with n-3 PUFA treatment, which
correlated with lowered transcription factor activity, suggesting that
n-3 PUFA may affect early signal transduction events that lead to
altered transcription factor activity (see Table 2
).
iii) Lipid peroxidation: Long-chain PUFA are more sensitive to lipid peroxidation than are monounsaturated or saturated fatty acids. Thus n-3 PUFA incorporation into cell membranes may increase the host requirement for antioxidant nutrients [32 ]. Because lipid peroxides are toxic to cells, it is possible that the inhibitory effects of feeding large amounts of EPA/DHA on immune cell function could be a result of lipid peroxidation in the absence of adequate dietary antioxidants. There is some support for this mechanism (see Table 2 ), but other studies have found that supplying antioxidants does not reverse the immune effects of dietary n-3 PUFA [47 , 48 ]. Further research is needed to establish a risk for peroxidation of immune cells when n-3 PUFA are fed.
Summary
It is well accepted that long-chain n-3 PUFA have immunomodulatory
effects, but further work needs to be done to clarify their precise
effects (e.g., immunosuppression vs. immunostimulation) in healthy
subjects as well as in different disease conditions such as infection.
Exciting work has been published recently identifying several
mechanisms by which n-3 PUFA affect immune functions. Future studies
pursuing the proposed mechanisms will likely provide further insight
into the roles of n-3 PUFA in immunomodulation.
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VITAMIN A |
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Clinical and functional evidence for the essentiality of vitamin A
to the immune system
The immune efficacy of supplementing vitamin A on infection rates
has been examined in several randomized, double-blind,
placebo-controlled trials of malnourished children in various regions
of the developing world. Antibody-mediated immunity has been shown to
be severely impaired in individuals with vitamin A deficiency
[56
]. Provinding vitamin A supplements has been found to
improve the antibody titer response to measles vaccines
[57
], maintain gut integrity [58
], lower
the incidence of respiratory tract infections [59
,
60
], and reduce mortality associated with diarrhea and
measles [54
, 59
60
61
] but not pneumonia
[61
]. There is clinical data suggesting that vitamin A
deficiency in HIV-1-infected individuals contributes to mortality
[62
], disease progression [62
], and
maternal-infant disease transfer [63
, 64
].
This type of support has contributed to the World Health
Organization’s recommendation that vitamin A supplements be given to
all individuals in developing countries who contract measles whether or
not they have symptoms of vitamin A deficiency [54
]. In
animal studies, vitamin A deficiency inhibits mitogen-stimulated,
T-cell proliferation [65
66
67
68
], antigen-specific antibody
production [66
], and the ability to produce
immunoglobulin (Ig)A [69
] and IgG [70
].
It also reduces the ability of CD4 cells to provide the B-cell stimulus
for antigen (Ag)-specific IgG1 responses [70
]; limits
Th-2-type cytokine-gene expression [49
]; decreases the
ability of neutrophils to phagocytose infectious organisms
(Pseudomonas aeruginosa) and generate active oxidant
molecules [71
]; and reduces the resistance to several
infectious organisms [66
, 68
]. Most of
these negative effects on host defense that have been associated with
low vitamin A status appear to be reversible with restoration of
vitamin A status [67
, 68
, 71
,
72
].
Proposed mechanisms for the effects of vitamin A on immune function
Indirect mechanisms
Vitamin A has been shown to control differentiation of epithelial
cells by regulating the synthesis of keratin [50
], and
deficiency results in altered epithelial structure (squamous
metaplasia) and a reduced number of mucus-secreting cells
[73
] (Table 3
). The rapidly dividing epithelia at mucosal surfaces (gut and
lung) are especially susceptible to vitamin A deficiency, which results
in a loss of gap junctions between epithelial cells
[50
], increasing the risk of bacterial translocation
[58
]. In addition, vitamin A deprivation has been shown
to reduce the replication rate of basal and mucous cells and the
proportions of preciliated and ciliated cells, which would further
enhance the susceptibility to infection [55
]. Because
vitamin A is needed for glycoprotein synthesis [74
], a
deficiency of it would likely impair the synthesis of the many
glycoproteins involved in the immune response (e.g., integrins,
fibronectin, and globulins) [50
].
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, because
provision of RA has been shown to increase mRNA levels of RAR- in T
lymphocytes [75
, 76
]. Substantial evidence
supports a role for vitamin A in negatively regulating IFN-
secretion, thus influencing the development of Th-2- versus Th-1-type
responses (Table 3)
. Vitamin A deficiency in mice strongly favors the
production of IFN- (a Th-1-type cytokine) [49
,
77
], but adding RA in vitro to T lymphocytes from vitamin
A-deficient mice inhibits IFN- production [49
,
77
]. RA was shown to alter IFN- synthesis at the level
of transcription [49
], implicating direct effects of
this vitamin on cytokine genes. The promotion of Th-1-type responses,
via excessive IFN- production and limited Th-2 cell growth and
differentiation, would contribute to the impaired humoral
immune-response capacity observed in animals and humans deficient in
vitamin A [70
, 77
].
Hypothesized immune effects of excessive vitamin A intake
Although the toxic effects of excess vitamin A have not been
studied in humans, animal studies have shown excessive intakes to be
associated with toxicity, including suppressed hematopoiesis
[68
], mitogen-induced T-cell proliferation
[65
, 76
], antigen-specific antibody
production [68
], and an increased susceptibility to
infectious organisms [66
]. Although the mechanisms by
which excessive vitamin A intake depresses immune responses are not
known, some hypothesize that high circulation levels may down-regulate
nuclear receptors for vitamin A (thus decreasing transcription and
expression of several immune molecules such as cytokines), or that
there is a direct toxic effect of the elevated retinyl esters in blood
[67
].
Summary
Vitamin A is essential for cells of the immune system. The
considerable immune benefits (to cells of the innate and acquired
immune system), which would contribute to reduce the risk of various
pathogen-mediated diseases, warrants a recommendation to supplement
individuals with minimal or poor vitamin A status. Today, however,
there is not sufficient evidence to determine if there are immune
benefits of providing additional vitamin A to those with sufficient
status. Animal studies suggest that excessive intakes of vitamin A
suppress various aspects of T- and B-cell function and may even
increase the susceptibility to infectious diseases.
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VITAMIN C |
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Vitamin C intakes above the recommended daily intake and immune
function
There has been a long-standing debate concerning the possible
function of high doses of vitamin C in "boosting" immunity
(reviewed in ref [79
]). A wealth of epidemiological
studies suggest that higher intakes of vitamin C and other antioxidants
are associated with a lower risk of chronic disease (such as cancer and
cardiovascular disease, which involve the immune system to some
extent), but there have been few intervention studies that measure
specific components of the immune system. The results of animal studies
and a few human studies have suggested that immune effects, such as
antiviral resistance and anticarcinogenic effects, are increased with
higher intakes of vitamin C [79
]. However, most studies
have complicated the interpretation of the results by administering a
number of antioxidant nutrients in addition to vitamin C.
Because of the early literature review and sustained advocacy by Linus Pauling, subsequent studies on mega-dosing with vitamin C have not been shown unequivocally to prevent and/or treat colds and upper respiratory tract infections [80 ]. Some components of the study designs of several early trials demonstrating beneficial effects in this area have been challenged recently (reviewed in ref [81 ]). In a recent analysis of six large vitamin C supplementation (> or = 1 g/day) trials in Britain, four out of six studies (conducted on women) concluded that there was no evidence to support the claim that taking high doses of vitamin C decreases the incidence of colds [81 ]. However, four studies of vitamin C supplementation in male schoolchildren and students show a statistically significant reduction in the incidence of colds with vitamin C supplementation [81 ]. From this same analysis in yet another study in a group of males receiving vitamin C supplementation, the authors described a statistically significant reduction in recurrent common cold infections [81 ]. It has been suggested that physical stress and/or low nutritional intakes may have contributed to the positive effects of supplementation in some subjects [81 ], but the possibility of a beneficial effect of vitamin C on viral infections cannot be completely ruled out.
Despite the inconclusive results of the clinical trials, supplementation trials have demonstrated benefits of vitamin C supplementation on several immune functions (reviewed in ref [79 ]). For example, Delafuente et al. [82 ] demonstrated that providing 1 g of vitamin C (and 200 mg vitamin E) daily for 16 weeks resulted in a significant increase in the lymphoproliferative capacity (proliferative response to mitogens) and in the phagocytic functions of peripheral blood neutrophils (adherence to vascular endothelium, chemotaxis, and phagocytosis of latex beads and superoxide anion production) as well as a significant decrease of serum levels of lipid peroxides and cortisol, both in the healthy aged women and in the aged women with coronary heart disease.
Vitamin C and immune disorders
Vitamin C supplementation has also been shown to have some
clinical usefulness in the treatment of several autoimmune diseases,
allergy, asthma, phagocytic dysfunction disorders (Chediak-Higashi and
granulomatous disease), and immunosuppressive disorders, including HIV
(reviewed in ref [83
]). After exposure to toxic
environmental chemicals, a high oral dose of vitamin C restored the
blastogenic responses of immune cells to T- and B-cell mitogens and
enhanced NK activity tenfold in human subjects [79
,
84
]. Similarily, in animals, the toxic effects of cadmium
on the immune system (phagocytic activity of polymorphonuclear
leukocytes and monocytes and the percentage of active and total T
lymphocytes in peripheral blood) were reduced by vitamin C
supplementation [85
].
Immune toxicity associated with high intakes of vitamin C?
Unlike many other dietary antioxidants, even when consumed at very
high levels (5000 mg/day), vitamin C appears to be safe, and no
negative or suppressive effects on immune cell function (e.g., NK cell
activity, apoptosis, or cell cycle progression) or structure have been
found [86
, 87
]. One might still remain
cautious, however, because some in vitro experiments demonstrate that
very high levels of vitamin C suppress T-cell proliferation (IL-2
production) and adhesion [88
] and reduce the ability of
neutrophils to phagocytose Candida albicans
[88
]. The effect of these in vitro changes on
physiological function has not been established.
Proposed mechanisms
Many investigations have been undertaken to elucidate the
mechanism by which vitamin C might enhance systemic immunity,
particularly in defense of viral diseases (Table 4
). The actions of vitamin C as a reducing agent and oxygen-radical
quencher are well-established. Although frequently stated, exactly how
this potent antioxidant enhances immune function is not well
understood. The general belief is that reduction of free radicals will
prevent DNA damage to immune cells, thereby maintaining their
functional and structural integrity. Indeed, the immune system (which
relies heavily on membrane receptors and signals) is particularly
sensitive to oxidative stress [89
]. Several cellular
mechanisms have been identified with dietary supplementation or in
vitro treatment of immune cells that might explain a role of vitamin C
in antioxidant protection (Table 4)
. Ascorbic acid can reduce directly
[90
] or indirectly through the regeneration of vitamin E
[91
] damage to lymphocytes by reactive oxygen
intermediates (ROI). It was suggested recently that ascorbate levels
exert this effect by down-regulating ROI-dependent expression of
proinflammatory IL genes via inhibition of transcription of NF-B
[78
].
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Summary
Clearly the essentiality of vitamin C to cells of the immune
system has been established. Although not all clinical data agree with
an effect of vitamin C on viral infections, there is convincing
evidence from feeding studies in humans and animals and experiments
done on primary cultures that vitamin C has a positive effect on host
defense. Unfortunately, we are far from being able to define the
optimal levels of intake required to maintain an optimal immune
response to prevent or treat viral or other infectious diseases.
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VITAMIN E AND SELENIUM |
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-tocopherol) and the trace element selenium (Se) are
discussed together as they function synergistically (by related but
independent mechanisms) in tissues to reduce damage to lipid membranes
by the formation of reactive oxygen species (ROS) during infections
[93
].
Influence of vitamin E on immune function
Several excellent reviews describe the effects of vitamin E on
various immune parameters [94
95
96
]. Vitamin E is a lipid
soluble antioxidant, and deficiency results in increased free
radical-induced membrane damage to red blood cells [73
].
The effect of providing vitamin E to individuals at risk of deficiency
(i.e., elderly) has been reviewed recently [97
,
98
]. Supplementation with vitamin E to those believed to
have marginal status increased DTH skin test response, enhanced
mitogen-induced lymphocyte proliferation and IL-2 production, and
improved the antibody (Ab) responses to vaccines, while decreasing the
synthesis of the immunosuppressive eicosanoid PGE2
[99
, 100
]. Similarly, supplementing old
rats with vitamin E alleviated the age-related impairment in some
immune functions (e.g., lymphocyte proliferation, IL-2 production, and
macrophage function) [101
].
Providing vitamin E to healthy individuals was shown to increase the CD4/CD8 ratio, enhance T-cell proliferation, and lower measures of oxidative stress (urinary, plasma, and peripheral blood lymphocyte H2O2 production; ref [102 ]). However, supplementation of vitamin E to "healthy" individuals did not attenuate oxidative DNA damage in peripheral blood lymphocytes [103 ]. Animal studies support the immune benefits of supplemental vitamin E, which increased CD4+CD8- thymocytes and IL-2 production in rodents [104 , 105 ], and improved responses to infection in swine [106 ].
The optimal intake of vitamin E required to provide immune benefits has not been established and likely depends on vitamin E status and the presence or absence of other conditions. Studies have demonstrated immune effects with 200–800 mg/day doses [94 , 100 ]. Vitamin E is generally considered safe when supplemented in very high amounts [73 ]. However, providing 300 mg/day (considered megadose) of vitamin E for three weeks depressed the bactericidal activity and proliferation of peripheral leukocytes in humans [107 ] and reduced vaccine titers in animals (150 mg/kg) [108 ], indicating that there may be an upper limit above which immune impairment results.
Influence of Se on immune function
Se plays a role in balancing the redox state of the cell and
removing reactive oxygen species, which likely contributes to its
anti-inflammatory effects [109
]. Se deficiency has been
shown to decrease the production of free radicals and killing by
neutrophils [110
], IL-2R affinity and expression on T
cells [111
, 112
], T-cell proliferation and
differentiation [111
, 113
], and lymphocyte
cytotoxicity [111
, 114
]. Se deficiency in
vitro enhances neutrophil adherence to endothelial cells, an important
preliminary event in inflammation [115
]. These
alterations in immune function likely contribute to the increased
cancer susceptibility associated with Se deficiency and implicate Se
deficiency in the pathogenesis and exacerbation of some chronic
inflammatory and viral diseases [110
].
Conversely, supplementation with Se increases lymphocyte proliferation, expression of the high-affinity IL-2R [116 ], cytolytic T lymphocyte (CTL) tumor destruction, and NK-cell function in humans [117 ] and increases lymphocyte proliferation, IL-2R expression, and macrophage and CTL tumor cytotoxicity in mice [111 , 113 , 118 ]. There is also substantial evidence for a benefit of providing Se during HIV-1 infection, where it has been demonstrated to reduce oxidative stress, modulate cytokine synthesis (increase IL-2; decrease TNF and IL-8), improve T-cell proliferation and differentiation, and reduce cytokine-induced HIV-1 replication [119 ]. Recently, it was demonstrated that Se deficiency in the host enhances the mutation rate of coxsackievirus [120 ] and influenza A virus [121 ]. This suggests that the oxidative stress status of the host can alter the genome and pathogenicity of an infectious virus [121 ]. Although the amount of Se necessary for maximum immune benefit has not been established, it has been suggested that 200 mg/day may be sufficient [116 ]. However, excessive intakes of Se are toxic to many tissues and are associated with impaired cell-mediated and humoral immunity [110 ].
Proposed mechanisms for the effects of vitamin E and Se on immune
function
Vitamin E is an oxidant scavenger that acts to protect cell
membranes from damage by reactive oxygen species (Table 5
). Immune cells are particularly susceptible to oxidative damage
because of their highly unsaturated membranes [122
] and
their ability to produce large amounts of free radicals (i.e., during
inflammation; ref [102
]). The ability of vitamin E to
scavenge lipid soluble-free radicals is dependent to some extent on the
status of two other antioxidant compounds, vitamin C and glutathione,
which are involved in reducing oxidized vitamin E back to a reusable
(i.e., able to be oxidized) form [91
]. Additionally,
vitamin E may improve T-cell function by decreasing macrophage
PGE2 production by modulating the AA cascade initiated by
lipoxygenase and/or cyclooxygenase [91
,
94
]. Furthermore, vitamin E influences lymphocyte
maturation, possibly by stabilizing membranes and allowing enhanced
binding of antigen-presenting cells (APC) to immature T cells via
increased expression of intercellular adhesion molecule-1 (ICAM-1;
Table 5
) [105
].
|
B [110
]. In addition to
reducing thioredoxin, this enzyme breaks down hydroperoxide and lipid
peroxides in the presence of reduced nicotinamide adenine dinucleotide
phosphate (NADPH) more efficiently than GPX [110
], thus
making it an effective protector against ROS.
In addition to its antioxidant role, Se may have additional immune
properties involving membrane receptor expression. The stimulation of
T-cell proliferation, CTL and macrophage cytotoxicity, and NK activity
by Se may be a result of the ability of Se to enhance the expression of
the and/or ß subunits of the IL-2R on these activated immune
cells [111
, 114
, 123
]. This
results in a greater number of functional IL-2R/cell and in enhanced
proliferation and clonal expansion of cytotoxic precursor cells
[123
]. Se deficiency causes in increased neutrophil
adhesion and increased expression of E-selectin and ICAM-1
[115
], suggesting that Se can down-regulate neutrophil
activation.
Summary
Vitamin E and Se are essential to immune function and are
supplemented routinely in the diets of domestic animals for their
immune benefits [94
]. These nutrients have long been
known to have anticarcinogenic effects by means of their antioxidant
properties. The potential of Se as a chemopreventive agent also
involves its ability to enhance the clonal expansion of
immunocompentent cells [NK cells, CTL, and lymphokine-activated killer
(LAK)] [111
]. Further research into the mechanisms of
these nutrients would be beneficial, particularly in terms of how they
influence expression of cell-surface molecules.
|
IRON (Fe) |
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TOPABSTRACTINTRODUCTIONLONG-CHAIN POLYUNSATURATED FATTY...VITAMIN AVITAMIN CVITAMIN E AND SELENIUMIRON (Fe)ZINC (Zn)NUCLEOTIDESCONCLUSIONSREFERENCES |
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Iron and immune function
It is well-documented that iron regulates the function of T
lymphocytes, and in most studies (in vivo and in vitro), a deficiency
results in impaired cell-mediated immunity [124
,
125
, 127
128
129
]. Iron deficiency may also
delay the development of cell-mediated immunity [124
].
Immune cells appear to differ from one another in their synthesis and
use of iron-binding proteins and in the amount of iron they take up and
store; this suggests that there would be differential effects of iron
status on various immune functions [130
]. Details on
iron metabolism in immune cells have been reviewed elsewhere
[128
]. Numerous studies describe normal
T-lymphocyte-proliferative responses to mitogens and limited effect on
other immune functions in humans and animals with mild-to-moderate iron
deficiency (reviewed in ref [124
]). This suggests that
the immune response may not be impaired by alterations in iron
availability to the same extent as are other organs. Indeed,
lymphocytes meet an increased iron requirement during proliferation or
other conditions by increasing the synthesis and expression of surface
transferrin receptors [131
]. This, along with the
clinical and experimental data, suggests that T cells may be able to
sequester iron better than other cells when there is a limited iron
supply, and only in a "deficient state" might the essentiality of
iron to the immune system be evident. Humoral immunity may be less
affected by iron deficiency than cellular immunity, because antibody
production in response to immunization with most antigens is preserved
in animals and humans with poor iron status (reviewed in refs
[124
, 125
]).
Neutrophil function (decreased myeloperoxidase activity and
bactericidal activity) and NK activity are impaired with iron
deficiency [125
]. Macrophage phagocytosis is generally
unaffected by iron deficiency, but bactericidal activity of these cells
is attenuated [132
]. It has been proposed that the
immunosurveillance role of macrophages may be mediated in part by
modulation of iron status in cells [133
]. Unlike other
cells, macrophages acquire iron for metabolic use via phagocytosis of
effete erythrocytes, which is subsequently released into the
circulation, where it is bound to transferrin and available to other
cells [124
, 126
]. When activated (i.e.,
during inflammation, possibly signaled by IL-1 and IFN-),
macrophages increase their uptake of iron and bind it in the cells (via
increased transferrin receptors and ferritin synthesis; refs
[124
, 126
]). This sequestration of iron in
macrophages has been proposed to be beneficial during the early, acute
stages of infection with pathogens, because it would limit availability
to microorganisms (particularly intracellular microorganisms); however,
it would also limit availability to other immune cells, and this would
impair host resistance [125
, 126
,
134
].
Many of the immune abnormalities associated with iron deficiency appear to be reversible with iron repletion, but this has been difficult to demonstrate in clinical and observational studies [125 ]. Experimental and clinical data suggest that there is an increased risk of infection during iron deficiency, although a few studies indicate otherwise (reviewed in ref [125 ]). Interpretation of many of the human studies is confounded by the existence of multiple nutrient deficiencies and uncontrollable environmental factors associated with poverty [124 ]. Experimental studies in laboratory animals uniformly show reversible deleterious effects of iron deficiency on most measures of functional immunity (reviewed in ref [125 ]). Many of these effects appear to occur even in mild-to-marginal iron-deficient states in animal studies [125 ]. However, as discussed above, there is still little information available on whether mild or moderate iron deficiency influences immune effects in humans [125 ].
Iron supplementation and immune function
The major dilemma in alleviating iron deficiency revolves around
the relationship between iron repletion/supplementation and increased
morbidity from acute and chronic infections (reviewed in refs
[124
, 125
, 135
,
136
]). Microbiology studies show a close relationship
between the availability of iron and bacterial virulence (reviewed in
ref [125
]); one might conclude therefore that providing
iron would benefit the infectious organisms. Indeed, it is well
established that administration of parenteral iron has been shown in
human and animal studies to be harmful when administered during
infection [134
]. This unresolved debate has been
reviewed extensively [125
], and it was concluded
recently that there is little evidence that oral iron supplementation
to deficient individuals inhibits immune function or increases the
susceptibility to most infectious agents (with the possible exceptions
of malaria-related disease, HIV, and tuberculosis)
[125
]. Animal studies of morbidity that have used a wide
range of infectious organisms are even less consistent, and a recent
study concluded that iron deficiency may be more likely to protect
against intracellular (i.e., plasmodia, mycobacteria, and invasive
salmonella) than extracellular pathogens [125
]. This is
likely a function of the ability of the organism to acquire iron from
the host [125
].
Mechanisms for the importance of iron to the immune system
The molecular and cellular mechanisms responsible for immune
changes during iron deficiency are complex and remain unclear. This is
because iron is important in several crucial, metabolic pathways in
immune cells. Knowledge concerning the roles of iron and iron-binding
proteins in lymphocyte physiology and pathology has developed rapidly
over the last few years. The genes for the major iron-binding proteins
have been cloned and sequenced and are now being studied regarding
transcriptional and posttranscriptional regulatory mechanisms in T
cells, B cells, macrophages, and NK cells [130
]. Some of
the known cellular and molecular changes associated with iron
deficiency are summarized in Table 6
.
|
Summary
Iron deficiency remains a public health nutrition problem
affecting millions of children and women of child-bearing age. This
nonexhaustive review supports the essential role of iron in immune
function, the potential deleterious effects of supplementation during
some infections, and the potential for iron toxicity.
|
ZINC (Zn) |
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TOPABSTRACTINTRODUCTIONLONG-CHAIN POLYUNSATURATED FATTY...VITAMIN AVITAMIN CVITAMIN E AND SELENIUMIRON (Fe)ZINC (Zn)NUCLEOTIDESCONCLUSIONSREFERENCES |
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Clinical and experimental evidence for the essentiality of zinc
A number of experimental trials have examined the ability of Zn to
improve immune function during various diseases. For example, Zn
supplementation resulted in a reduced duration and severity of cold
symptoms [147
]. However, other studies have shown that
Zn compounds appear to have limited effectiveness for common cold
treatment [148
, 149
], and a meta-analysis
of eight published, randomized clinical trials showed that the evidence
for effectiveness of Zn salts lozenges in reducing the duration of
common colds is still lacking [150
]. In patients with
sickle-cell disease, Zn supplementation increased IL-2 production,
decreased incidence of bacteriologically positive infections, decreased
the number of hospitalizations, and decreased the number of
vasoocclusive pain crises [151
]. In young children, Zn
supplementation reduced diarrhea duration [152
153
154
],
pneumonia [155
], growth-stunting [154
,
156
, 157
], acute lower respiratory
infections and morbidity [157
, 158
],
respiratory morbidity, incidence of dysentery, and altered intestinal
permeability [112
, 153
]. Children receiving
Zn supplementation had a significantly higher proportion of CD4+CD3+
cells (CD3, CD4, and CD4/CD8 ratio) in peripheral blood and improved
T-cell-mediated immunity (CMI) [159
].
Animal studies have confirmed that Zn deficiency is associated with a significant reduction in T-helper cell function [160 ], impaired DTH responses [161 ], compromised B-cell development [145 ], low IgG production [162 ], decreased NK lytic activity [141 , 146 ], and increased mortality to various infectious organisms [163 ]. Maternal Zn deprivation results in offspring with reduced thymus and spleen size, splenocyte numbers, mitogen responses [164 ], and antibody production [165 ]. However, the poor Ab-mediated response capacity and defective DTH could be restored by Zn supplementation [161 , 165 ]. It is interesting that the effects of Zn deficiency may be immune cell-type specific, because one study suggests that myeloid cell numbers and function are not compromised by such a deficiency [166 ].
Proposed mechanisms for the immune essentiality of zinc
The proposed mechanisms by which Zn influences immune functions
include generation of oxygen radicals, lymphocyte maturation, cytokine
production, and the regulation of apoptosis and gene expression as
described in Table 7
.
|
Furthermore, the capacity of macrophages to engulf and kill parasites can be restored after treatment with Zn [169 ]. Whether impaired killing ability of macrophages is a result of decreased production of H2O2 or of another Zn-related function or process remains to be established [168 ].
The decreased cell-mediated immune functions and the increased
frequency of infection in Zn-deficient subjects [170
]
may be linked to the effects of Zn on cytokine production (decreased
IL-2 production), a decrease in CD4+/CD8+ cell ratio, and a decrease in
the production of antigen mature CD4+CD45R0+ cells, suggesting an
effect on T-helper cell maturation (Table 7)
. Zn influences the
activity of multiple enzymes at the basic level of replication and
transcription [146
]. For example, Zn is needed for the
activity of thymidine kinase during the S-phase of cell growth
[171
] and for the activation of the Zn finger protein
NF-B that is involved in IL-2 and IL-2R expression
[146
]. In Zn-deficient cells, the activation,
translocation, and binding of NF-B to DNA are inhibited
[146
]. NK activity and cytotoxic T-cell precursors
(CD8+CD73+) are decreased with Zn restriction [170
,
172
], which may be linked to decreased IL-2 production.
Zn deficiency is also associated with an increase in plasma
corticosterone, which can contribute to T-cell immunosuppression
[160
].
Some of the changes in T-cell maturation and function observed during Zn deficiency are likely related to decreases in Zn-dependent thymulin activity [143 ]. Zn deficiency in experimental animals results in atrophy of thymic and lymphoid tissue [143 ], with losses of precursor T and B cells in the bone marrow [140 ]. This is demonstrated by the dose-related decline in the number of pre-B cells (B220+) [173 , 174 ], immature B cells (B220+IgM+IgD-) [173 ], and mature B cells (IgM+IgD+) [173 ].
In vitro, low concentrations of Zn have been shown to induce apoptosis in mouse CD4+CD8+ thymocytes, [175 ], whereas high zinc concentrations have been shown to block apoptosis [144 ]. In vitro, high concentrations of Zn blocked apoptosis by preventing activation of the endonuclease, which is involved in DNA fragmentation [176 ] and inhibited steroid binding (possibly by binding to the vicinal cysteines in the receptor-ligand-binding site) [144 ] to the glucocorticoid receptor during glucocorticoid-induced apoptotic death.
Summary
Although clinical Zn deficiency is more common in children and in
elderly persons [140
], it is estimated that a large
proportion of the North American population has marginal intakes of Zn
and may be at risk of deficiency. The evidence is quite convincing that
ensuring an adequate intake of Zn is essential to optimal immune
function and protection from infectious pathogens.
|
NUCLEOTIDES |
|---|
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TOPABSTRACTINTRODUCTIONLONG-CHAIN POLYUNSATURATED FATTY...VITAMIN AVITAMIN CVITAMIN E AND SELENIUMIRON (Fe)ZINC (Zn)NUCLEOTIDESCONCLUSIONSREFERENCES |
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Animals fed nucleotide-free diets suffer impaired cellular and humoral immune function, including decreased NK cell and macrophage activity [181 ], lower DTH responses and cytokine production [182 ], decreased antibody production [178 ], and increased susceptibility to infections [182 ]. The addition of nucleotides to nucleotide-free diets has been shown to reverse or restore many of the changes observed with nucleotide deficiency, such as increasing Th1-type cytokines [183 184 185 ], increasing antibody production (IgG2a; refs [184 , 186 ]), and increasing spleen cell proliferation [185 ]. In addition, human infants fed breast milk or formula supplemented with nucleotides had higher NK cell activity and IL-2 production compared with infants fed formula without nucleotides [181 ]. The beneficial effects of additional dietary nucleotides on immune function are supported by animal studies [187 ]. Clinical benefits (i.e., shorter hospital stays and reduced incidence of infection among critically ill patients) have also been demonstrated with the use of enteral formulas containing nucleotides [188 ]. Unfortunately, many studies examining nucleotide supplementation have fed mixtures that contain other "immunonutrients" (e.g., fish oil and amino acids), making it impossible to identify specific nucleotide effects on immune and clinical parameters.
The precise mechanism by which exogenous nucleotides modulate immune function is not known, but it is logical that they would contribute to the pool of nucleotides available to immune cells [181 ]. Nucleotides are building blocks for DNA and RNA synthesis and are involved in diverse cellular processes, serving as sources of chemical energy [e.g., 5'-triphosphate (ATP)] and intracellular signals (e.g., adenosine cyclic 3',5'-adenosine monophosphate and cyclic 3'5'-guanosine monophosphate) [189 ]. Further research is needed to identify the specific functions and mechanisms and to define the importance of these nutrients, particularly in feeding situations such as enteral supplements and infant formula where the intake of nucleotides would be low.
|
CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONLONG-CHAIN POLYUNSATURATED FATTY...VITAMIN AVITAMIN CVITAMIN E AND SELENIUMIRON (Fe)ZINC (Zn)NUCLEOTIDESCONCLUSIONSREFERENCES |
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ACKNOWLEDGEMENTS |
|---|
Received October 12, 2001; accepted October 15, 2001.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONLONG-CHAIN POLYUNSATURATED FATTY...VITAMIN AVITAMIN CVITAMIN E AND SELENIUMIRON (Fe)ZINC (Zn)NUCLEOTIDESCONCLUSIONSREFERENCES |
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