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Selected vitamins and trace elements support immune function by strengthening epithelial barriers and cellular and humoral immune responses

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Adequate intakes of micronutrients are required for the immune system to function efficiently. Micronutrient deficiency suppresses immunity by affecting innate, T cell mediated and adaptive antibody responses, leading to dysregulation of the balanced host response. This situation increases susceptibility to infections, with increased morbidity and mortality. In turn, infections aggravate micronutrient deficiencies by reducing nutrient intake, increasing losses, and interfering with utilization by altering metabolic pathways. Insufficient intake of micronutrients occurs in people with eating disorders, in smokers (active and passive), in individuals with chronic alcohol abuse, in certain diseases, during pregnancy and lactation, and in the elderly. This paper summarises the roles of selected vitamins and trace elements in immune function. Micronutrients contribute to the body's natural defences on three levels by supporting physical barriers (skin/mucosa), cellular immunity and antibody production. Vitamins A, C, E and the trace element zinc assist in enhancing the skin barrier function. The vitamins A, B6, B12, C, D, E and folic acid and the trace elements iron, zinc, copper and selenium work in synergy to support the protective activities of the immune cells. Finally, all these micronutrients, with the exception of vitamin C and iron, are essential for antibody production. Overall, inadequate intake and status of these vitamins and trace elements may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition. Therefore, supplementation with these selected micronutrients can support the body's natural defence system by enhancing all three levels of immunity.
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Selected vitamins and trace elements support immune function by
strengthening epithelial barriers and cellular and humoral immune responses
Silvia Maggini
1
*, Eva S. Wintergerst
2
, Stephen Beveridge
1
and Dietrich H. Hornig
3
1
Bayer Consumer Care Ltd, Peter Merian-Strasse 84, P.O. Box, 4002 Basel
2
Bayer Diabetes Care Ltd, Peter Merian-Strasse 84, P.O. Box, 4002 Basel and
3
Reinach, Switzerland
Adequate intakes of micronutrients are required for the immune system to function efficiently. Micronutrient deficiency suppresses immunity by
affecting innate, T cell mediated and adaptive antibody responses, leading to dysregulation of the balanced host response. This situation increases
susceptibility to infections, with increased morbidity and mortality. In turn, infections aggravate micronutrient deficiencies by reducing nutrient
intake, increasing losses, and interfering with utilization by altering metabolic pathways. Insufficient intake of micronutrients occurs in people
with eating disorders, in smokers (active and passive), in individuals with chronic alcohol abuse, in certain diseases, during pregnancy and lacta-
tion, and in the elderly. This paper summarises the roles of selected vitamins and trace elements in immune function. Micronutrients contribute to
the body’s natural defences on three levels by supporting physical barriers (skin/mucosa), cellular immunity and antibody production. Vitamins A,
C, E and the trace element zinc assist in enhancing the skin barrier function. The vitamins A, B
6
,B
12
, C, D, E and folic acid and the trace elements
iron, zinc, copper and selenium work in synergy to support the protective activities of the immune cells. Finally, all these micronutrients, with the
exception of vitamin C and iron, are essential for antibody production. Overall, inadequate intake and status of these vitamins and trace elements
may lead to suppressed immunity, which predisposes to infections and aggravates malnutrition. Therefore, supplementation with these selected
micronutrients can support the body’s natural defence system by enhancing all three levels of immunity.
Vitamins B
6
: Folate: B
12
: C: A: D: E: Trace elements Selenium: Zinc: Copper: Iron; Effects on immune response: Nutrient deficiency:
Supplementation
Excellent reviews on the immune system are available
1–4
. The
immune system is an intricate network of specialized tissues,
organs, cells, and chemicals protecting the host from infec-
tious agents and other noxious insults. The immune response
to invaders can be divided into two interactive systems:
innate and adaptive immunity. Innate immunity is present at
birth and provides the first barrier against “invaders” consist-
ing of e.g. skin, mucus secretions, and the acidity of the
stomach. Adaptive immunity is the second barrier to infection
and is acquired later in life, such as after an immunization or
successfully fighting off an infection. It retains a memory of
all the invaders it has faced and this accelerates antibody pro-
duction. Although defence mechanisms of innate and adaptive
immunity are very complex, they can be described as being
organized in three main clusters: physical barriers (e.g. skin,
mucosa, mucus secretions), immune cells and antibodies.
Inter-individual variations in many immune functions exist
within the normal healthy population and are due to genetics,
age, gender, smoking habits, habitual levels of exercise, alco-
hol consumption, diet, stage in the female menstrual cycle,
stress, etc
5
. Nutrient status is an important factor contributing
to immunocompetence and the profound interactions among
nutrition, infection, and health have been recognised
6,7
. In the
recent decade, substantial research has focused on the role of
nutrition and especially on the contribution of the role of
micronutrients to an optimum functioning of the immune
system. The objective of this overview is to demonstrate
that selected micronutrients work in synergy and support the
different components of the immune system such as physical
barriers, cellular response and antibody production. An
inadequate or deficient micronutrient status negatively influ-
ences the body’s defences and thus impairs the body’s overall
ability to combat infections (Table 1).
Vitamins and immune function
Vitamin A
Vitamin A, acting via all-trans retinoic acid, 9-cis retinoic
acid, or other metabolites and nuclear retinoic acid receptors,
plays an important role in the regulation of innate and cell-
mediated immunity and humoral antibody response
8,9
. In vita-
min A deficiency the integrity of mucosal epithelium is
altered. As a consequence, an increased susceptibility to var-
ious pathogens in the eye, and in the respiratory and gastroin-
testinal tracts is observed. Vitamin A deficient children have
an increased risk of developing respiratory disease
10
, and
increased severity of diarrhoeal disease
11
. The benefits of vita-
min A supplementation in reducing the morbidity and mor-
tality from acute measles in infants and children, diarrhoeal
diseases in pre-school children in developing countries,
acute respiratory infections, malaria, tuberculosis, and infec-
tions in pregnant and lactating women have been
reviewed
12 14
.
* Corresponding author: Dr Silvia Maggini, fax þ 41 58 272 7502, email silvia.maggini.sm@bayer.ch
British Journal of Nutrition (2007), 98, Suppl. 1, S29–S35 doi: 10.1017/S0007114507832971
q The Authors 2007
British Journal of Nutrition
Vitamin A deficiency is associated with diminished phago-
cytic and oxidative burst activity of macrophages activated
during inflammation
15
, and a reduced number and activity of
natural killer (NK) cells
16
. The increased production of IL-
12 (promoting T cell growth) and pro-inflammatory TNF-a
(activating microbicidal action of macrophages) in a vitamin
A deficient state may promote an excessive inflammatory
response, but supplementation with vitamin A can reverse
these effects
17
.
Lymphocyte proliferation is caused by activation of reti-
noic acid receptors and therefore vitamin A is playing an
essential role in the development and differentiation of Th1
and Th2 lymphocyte subsets
18
. Vitamin A maintains the
normal antibody mediated Th2 response by suppressing IL-
12, TNF-a, and IFN-g production of Th1 lymphocytes. As
a consequence, in vitamin A deficiency there is an impaired
ability to defend against extracellular pathogens
19
. Antibody-
mediated immunity is strongly impaired in vitamin A
deficiency
20
. Oral vitamin A supplementation increases
delayed type hypersensitivity (DTH) in infants which may
reflect vitamin A-related up-regulation of lymphocyte func-
tion
21
. In humans, vitamin A supplementation has been
shown to improve antibody titre response to various vac-
cines
22,23
.
Vitamin D
Besides the effects in calcium and bone metabolism, vitamin
D and especially its biologically active metabolite 1,25-dihy-
droxycholecalciferol (1,25(OH)
2
D3) act as powerful immu-
noregulators
24 26
. The discovery of significant quantities of
vitamin D receptors in monocytes, macrophages, and thymus
tissue suggests a specific role of vitamin D and its metabolites
in the immune system. Most cells of the immune system
except B cells express vitamin D receptors
27
.
There is evidence from human epidemiological and animal
studies that vitamin D status influences the occurrence of
Th1-mediated autoimmunity diseases which is in accordance
with the ability of 1,25(OH)
2
D3 to inhibit maturation of
dendritic cells (DC) and down-regulate production of the
immunostimulatory IL-12, and the observed increase in immu-
nosuppressive IL-10
28,29
. Human epidemiological studies
indicate supplementation with 1,25(OH)
2
D3 as an independent
protective factor influencing the occurrence of Th-1 mediated
autoimmunity
30,31
.
1,25(OH)
2
D3 acts as an immune system modulator, pre-
venting excessive expression of inflammatory cytokines and
increasing the ’oxidative burst’ potential of macrophages. Per-
haps most importantly, it stimulates the expression of potent
anti-microbial peptides, which exist in neutrophils, monocytes,
NK cells, and in epithelial cells lining the respiratory tract
where they play a major role in protecting the lung from infec-
tion
32
. Volunteers inoculated with live attenuated influenza
virus are more likely to develop fever and serological evi-
dence of an immune response in the winter, a period of the
year characterized by vitamin D insufficiency
32
. Vitamin D
deficiency predisposes children to respiratory infections.
Ultraviolet radiation (either from artificial sources or from
sunlight) reduces the incidence of viral respiratory infections,
as does cod liver oil (which contains vitamin D)
32
.
Vitamin E
Free radicals and lipid peroxidation are immunosuppressive and
due to its strong lipid-soluble antioxidant activity vitamin E is
able to optimise and enhance the immune response. Supplemen-
tation with vitamin E increases lymphocyte proliferation in
response to mitogens, production of IL-2, NK cell cytotoxic
activity, and phagocytic activity by alveolar macrophages, and
causes an increased resistance against infectious agents indicat-
ing that higher vitamin E intake is promoting a Th1 cytokine
mediated response and suppressing a Th2 response
33
.
Immune function in humans declines with age (immunose-
nescence). Alterations include impaired T cell-dependent
functions such as T-cell proliferation to mitogens, antibody
response after primary immunization with T-cell dependent
antigens, impaired DTH and IL-2 production, whereas IL-4
and IL-6 are elevated. These findings could indicate a shift
from a pro-inflammatory Th1 to a more anti-inflammatory
Th2 cytokine response due to ageing
34 36
. Since deregulation
of the responses with age is associated with a higher morbidity
and mortality from infections and neoplastic diseases, vitamin
E has been investigated in human studies with regard to its
potential to improve the overall immune response, especially
in the elderly
37 46
. Further support for a more specific role
of vitamin E is provided by the finding that vitamin E sup-
plementation increases IL-2 production of T cells and
enhances a Th1 response and decreased the expression of
IL-4, a stimulator of Th2 response. Other studies indicate
that vitamin E causes a shift toward greater proportions of
antigen-experienced memory T cells with fewer naive T
cells
47
. Recent reviews comprehensively confirmed the
role of vitamin E and immunity in man, especially in the
elderly
4,33
.
Vitamin C
Reactive oxygen species (ROS), generated by activated immune
cells during the process of phagocytosis, can be scavenged by
non-enzymatic antioxidants, such as vitamin C or by enzyme
action. Whereas ROS play essential roles in intracellular killing
of bacteria and other invading organisms, the immune system
and other body’s molecules may be vulnerable to oxidative
attack. If ROS are produced in high concentrations, this fact
can cause oxidative stress and lead to impaired immune
response, loss of cell membrane integrity, altered membrane
Table 1. Summary of the sites of action of micronutrients on the
immune system
Epithelial barriers Cellular immunity Antibody production
Vitamin A Vitamin A Vitamin A
Vitamin C Vitamin B
6
Vitamin B
6
Vitamin E Vitamin B
12
Vitamin B
12
Zinc Vitamin C Vitamin D
Vitamin D Vitamin E
Vitamin E Folic acid
Folic acid Zinc
Iron Copper
Zinc Selenium
Copper
Selenium
Silvia Maggini et al.S30
British Journal of Nutrition
fluidity, and alteration of cell-cell communication. These
alterations could contribute to degenerative disorders such as
cancer and cardiovascular disease
7,48,49
.
The immune-enhancing role of vitamin C has recently been
reviewed
50
. Vitamin C is highly concentrated in leukocytes
and is used rapidly during infection. In fact, it has been
defined as a stimulant of leukocyte functions, especially of
neutrophil and monocyte movement. Vitamin C supplements
have been shown to enhance neutrophil chemotaxis in healthy
adults (1 3 g/day) and children (20 mg/kg/day)
51
. In addition,
supplementation with vitamin C has been demonstrated to
stimulate the immune system by enhancing T-lymphocyte pro-
liferation in response to infection increasing cytokine pro-
duction and synthesis of immunoglobulins
52
. Vitamin C may
also play a significant role in the regulation of the inflamma-
tory response
53
.
Administration of vitamin C results in improvement in
several components of human immune response such as
anti-microbicidal and NK cell activities, lymphocyte pro-
liferation, chemotaxis, and DTH response
54 57
. Based on
its immune-stimulating properties
51
, vitamin C was postu-
lated to be effective in ameliorating symptoms of upper res-
piratory tract infections, especially the common cold.
Further, plasma and leukocyte vitamin C concentrations
fall rapidly with the onset of the infection and return to
normal with the amelioration of the symptoms suggesting
dosage with vitamin C could be beneficial for the recovery
process
58
. A review of the large numbers of studies on a
potential effect of vitamin C on the common cold and res-
piratory infections concluded that administration of more
than 1 g/day had no consistent effect on the incidence of
common colds, but supported a moderate benefit on duration
and severity of symptoms which may also be of economic
advantage
59
.
Vitamin B
6
Vitamin B
6
is essential in nucleic acid and protein biosyn-
thesis, hence an effect on immune function is logical, since
antibodies and cytokines built up from amino acids and
require vitamin B
6
as coenzyme in their metabolism
60,61
.
Human studies demonstrate that vitamin B
6
deficiency
impairs lymphocyte maturation and growth, and antibody pro-
duction and T-cell activity. Lymphocyte mitogenic response is
impaired by dietary vitamin B
6
depletion in elderly subjects
and restored by administration of vitamin B
6
. Effects of
deficiency were seen in a decreased antibody DTH response,
IL-1-b, IL-2, IL-2 receptor, NK cell activity, and in lympho-
cyte proliferation
62 64
.
Marginal vitamin B
6
deficiency alters the percentage of
T-helper cells and slightly decreased serum immunoglobulin
D
65
. Marginal vitamin B
6
deficiency in the elderly is associ-
ated with decreased numbers and function of circulating
T-lymphocytes which can be corrected by short-term
(6 weeks) supplementation with 50 mg of vitamin B
6
/day
66
.
Decreased IL-2 production, T lymphocyte numbers, and T
lymphocyte proliferation is observed in subjects undergoing
vitamin B
6
depletion, indicating that vitamin B
6
deficiency
suppresses a Th1 and promotes a Th2 cytokine mediated
activity, whereas repletion reverses it
20
.
Folate
Folate plays a crucial role in nucleic acid and protein synthesis
by supplying in concert with vitamins B
6
and B
12
one-carbon
units, and therefore inadequate folate significantly alters the
immune response. Folate deficiency modulates immune com-
petence and resistance to infections and affects cell-mediated
immunity by reducing the proportion of circulating T lympho-
cytes and their proliferation in response to mitogen activation.
This effect in turn decreases resistance to infections
67
.
In vitro data suggest that folate status may affect the
immune system by inhibiting the capacity of CD8
þ
T lympho-
cytes cells to proliferate in response to mitogen activation.
This might explain the observation that folate deficiency
enhances carcinogenesis, next to increased damage to DNA
and altered methylation capacity
68
.
Folate supplementation of elderly individuals improves
overall immune function by altering the age-associated
decrease in NK cell activity supporting a Th1 response thus
providing protection against infections
69
. Large intakes of
folic acid (folate-rich diet and supplements . 400 mg/day)
were shown in one study to possibly impair NK cytotoxicity
69
,
whereas another study reported no correlation between total
plasma folate concentration and NK cell cytotoxicity in Italian
elderly
70
.
NK activity was followed in a trial with 60 healthy subjects
aged over 70 years who received over 4 months in addition to
the regular diet a special nutritional formula providing, among
other nutrients, 400 mg folic acid, 120 IU vitamin E and 3·8 mg
vitamin B
12
. NK cell cytotoxicity increased in supplemented
subjects and decreased in non-supplemented participants. Sup-
plemented subjects reported less infections, suggesting that
this nutritional supplement increased innate immunity and
provided protection against infections in elderly people
71
.
Vitamin B
12
Vitamin B
12
is involved in carbon-1 metabolism and there are
interactions with folate metabolism. In a vitamin B
12
-deficient
state the irreversible reaction that forms 5-methyl tetrahydro-
folate (THF) results in an inactive form of folate if it is not
de-methylated by methionine synthase. The “trapping” of
5-methyl THF may result in a secondary folate deficiency
with impairments in thymidine and purine synthesis and sub-
sequently in DNA and RNA synthesis, leading to alterations in
immunoglobulin secretion
72
.
A human study in vitamin B
12
deficient patients evaluated
the alterations of immunological indicators following adminis-
tration of vitamin B
12
. In these patients, a significant decrease
was found in the number of lymphocytes and CD8
þ
cells and
in the proportion of CD4
þ
cells. In addition, findings showed
an abnormally high CD4
þ
/CD8
þ
ratio, and suppressed NK
cell activity. Supplementation with vitamin B
12
reversed
these effects indicating that it may act as a modulatory
agent for cellular immunity, especially in relation to CD8
þ
and NK cells
73
.
In elderly subjects (aged . 70 years) who received over
4 months in addition to the regular diet a special nutritional
formula providing, among other nutrients, 120 IU vitamin E,
8 mg vitamin B
12
, and 400 mg folic acid, NK cell cyto-
toxic activity increased in supplemented subjects, indicating
Vitamins and trace elements support immune function S31
British Journal of Nutrition
increased innate immunity in elderly people
71
. Immunocom-
petent adults (aged . 65 years) with low vitamin B
12
serum
concentrations, had an impaired antibody response to pneumo-
coccal polysaccharide vaccine
74
. These few studies demon-
strate the importance of a sufficient vitamin B
12
status to
maintain an adequate immune response, especially in the
elderly who have a high percentage (up to 15 %) of low
serum vitamin B
12
concentrations
75
.
Trace elements and immune function
The role of trace elements is covered by other authors in this
special issue and is only briefly sketched here.
Selenium
Selenium is essential for optimum immune response and influ-
ences the innate and acquired immune systems. It plays a key
role in the redox regulation and antioxidant function through
glutathione peroxidases that remove excess of potentially
damaging radicals produced during oxidative stress. Thus, sel-
enium plays an important role in balancing the redox state,
and helping to protect the host from oxidative stress generated
by the microbicidal effects of macrophages and during inflam-
matory reactions. The selenoenzyme thioredoxin reductase
affects the redox regulation of several key enzymes, transcrip-
tion factors and receptors, including ribonucleotide reductase,
glucocorticoid receptors, anti-inflammatory protein AP-1, and
nuclear factor-kappa B (NFkB), which binds to DNA and acti-
vates expression of genes encoding proteins involved in
immune response (cytokines, adhesion molecules). Selenium
deficiency decreases immunoglobulin titres and aspects of
cell-mediated immunity. Selenium supplementation can coun-
teract these effects
4,76 79
.
Zinc
The immune related functions of zinc have been reviewed in
the last few years
50,80 82
. Zinc is essential for highly prolifer-
ating cells, especially in the immune system and influences
both innate and acquired immune functions. It is involved in
the cytosolic defence against oxidative stress (superoxide dis-
mutase activity) and is an essential cofactor for thymulin
which modulates cytokine release and induces proliferation.
Adequate zinc intake supports a Th1 response, and helps to
maintain skin and mucosal membrane integrity and unbound
zinc ions exert a direct antiviral effect on rhinovirus replica-
tion. Zinc supplementation increases cellular components of
innate immunity (e.g. phagocytosis by macrophages and neu-
trophils, NK cell activity, generation of oxidative burst, DTH
activity), antibody responses, and the numbers of cytotoxic
CD8
þ
T cells (Th1 response).
Copper
Copper has been shown to have a role in the development and
maintenance of the immune system and a large number of
experimental studies have demonstrated that copper status
alters several aspects of neutrophils, monocytes and superoxide
dismutase. Working together with catalase and glutathione
peroxidase in the cytosolic antioxidant defence against ROS,
copper is essential in the dismutation of superoxide anion to
oxygen and H
2
O
2
, and diminishes damage to lipids, proteins,
and DNA. Both copper deficiency and high intakes over
longer periods can modulate several aspects of the immune
response
79,83 87
.
Iron
The immune related functions of iron have been subject to
several reviews since 2001
88 91
. Iron is essential for electron
transfer reactions, gene regulation, binding and transport of
oxygen, and regulation of cell differentiation and cell
growth. Iron is a critical component of peroxide and nitrous
oxide generating enzymes. It is involved in the regulation of
cytokine production and mechanism of action, and in the acti-
vation of protein kinase C, which is essential for phosphoryl-
ation of factors regulating cell proliferation. In addition, iron
is necessary for myeloperoxidase activity which is involved
in the killing process of bacteria by neutrophils through the
formation of highly toxic hydroxyl radicals. Therefore, any
alteration in cellular iron homeostasis to either deficiency or
overload has unfavourable functional consequences on the
immune system. Since pathogens such as infectious microor-
ganisms and viruses require iron and other micronutrients
for replication and survival as well, it seems essential to
restrict access of the infecting microorganism to iron, but to
maintain a suitable concentration of iron that the host can
mount an optimum immune response and avoid the possibility
of excess amounts of iron which may induce free radical
mediated damage
91
.
Conclusions
Inadequate intake and status of vitamins and trace elements
may lead to suppressed immunity, which predisposes to infec-
tions and aggravates undernutrition. Evidence has accumu-
lated that in humans certain nutrients selectively influence
the immune response, induce dysregulation of a coordinated
host response to infections in cases of deficiency and oversup-
ply, and that deficiency may impact virulence of otherwise
harmless pathogens. Thus, micronutrients are required at
appropriate intakes for the immune system to function opti-
mally. Available data indicate a role of vitamins (A, D, E,
B
6
,B
12
, folate, and C), and trace elements (selenium, zinc,
copper, and iron) on the immune response. They contribute
to the body’s natural defences on three levels by supporting
physical barriers (skin/mucosa), cellular immunity and anti-
body production. Vitamins A, C, E and the trace element
zinc assist in enhancing the skin barrier function. The vitamins
A, B
6
,B
12
, C, D, E and folic acid and the trace elements iron,
zinc, copper and selenium work in synergy to support the pro-
tective activities of the immune cells. Finally, all these micro-
nutrients, with the exception of vitamin C and iron, are
essential for antibody production. Vitamin B
6
, selenium,
copper and zinc have a direct impact on antibody production
or B-cell proliferation, vitamins A, D and E stimulate Th2
response which in turn promotes humoral immunity, and the
remaining micronutrients act indirectly by their roles in pro-
tein synthesis / cell growth. Overall, inadequate intake and
status of these vitamins and trace elements may lead to
Silvia Maggini et al.S32
British Journal of Nutrition
suppressed immunity, which predisposes to infections and
aggravates malnutrition. Therefore, supplementation with
these selected micronutrients can support the body’s natural
defence system by enhancing all three levels of immunity.
Conflict of interest statement
SB, SM and ESW are employees of Bayer Health Care, a
manufacturer of multivitamins. DHH is a consultant for
Bayer Consumer Care. SM, ESW, SB and DHH co-wrote
the manuscript.
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British Journal of Nutrition
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... An inadequate intake of micronutrients is known to result in low energy and fatigue [7,27], and can weaken our immune system and reduce resistance to infections [11,12]. Thus, in everyday life it is essential that we consume sufficient amounts of micronutrients to maintain basic health. ...
... Vitamin A contributes to immune function through the restoration of the skin and respiratory and intestinal epithelium so contributing to the strength of these barriers which function to protect people against invading pathogens [20]. Vitamin A also plays a direct role in the growth and production of the different types of immune cells. ...
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Selenium as an essential component of selenocysteine-containing protein is involved in most aspects of cell biochemistry and function. As such, there is much potential for selenium to influence the immune system. For example, the antioxidant glutathione peroxidases are likely to protect neutrophils from oxygen-derived radicals that are produced to kill ingested foreign organisms. When the functions of all selenoproteins are described, only then will it be possible to fully understand their role in maintaining optimal immune function.
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This paper presents a summary of the main findings, and their interpretation, of a review of controlled studies on the effect of vitamin A supplementation on young child morbidity and mortality. In presenting interpretations, special emphasis has been placed on findings and interpretations that appear particularly relevant to policy development and programme design. -from Authors