Download on Immune Function

Relationship between nutrition
and infectious
The duration and severity of many
infectious diseases are related to
host immunity and nutritional
status.
Lack of specific nutrients may lead
to dysregulated or ineffective
immune response and higher
morbidity and mortality.
1
HISTORICAL OVERVIEW
The relationship between less obvious
malnutrition and infection was largely
characterized in the twentieth century.
Outbreaks of infections were observed among
animals subjected to certain experimental
diets
An increased susceptibility to infections was
especially common in animals that were
deficient in vitamin A, and soon vitamin A
became known as the antiinfective vitamin
2
HISTORICAL OVERVIEW
An increased susceptibility to infection and mortality in
infants and young children to the lack of vitamin A,
and he advocated the use of milk, cream, and butter
for children to reduce their infections
In 1932 in London, Joseph Ellison discovered that
vitamin A supplementation reduced the mortality of
children with measles
From 1920 through 1940, vitamin A underwent
considerable evaluation in at least 30 therapeutic
trials for different infectious diseases
By the early 1940s, it was generally accepted that
vitamin A was important in maintaining mucosal
immunity against infections
3
HISTORICAL OVERVIEW
In the late 1980s and 1990s, zinc
supplementation was evaluated as
therapy for diarrheal disease,
pneumonia, malaria, and child growth
and development
Zinc was recommended as therapy for
infections such as diarrhea and
dysentery as early as the nineteenth
century
4
Relationship between
nutrition and infectious
Poor nutrition increased
susceptibility to infectious
diseases, leading to
immunological dysfunction
and metabolic responses
5
6
Relationship between
nutrition and infectious
Malnutrition resulted in increased
susceptibility to infection, and that
infection caused deterioration of
nutritional status.
The cycle of malnutrition–infection–more
nutritional deterioration– more
infection was a powerful pathway.
Infection caused a loss of critical body
stores of protein, energy, minerals and
vitamins.
7
Relationship between
nutrition and infectious
Part of the defect in antibody
immunity in malnourished persons
was shown to be attributed to the
profound effect of these deficits on
the maturation of T-cells, resulting
in a reduction in fully functional
mature T-cells and an excess of
poorly functional immature T-cells.
8
Relationship between
nutrition and infectious
Recurrent infections increase the risk of
malnutrition.
Poor nutritional status results in lowered
immune status and predisposes to
infectious disease thus propagating the
vicious cycle of infection and
malnutrition.
9
Relationship between nutrition
and infectious
Nutritional deficiencies can alter a host's
immune response and increase
susceptibility to infection.
From a nutritional point of view, the
process of nutrient loss and
redistribution has the potential for
being exploited to the benefit of the
infected malnourished host.
10
Relationship between nutrition
and infectious
Cycle of malnutrition and
infection is the main cause of
morbidity and mortality in
children in underdeveloped
countries.
11
Nutrient/Food Compounds that Influence
Immune Function
12
Perinatal infection is a major cause of
maternal, fetal and neonatal morbidity and
mortality.
Perinatal infections are more common among
the poorest women and in the geographic
areas with the least resources as well as with
the most malnutrition; these facts have given
rise to speculation that the relationship
between infection and adverse pregnancy
outcomes is at least in part mediated by
some nutritional deficiency
13
Nutritional deficits may increase the risk of
perinatal infection by diminishing or
abolishing protective mechanisms. Various
epithelial surfaces such as the squamous
epithelium of the skin and the mucosal
surfaces of the lung, gastrointestinal tract
and genitourinary tract provide the first line
of defense against various microorganisms;
various nutritional deficiencies have a welldocumented negative effect on skin and
mucus membrane integrity.
14
The ability of various cells such as leukocytes
and macrophages to phagocytize invading
organisms is another type of defense. Cellmediated responses of the T cells and
natural killer (NK) cells play a crucial role in
controlling invading organisms as do the
antibody-producing B cells.
Other immune cell products such as cytokines
and metalloproteases, as well as
complement, are important components of
the immune system that act together to
protect pregnant women from infection
(Table 1). Nutritional deficiencies have been
linked to decreases of all cellular and serum
immune
functions.
15
Protein energy malnutrition
Protein-energy-malnutrition (PEM) is one
of the major causes of
immunodeficiency worldwide.
Lymphoid atrophy, for example, is a
prominent feature of PEM, with
substantial reductions seen in the size
of the thymus and the spleen.
Because immune cells have a high
requirement for energy and amino
acids for both cell division and protein
synthesis.
16
Protein energy malnutrition
Therefore, reduced availability of both energy
and amino acids appears to substantially
reduce the ability of the host to mount an
appropriate immune response to various
types of bacteria, viruses and other
pathogens.
Other immune deficiencies associated with
PEM are decreased phagocytic activity by
neutrophils and macrophages, decreased
numbers of circulating T cells and impaired
lymphokine production
17
Protein energy malnutrition
PEM is also associated with
impairment of many of the host
barriers to infection, such as the
integrity of the skin and mucus
membranes.
On the other hand, antibody
response is usually maintained.
18
MALNUTRITION AND SPECIFIC
INFECTIOUS DISEASES
The impact of malnutrition on the severity of
infection has been investigated most
extensively in children with measles,
diarrheal disease, respiratory infections, and
malaria and in children and adults with
tuberculosis and human immunodeficiency
virus (HIV) infection. In general, the severity
of morbidity and mortality during different
infections is worse among persons with
malnutrition.
19
Measles
Measles is estimated to account for 1 million
deaths and a great deal of morbidity among
the 30 million cases of measles per year,
most of which occur in developing countries
where malnutrition is more prevalent.
Deaths from measles are largely the result of
an increased susceptibility to secondary
bacterial and viral infections, and the
underlying mechanism includes immune
suppression related to malnutrition,
especially vitamin A deficiency
20
Measles
21
Measles
Malnutrition is an important determinant of the
severity of measles
More persistent measles infection and viral
shedding have been reported in
malnourished children
A close synergism exists between measles
and vitamin A deficiency, because children
with measles who are vitamin A deficient
have a much higher risk of xerophthalmia,
corneal ulceration, keratomalacia, and
subsequent blindness
22
Measles
Vitamin A supplementation reduces the
morbidity and mortality of measles among
preschool children
Vitamin A supplementation appears to reduce
the infectious complications associated with
measles immune suppression, such as
pneumonia and diarrheal disease, and these
effects have been associated with
modulation of immune responses by vitamin
A
Zinc supplementation does not appear to have
an effect on morbidity among children with
23 measles that is accompanied by pneumonia
Malaria
Malaria, a parasitic infection with protozoan
organisms of the genus Plasmodium ,causes
an estimated 1 to 3 million deaths worldwide
each year.
Of the four malaria species that infect humans
(P. falciparum, P. vivax, P. malariae ,and P.
ovale) the most serious morbidity and
mortality are caused by P. falciparum ,and
nearly 90% of all cases and fatalities occur in
sub-Saharan Africa
24
Malaria
Severity of malaria may be related to
nutritional status.
Persons with better nutritional
status have less severe malaria
and a lower risk of death
Nutritional indicators of poor
vitamin A status have been
associated with malaria
25
Malaria
Vitamin A significantly reduced the
incidence of malaria attacks by about
20 to 50% for all except those with
extremely high levels of parasitemia.
Zinc supplementation was associated
with a 30% reduction in the incidence
of clinical malaria episodes, and 38%
reduction in malaria morbidity.
26
Malaria
Zinc supplementation did not appear to
reduce the morbidity of malaria
(reduction of fever or parasitemia)
when it was given as adjunct therapy
with chloroquine to children, aged 6
months to 5 years, who presented with
an attack of acute uncomplicated
falciparum malaria
27
Diarrheal Disease
Diarrheal diseases cause an estimated 3.5
million deaths/year, mostly among those less
than 2 years of age
The main causes of diarrheal diseases among
children in developing countries are
rotavirus, Escherichia coli, and Shigella,
Vibrio cholerae, Salmonella, and Entamoeba
histolytica.
The epidemiology, clinical features,
immunology, and pathogenesis of diarrhea
may differ according to characteristics of the
pathogen, such as production of toxins,
tissue invasion, fluid and electrolyte loss,
and
location
of
infection
28
Diarrheal Disease
In developing countries, community-based
studies suggest that children less than 5
years of age have a median incidence of 2.6
diarrheal episodes/year
In general, host defenses in the gut include
gastric acidity, the presence of normal
microflora, gut motility, mucus production,
integrity of microvilli, local secretion of
antibody, and cell-mediated immunity, and
micronutrient malnutrition may impair some
of these host defenses.
29
Diarrheal Disease
Malnourished infants and children are at
higher risk of more severe disease and
higher mortality from diarrhea and an
increased incidence of diarrhea is
found among children with evidence of
depressed immunity.
Clinical vitamin A deficiency is
associated with diarrheal disease in
children
30
Diarrheal Disease
Vitamin A supplementation or
fortification has been shown to reduce
the morbidity and mortality of diarrheal
diseases among preschool children in
clinical trials conducted in developing
countries over the last 2 decades
The severity of diarrheal disease and
mortality was reduced by vitamin A
supplementation
31
Diarrheal Disease
One of the mechanisms by which vitamin A •
may improve clinical outcomes in diarrheal
disease is through restoration of gut
integrity
Urinary losses of vitamin A during diarrhea •
may be substantial in some children, and
persistent diarrhea may reduce the
bioavailability of vitamin A. Vitamin A
supplementation (60 mg retinol equivalents)
reduces morbidity in children with acute
shigellosis.
32
Diarrheal Disease
Zinc supplementation can reduce the
incidence of diarrhea by about 18%
Zinc supplementation also reduces the
incidence of pneumonia, because a
pooled analysis showed a reduction of
mortality of 41%
Zinc supplementation reduced the
duration of diarrhea.
33
Acute Respiratory Infections
Acute respiratory infections are a major
cause of morbidity and mortality
among infants and children in
developing countries, and these
infections account for an estimated 4
million deaths per year
34
Acute Respiratory Infections
Malnutrition is a major determinant of
morbidity and mortality during acute
respiratory infections in children
The main causes of acute lower respiratory
infections in children are respiratory
syncytial virus, adenovirus, parainfluenza
virus, influenza virus, Streptococcus
pneumoniae, and Haemophilus influenzae
Acute respiratory infections in children have
been associated with poor weight gain and
stunting
35
Acute Respiratory Infections
Zinc supplementation reduced the incidence of
pneumonia among children.
Zinc supplementation decreased the incidence
of pneumonia by 41%.
Among infants and young children, zinc
supplementation reduced the morbidity of
severe acute lower respiratory infection.
Vitamin A supplementation has shown little to
no effect on reducing the incidence or
severity of acute respiratory infections
among preschool children, but it does
reduce the morbidity of acute respiratory
infections associated with measles infection
36
Hookworm Infection
About one fourth of the world's population is •
infected with hookworm
Hookworm infection is a major cause of iron •
deficiency.
Two species of hookworm, Ancyclostoma •
duodenale and Necator americanus, account
for a great deal of human morbidity and
mortality.
Hookworm is usually spread from person-to- •
person through contamination of soil and
vegetation with feces that contain hookworm
eggs.
37
Hookworm Infection
In the soil, the eggs develop into larvae that
can penetrate human skin on contact.
The hookworms attach to the intestinal
mucosa and cause chronic blood loss and
depletion of iron stores
Hookworm infection is associated with growth
retardation among infants and children, iron
deficiency and impaired mental development
in school children, and fatigue and
decreased work capacity among adults
38
Hookworm Infection
Poor hygiene is the major risk factor for
hookworm infection, and hookworm
infection, in turn, increases the risk of iron
and other micronutrient deficiencies.
Hookworm infection was associated with poor
mental development, and treatment for
hookworm in infected children improved
performance on mental development tests
compared with infected children who were
not treated.
39
Hookworm Infection
Treatment of school children for
hookworm infection was
associated with improved iron
status and better growth
Combination of hookworm treatment
and iron supplementation was
associated with improved
cognitive performance and growth
40
Human Immunodeficiency Virus
Infection
An estimated 39.4 million persons are infected
with HIV worldwide
HIV infection causes a progressive
decline in immunity that can lead to the
acquired immunodeficiency syndrome
(AIDS). HIV-1 is spread person-to-person by
three major routes: sexual contact, motherto-child transmission, and through
transmission by blood products such as
shared needles and syringes.
41
Human Immunodeficiency Virus
Infection
Poor nutrition may play an important role
in disease progression in HIV-infected
persons
During HIV infection, nutritional intake
may be affected by anorexia, central
nervous system disease, dysphagia,
and odynophagia (painful swallowing)
42
Human Immunodeficiency Virus
Infection
Fairly high proportions of HIV-infected
individuals do not consume at least the
recommended dietary allowance for
some B-complex vitamins, vitamin E,
and zinc and it has been suggested
that the recommended dietary
allowances should be higher for
persons with HIV infection .
43
Human Immunodeficiency Virus
Infection
Diarrhea and malabsorption of fats,
carbohydrates, and vitamin B12 appear to be
common in all stages of HIV infection.
Cryptosporidia, microsporidia,
cytomegalovirus, and Mycobacterium aviumintracellulare are major causes of diarrhea in
patients with AIDS, and many pathogens are
resistant to treatment and lead to severe
weight loss and death
Fat malabsorption may be common during HIV
infection and can reduce the absorption of
fat-soluble vitamins, such as vitamins A and
E.
44
Human Immunodeficiency Virus
Infection
A fairly high prevalence of micronutrient
deficiencies has been reported in many HIVinfected risk groups
Vitamin A deficiency is common among HIVinfected pregnant women and children in
developing countries.
A few studies suggested that serum vitamin C
concentrations are lower among HIV-infected
adults compared with healthy controls.
A high proportion of HIV-infected adults appear
to have low levels of vitamin B6, vitamin B12,
and folate.
45
Human Immunodeficiency Virus
Infection
Iron deficiency is common among HIVinfected pregnant women, female injection
drug users, and children.
Low blood zinc concentrations have been
described in HIV-infected adults
Low serum or plasma levels of selenium
consistent with deficiency have been
reported in HIV-infected adults (148).
46
Human Immunodeficiency Virus
Infection
Antioxidant nutrients such as the carotenoids,
tocopherols, vitamin C, and selenium have been
implicated in the pathogenesis of HIV infection
through their interactions with reactive oxygen
intermediates and nuclear factor-Kp B.
47
Human Immunodeficiency Virus
Infection
Vitamin A plays a central role in the
growth and function of T and B cells,
antibody responses, and maintenance
of mucosal epithelium, including that of
the respiratory, gastrointestinal, and
genitourinary tracts
Zinc plays an important role in the
growth, development, and function of
neutrophils, macrophages, natural
killer cells, and T and B lymphocytes
48
Human Immunodeficiency Virus
Infection
Low plasma or serum vitamin A levels are
associated with accelerated HIV progression
increased mortality , and, in children, growth
failure
High serum vitamin E levels were associated
with a lower risk of progression to AIDS(
The risk of progression to AIDS may be higher
in those with vitamin B 12deficiency
Low serum zinc levels are associated with
reduced secretory function of the thymus
and HIV disease progression
49
Human Immunodeficiency Virus
Infection
Low serum or plasma selenium concentrations
are associated with an increased risk of
progression to AIDS and higher mortality
Multivitamin supplementation slowed
progression to AIDS when this therapy was
given to HIV-infected pregnant women
through pregnancy and during lactation, and
it also reduced fetal deaths and low birth
weight. Vitamin A and β-carotene
supplementation reduced preterm delivery
among pregnant women
50
Tuberculosis
Tuberculosis is an infection caused by
Mycobacterium tuberculosis or related
organisms such as M. bovis .M.
tuberculosis ,a slowly growing acid-faststaining bacillus, is the most common cause
of tuberculosis in humans.
The spectrum of disease ranges from
asymptomatic latent tuberculous infection to
disseminated disease. The most common
form of tuberculosis is latent infection.
Active tuberculosis, the form of disease that
disrupts normal host physiology to produce
symptoms, is generally classified as
pulmonary
or
extrapulmonary
disease
.
51
Tuberculosis
Pulmonary disease, the most common form of active
tuberculosis, accounts for about 80% of cases, and
clinical manifestations include chronic cough and
sometimes hemoptysis, dyspnea, and chest pain.
Other constitutional symptoms include fevers, night
sweats, and weight loss.
Extrapulmonary disease accounts for about 20% of
active tuberculosis cases, and the most common
extrapulmomary sites are the lymph nodes (most
often the cervical lymph nodes), pleura, kidneys,
meninges, and bone or joints .
52
Tuberculosis
Malnutrition increases the risk of
developing clinical disease. In the
absence of effective chemotherapy,
tuberculosis is characterized by
wasting and high mortality.
53
Tuberculosis
Worldwide, tuberculosis is the leading
infectious cause of death, accounting for 2
million deaths annually
About one third of the world's population, or
1.8 billion persons, are infected with M.
tuberculosis ,and this group represents an
enormous pool of persons at risk of
development of future disease.
In sub-Saharan Africa, the Indian subcontinent,
and southeast Asia, half or more of adults
have latent tuberculosis infection.
54
Tuberculosis
Each year, between 7 and 8 million people
throughout the world develop active
tuberculosis, and most cases occur in subSaharan Africa and Asia.
Tuberculosis is responsible for about one
fourth of all preventable deaths in
developing countries, and many of these
deaths are associated with underlying HIV
infection.
55
Tuberculosis
Malnutrition is well known among adults with
tuberculosis
In general, adults gained weight during 6 months of
treatment with chemotherapy, but weight was lost
after treatment had finished.
Progressive nutritional recovery generally occurs
during tuberculosis chemotherapy; however, serum
albumin levels and mean arm muscle circumference
have been reported as subnormal after 12 months, a
finding suggesting that body protein reserves may
not be fully recovered during treatment
56
Tuberculosis
Altered amino acid metabolism may contribute
to wasting in tuberculosis Body composition
studies suggest that body cell mass is
relatively depleted in adults with tuberculosis
and HIV infection
Experimental animal studies showed that
protein-calorie malnutrition has a marked
effect on resistance to tuberculosis
Restoration of a full protein diet could reverse
the fatal course of tuberculosis in
malnourished mice.
57
Tuberculosis
Multiple micronutrient deficiencies are
common during tuberculosis
Cod liver oil, a rich source of vitamin A,
was a main treatment for tuberculosis
in the era before antibiotics
Animal studies suggest that vitamin A
improves immune responses to
tuberculosis and enhances survival
58
Effects of single-nutrient
deficiencies on immune function
59
Micronutrients: Examples of the effects
of trace elements on the immune system
60
Examples of the effect of
vitamins on the immune system
61
Vitamin A deficiency
Vitamin A deficiency is known to
result in keratinization of the
respiratory epithelium, leading
to a decrease in mucus
production and diminished
capacity of the respiratory
epithelium to clear bacterial
pathogens.
62
Vitamin A deficiency
Vitamin A likely plays a role in
reducing infection through its role
in enhancing epithelial cell
differentiation and the barrier
function of the host as well as
through its effect on more
traditional immune functions.
63
Vitamin A deficiency
Vitamin A regulates keratin synthesis by
squamous cells and appears to maintain the
integrity of mucosal epithelial surfaces—
especially of the gut and lung. In animals,
vitamin A deficiency decreases T-cell
proliferation and various types of antibody
production. The ability of neutrophils to
phagocytize various organisms and to
generate oxidant molecules appears to be
reduced in the absence of appropriate levels
of vitamin A
64
Vitamin A deficiency
Association between vitamin A deficiency
and infection whereas in
supplementation trials the prevalence
of a variety of infections have been
reduced.
Vitamin A supplementation improves
antibody response to vaccines,
maintains gut integrity and reduces the
incidence and severity of infections
65
associated with diarrhea and measles
Mechanisms of vitamin
A on immune function
Vitamin A has been shown to control
differentiation of epithelial cells by
regulating the synthesis of keratin
and deficiency results in altered
epithelial structure (squamous
metaplasia) and a reduced number
of mucus-secreting cells
66
Mechanisms of vitamin
A on immune function
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, increasing the risk of
bacterial translocation
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
67
Mechanisms of vitamin
A on immune function
Because vitamin A is needed for
glycoprotein synthesis, a
deficiency of it would likely impair
the synthesis of the many
glycoproteins involved in the
immune response (e.g., integrins,
fibronectin, and globulins)
68
Mechanisms of vitamin
A on immune function
Direct mechanisms
The role of vitamin A in lymphocyte
proliferation likely occurs through activation
of the retinoic acid receptor (RAR)-, because
provision of RA has been shown to increase
mRNA levels of RAR- in T lymphocytes.
Substantial evidence supports a role for
vitamin A in negatively regulating IFNsecretion, thus influencing the development
of Th-2- versus Th-1-type responses
69
mechanisms of vitamin
A on immune function
Vitamin A deficiency in mice strongly favors
the production of IFN- (a Th-1-type cytokine),
but adding RA in vitro to T lymphocytes from
vitamin A-deficient mice inhibits IFNproduction.
RA was shown to alter IFN- synthesis at the
level of transcription, 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
Mechanisms for the Essentiality of
Vitamin A to the Immune System
71
Vitamin C deficiency
Vitamin C deficiency is scurvy, a disease
marked by an increased incidence of
infections and decreased immune response
Vitamin C functions as an antioxidant and
appears to reduce oxidation mediated
damage to DNA in lymphocytes and may
enhance production of interleukin-1 and
tumor necrosis factor-a.
Vitamin C also reduces T-cell death and
increases NK activity. It is highly
concentrated in neutrophils and appears to
be used during infection to prevent oxidative
damage.
72
Vitamin C deficiency
Vitamin C supplementation may reduce
the incidence of the common cold and
other viral infections.
Vitamin C supplementation may also
increase lymphoproliferation and
phagocytosis by neutrophils and
macrophages.
Vitamin C can reduce damage to
lymphocytes by reactive oxygen
73
intermediates
Vitamin C
Ascorbic acid is an essential component
of every living cell.
Vitamin C is highly concentrated in
leukocytes and is used rapidly during
infection (e.g., to prevent oxidative
damage).
Reduced concentrations of this vitamin
in leukocytesis associated with
reduced immune function
74
Proposed mechanisms
The actions of vitamin C as a
reducing agent and oxygen-radical
quencher are well-established.
Reduction of free radicals will
prevent DNA damage to immune
cells, thereby maintaining their
functional and structural integrity.
75
Proposed mechanisms
Immune system (which relies heavily
on membrane receptors and
signals) is particularly sensitive to
oxidative stress
Ascorbic acid can reduce directly or
indirectly through the regeneration
of vitamin E damage to
lymphocytes by reactive oxygen
intermediates (ROI).
76
Proposed mechanisms
Ascorbate levels exert this effect by
down-regulating ROI-dependent
expression of proinflammatory IL
genes via inhibition of
transcription of NF-B
77
Proposed mechanisms
Vitamin C might “boost” T-cell
capacity via several mechanisms.
In vitro, three T-cell death
pathways (growth factor
withdrawal- , spontaneous- , and
steroid-induced death) were
inhibited when T cells were
incubated with ascorbic acid
78
Proposed Mechanisms for Effects of
Vitamin C on Immune Function
79
Vitamin E
Vitamin E is a potent antioxidant and
its deficiency results n increased
free radical membrane damage.
Supplementation with vitamin E
increases lymphocyte proliferation
and interleukin-2 responses and
improves antibody response to
vaccines.
80
Vitamin E
Providing vitamin E to healthy
individuals was shown to increase the
CD4/CD8 ratio, enhance T-cell
proliferation, and lower measures of
oxidative stress
However, supplementation of vitamin E
to “healthy” individuals did not
attenuate oxidative DNA damage in
peripheral blood lymphocytes
81
Vitamin E
Animal studies support the immune benefits of
supplemental vitamin E, which increased
CD4 CD8 thymocytes and IL-2 production in
rodents, and improved responses to
infection in swine.
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
82
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 antiinflammatory effects
Se deficiency has been shown to decrease the
production of free radicals and killing by
neutrophils , IL-2R affinity and expression on
T cells, T-cell proliferation and differentiation,
and lymphocyte cytotoxicity
83
Influence of Se on immune
function
Se deficiency in vitro enhances neutrophil
adherence to endothelial cells, an important
preliminary event in inflammation.
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
84
Influence of Se on immune
function
Supplementation with Se increases
lymphocyte proliferation, expression of
the high-affinity IL-2R , cytolytic T
lymphocyte (CTL) tumor destruction,
and NK- cell function in humans and
increases lymphocyte proliferation, IL2R expression, and macrophage and
CTL tumor cytotoxicity in mice
85
Influence of Se on immune
function
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 cytokineinduced HIV-1 replication
86
Influence of Se on immune
function
Se deficiency in the host enhances
the mutation rate of coxsackievirus
and influenza A virus
This suggests that the oxidative
stress status of the host can alter
the genome and pathogenicity of
an infectious virus
87
Mechanisms 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
Immune cells are particularly susceptible
to oxidative damage because of their
highly unsaturated membranes and
their ability to produce large amounts
of free radicals (i.e., during
inflammation)
88
Mechanisms of vitamin
E and Se on immune function
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)
89
Mechanisms of vitamin
E and Se on immune function
Vitamin E may improve T-cell function by
decreasing macrophage PGE2 production by
modulating the AA cascade initiated by
lipoxygenase and/or cyclooxygenase
Vitamin E influences lymphocyte maturation,
possibly by stabilizing membranes and
allowing enhanced binding of antigenpresenting cells (APC) to immature T cells
via increased expression of intercellular
adhesion molecule-1
90
Mechanisms of vitamin
E and Se on immune function
Se is essential for the function of
several selenoproteins, because of
the selenocysteine residues
present at their active sites.
Glutathione peroxidase (GPX) is a
selenoprotein that acts as an
oxidant scavenger and protects
against oxidative damage.
91
Mechanisms of vitamin
E and Se on immune function
Thioredoxin reductase is another
selenoprotein that affects the redox
regulation of a variety of key enzymes,
transcription factors, and receptors,
including ribonucleotide reductase, the
glucocorticoid receptor, AP-1, and NF-B. 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, thus making it an effective protector
against ROS.
92
Mechanisms of vitamin
E and Se on immune function
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
subunits of the IL-2R on these activated
immune cells. This results in a greater
number of functional IL-2R/cell and in
enhanced proliferation and clonal expansion
of cytotoxic precursor cells. Se deficiency
causes in increased neutrophil adhesion and
increased expression of E-selectin and
ICAM-1 , suggesting that Se can downregulate neutrophil activation.
93
Proposed Mechanisms for the Effects of
Vitamin E and Selenium on Immune Function
94
Fatty acids
Fish oil contains large quantities of the n–3
polyunsaturated fatty acids,
eicosapentaenoic acid and docosahexaenoic
acid.
These fatty acids have been shown to
modulate T-cell function.
Increasing intake of dietary fish oil suppresses
interleukin-2 secretion and T-cell
proliferation, thus accounting for the
antiinflammatory effects.
95
Fatty acids
Feeding n-3 PUFA has been shown to decrease
tumor growth, incidence, and/or metastasis
in a large number of animal studies and to
prolong survival of cancer patients in a
human clinical trial.
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
96
Fatty acids
Feeding EPA and DHA has been shown to
modulate specific functions of innate and
acquired immunity.
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.
97
Mechanisms by which n-3 PUFA
may modulate
immune function
Immunomodulatory effects of
dietary n-3 PUFA, including effects
on eicosanoid formation, signal
transduction, gene expression, and
lipid peroxidation
98
Mechanisms Responsible for the
Role of Long Chain n-3 PUFA (EPA
and DHA) on Immune Function
99
Iron deficiency
Iron deficiency appears to have a stronger
effect on cell-mediated immunity than on
antibody production
Both neutrophil and NK cell activity are
decreased with iron deficiency. Macrophages
sequester iron as part of their normal
function and this sequestration may limit
various microorganisms’ replication and
toxicity because these functions are often
iron dependent
100
Iron and immune function
Iron regulates the function of T
lymphocytes, and in most studies
(in vivo and in vitro), a deficiency
results in impaired cell-ediated
immunity
Iron deficiency may also delay the
development of cell-mediated
immunity
101
Iron and immune function
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
102
Iron and immune function
Lymphocytes meet an increased iron
requirement during proliferation or other
conditions by increasing the synthesis and
expression of surface transferrin receptors
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
103
Iron and immune function
Neutrophil function (decreased
myeloperoxidase activity and
bactericidal activity) and NK activity are
impaired with iron deficiency
Macrophage phagocytosis is generally
unaffected by iron deficiency, but
bactericidal activity of these cells is
attenuated
104
Iron and immune function
When activated (i.e., during
inflammation, possibly signaled by
IL-1 and IFN-γ, macrophages
increase their uptake of iron and
bind it in the cells (via increased
transferrin receptors and ferritin
synthesis).
105
Iron and immune function
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
106
Iron and immune function
Increased risk of infection during
iron deficiency.
Deleterious effects of iron deficiency
on most measures of functional
immunity
107
Iron supplementation and
immune function
Relationship between iron
repletion/supplementation and
increased morbidity from acute and
chronic infections.
Microbiology studies show a close
relationship between the availability of
iron and bacterial virulence; one might
conclude therefore that providing iron
would benefit the infectious organisms
108
Iron supplementation and
immune function
Administration of parenteral iron has
been shown in human and animal
studies to be harmful when
administered during infection.
109
Mechanisms Responsible for the Effects of
Iron Deficiency on Immune Function
110
Iron toxicity
Iron overload (hemochromatosis) include
decreased antibody-mediated and mitogen
stimulated phagocytosis by monocytes and
macrophages, reduced neutrophil migration,
alterations in T-lymphocyte subsets,
modification of lymphocyte distribution in
different compartments of the immune
system, suppression of the complement
system, and increased rate of infections.
111
Iron toxicity
Hydroxyl radicals, produced by the Fenton
reaction or by the Fe-catalyzed Haber-Weiss
reaction, are responsible for many of the
damaging effects of iron. Within minutes,
however, the immune system, iron and its
binding proteins have immunoregulatory
properties, and shifting these
immunoregulatory balances by providing too
much iron may result in deleterious
physiological effects.
In fact, the carcinogenic effects of excess iron
have been attributed to the suppressive
effect of excess iron on the host’s immune
system in addition to the formation of
hydroxyl radicals and promotion of cancer
112
cell multiplication
Zinc deficiency
Intake enough of zinc, reduced
levels of infections ,inflammation
and less oxidative stress.
In humans, severe zinc deficiency is
associated with frequent
infections, depressed immune
function and various types of
infectious dermatitis
.
113
Zinc deficiency
Zinc deficiency was associated with
lymphopenia and thymic atrophy
Zinc supplementation has reduced
various types of human infections in a
variety of settings
Zinc-deficient animals are susceptible to
a wide variety of infections, and
repletion often reverses this
susceptibility
114
Zinc deficiency
Zinc deficiency damages epithelial cells
as well as the cells lining the
gastrointestinal tract and pulmonary
system. It is therefore likely that
squamous and columnar epithelial cell
damage associated with zinc deficiency
allows various types of
microorganisms to enter the body and
become established in otherwise
protected sites
115
Zinc deficiency
Zinc deficiency reduces the ability to
develop acquired immunity through
repression of cytokine and antibody
production.
Zinc deficiency also inhibits normal
macrophage functions including
cytokine production, phagocytosis and
intracellular killing
116
Zinc
Ability of Zn to improve immune function
during various diseases
Zn supplementation resulted in a reduced
duration and severity of cold symptoms
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
117
Zinc
In young children, Zn
supplementation reduced diarrhea
duration, pneumonia , growthstunting, acute lower respiratory
infections and morbidity,
respiratory morbidity, incidence of
dysentery, and altered intestinal
permeability
118
Zinc
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-cellmediated immunity (CMI)
Animal studies have confirmed that Zn
deficiency is associated with a significant
reduction in T-helper cell function, impaired
DTH responses, compromised B-cell
development, low IgG production, decreased
NK lytic activity, and increased mortality to
various infectious organisms
119
Zinc
Maternal Zn deprivation results in offspring •
with reduced thymus and spleen size,
splenocyte numbers, mitogen responses,
and antibody production.
However, the poor Ab-mediated response •
capacity and defective DTH could be
restored by Zn supplementation.
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
120
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
121
Mechanisms Responsible for the
Essentiality of Zn to Immune Function
122
Proposed mechanisms for the immune
essentiality of zinc
During Zn deficiency, the presence of higher
proportions of granulocytes (as much as
50%) and monocytes (almost twofold)
suggest that the myelopoietic environment of
the marrow is more protected from, or even
up-regulated during, Zn deficiency . Although
the numbers may not be compromised, the
function of these cells may be. Zn-dependent
enzymes or reactions are involved in the
generation of oxygen radicals, and
suboptimal levels of Zn have been
demonstrated to lower the killing ability of
123
internalized parasites by macrophage
Proposed mechanisms for the immune
essentiality of zinc
Furthermore, the capacity of •
macrophages to engulf and kill
parasites can be restored after
treatment with Zn. 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
124
Proposed mechanisms for the immune
essentiality of zinc
The decreased cell-mediated immune
functions and the increased frequency
of infection in Zn-deficient subjects
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 CD4CD45R0 cells,
suggesting an effect on T-helper cell
maturation
125
Proposed mechanisms for the immune
essentiality of zinc
Zn influences the activity of multiple enzymes at the
basic level of replication and transcription. For
example, Zn is needed for the activity of thymidine
kinase during the S-phase of cell growth and for the
activation of the Zn finger protein NF-B that is
involved in IL-2 and IL-2R expression. In Zn-deficient
cells, the activation, translocation, and binding of
NF-B to DNA are inhibited. NK activity and cytotoxic
T-cell precursors (CD8CD73) are decreased with Zn
restriction, 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
126
Proposed mechanisms for the immune
essentiality of zinc
Some of the changes in T-cell maturation and •
function observed during Zn deficiency are
likely related to decreases in Zn-dependent
thymulin activity. Zn deficiency in
experimental animals results in atrophy of
thymic and lymphoid tissue, with losses of
precursor T and B cells in the bone marrow.
This is demonstrated by the dose-related
decline in the number of pre-B cells (B220),
immature B cells (B220IgMIgD), and mature B
cells (IgMIgD)
127
Proposed mechanisms for the immune
essentiality of zinc
In vitro, low concentrations of Zn have been •
shown to induce apoptosis in mouse CD4
CD8 thymocytes, whereas high zinc
concentrations have been shown to block
apoptosis.
In vitro, high concentrations of Zn blocked •
apoptosis by preventing activation of the
endonuclease, which is involved in DNA
fragmentation and inhibited steroid binding
(possibly by binding to the vicinal cysteines
in the receptor-ligandbinding site) to the
glucocorticoid receptor during
glucocorticoid induced apoptotic death
128
Other Micronutrients
Selenium appears to have several roles
in protection from infection.
First, often in conjunction with vitamin E,
selenium appears to act as an oxidant
scavenger and protects against
oxidative damage.
Selenium also appears to stimulate T-cell
proliferation and macrophage
cytotoxicity
129
NUCLEOTIDES
Dietary nucleotides are obtained from
nucleoprotein-rich foods, such as organ
meats, fish, and poultry, and are especially
high in human breast milk. In general, de
novo synthesis of nucleotides may be
sufficient for normal growth and
development in healthy persons, who
typically consume 5% (1–2 g/day in adults) of
their daily requirement for these compounds.
Nucleotides may become conditionally
essential during growth and immunological
challenges when demand may exceed de
novo synthetic capacity
130
NUCLEOTIDES
Animals fed nucleotide-free diets suffer
impaired cellular and humoral immune
function, including decreased NK cell and
macrophage activity, lower DTH responses
and cytokine production, decreased antibody
production, and increased susceptibility to
infections. 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, increasing
antibody production, and increasing spleen
cell proliferation
131
NUCLEOTIDES
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.
The beneficial effects of additional dietary
nucleotides on immune function are supported
by animal studies. 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.
132
NUCLEOTIDES
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.
133
NUCLEOTIDES
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. 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 35guanosine monophosphate). 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
134