Synergism of nutrition, infection, and immunity:

an overview13
Nevin S Scri,nshat’ and Jo/ui Paul SanGiovanni

ABSTRACT Infections, no matter how mild, have adverse I summarize the multiple ways in which infections can affect
effects on nutritional status. The significance of these effects nutritional status and then give an overview of the possible
depends on the previous nutritional status of the individual, the mechanisms for the reciprocal relation between malnutrition
nature and duration of the infection, and the diet during the and reduced resistance to infection. These include the
recovery period. Conversely, almost any nutrient deficiency, if following.
sufficiently severe, will impair resistance to infection. Iron defi-
ciency and protein-energy malnutrition, both highly prevalent, Anorexia
have the greatest public health importance in this regard. Remark- Nitrogen balance studies disrupted by intercurrent infections
able advances in immunology of recent decades have increased or even immunizations reveal consistent decreases in food

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insights into the mechanisms responsible for the effects of infec- intake. This is a factor in precipitating clinically evident defi-
tion. These include impaired antibody formation: loss of delayed ciencies of any nutrient that is already borderline or deficient in
cutaneous hypersensitivity: reduced immunoglobulin concentra- the individual.
tions; decreased thymic and splenic lymphocytes: reduced com-
plement formation, secretory immunoglobulin A. and interferon: Cultural and therapeutic practices
and lower T cells and T cell subsets (helper, suppressor-cytotoxic,
Withdrawal of food from individuals with fever, diarrhea, or
and natural killer cells) and interleukin 2 receptors. The effects
other symptoms of infection is an almost universal practice that
observed with single or multiple nutrient deficiencies are due to
exacerbates the effect of anorexia. In field studies it is not
some combination of these responses. In general. cell-mediated
possible to separate the effects of anorexia from those of
and nonspecific immunity are more sensitive than humoral immu-
deliberate withdrawal of food for cultural reasons, but the
nity. Am J Cli,, Nutr 1997;66:464S-77S.
combined effects can be devastating. In Matlab, Bangladesh,
food intakes as judged from dietary energy were > 40% re-
KEY WORDS Nutrition and infection, nutrition and im-
duced in children aged < 5 y during the acute stage of diarrhea
munity. vitamins and minerals, minerals and immunity
compared with after recovery (2). In Peru, energy intakes
decreased between 10% and 86% in breast-fed children with
INTRODUCTION diarrhea (3).

It is appropriate to begin a keynote lecture with a historical Decreased intestinal absorption

introduction. The 1968 WHO monograph Interactions of Nu-
In studies by the Institute of Nutrition of Central America of
Irition (l?1(/ Infection (I) suggested for the first time that the
Panama, protein absorption was generally reduced 10-30% and
relation between infection and malnutrition is synergistic. The
sometimes as much as 40% in children with diarrhea (4). In
monograph brought together extensive evidence for both the
Bangladesh, absorption during diarrhea caused by rotavirus
adverse effect of infections on nutritional status and the in-
averaged 43% for nitrogen. 42% for fat, 74% for carbohydrate,
creased susceptibility to infection of malnourished individuals.
and 55% for total energy (5). Corresponding values for diar-
Its thesis was that each worsened the other and that the bio-
rhea caused by enteropathogenic Esc/ierichia c’oli and Shigella
logical effects of malnutrition and infection combined were
were slightly higher.
greaten than the sum of the two for this reason.
The range of infections associated with malabsorption is
The monograph also tried to identify the mechanisms in-
wide. Included are bacterial, viral, and protozoan entenitides
volved in this interaction. Its documentation of the ways in
which infection worsens nutritional status was comprehensive
I From the Food and Nutrition Programme ftr Human and Social De-
and relatively complete even by today’s standards. However,
velopment, United Nations University (Program Office), Boston.
its review of the ways in which malnutrition can affect resis- 2 Presented at the symposium Nutrition, Immunity. and Infection, held in
tance to infection was written before the modern explosion in
Madrid, October 24-25, 1994.
immunologic research. This conference provides an opportu- 3 Reprints not available. Address correspondence to NS Scrimshaw.
nity to present and interpret the rapidly increasing knowledge UNU Food and Nutrition Programme for Human and Social Development.
of interactions between nutrient deficiencies and immune Charles Street Station, P0 Box 5(X), Boston, MA 021 14-0500. E-mail:
status. Scrimshaw@inf.uiiu.edu.

464S Am J C/i,i Nuir 1997;66:464S-77S. Printed in USA. U 1997 American Society for Clinical Nutrition
 NUTRITION, INFECTION. AND IMMUNITY 465S

and intestinal helminths (6). Vitamin A malabsorption also Energy

occurs during systemic febrile illnesses. Sivakumar and Reddy
The energy cost ofdepositing I g protein has been estimated
(7) reported that in children with acute diarrhea and respiratory
to be 100 kJ (24 kcal) on 25 kJ (6 kcal) of total weight gain.
infections only 30-70% of ingested vitamin A is absorbed. If this figure is applied to the observed protein losses summa-
nized above, calculated average energy losses from this source
Catabolic losses alone would be between 17 and 21 kJ kg . d (between 4
and S kcal kg ‘ ‘ d ‘). This amount seems small but it rep-
A catabolic response occurs with all infections even when
resents 14-29% of the requirements of a l-y-old child. In-
they are subclinical and not accompanied by fever (8-12).
creased protein loss during infections, estimated from in-
Under the stimulus of the release of interleukin 1 by leuko-
creased urinary 3-methylhistidine excretion. is the energy
cytes. endocrine changes are initiated that lead to the mobili-
equivalent of 29 kJ.kgt .dt (7 kcalkgt d . Jack-
zation of amino acids from the periphery, primarily from
son et al (15) in Jamaica measured the energy cost ofgrowth of
skeletal muscle (8). The amino acids are used for gluconeo-
children recovering from protein-energy malnutrition and ne-
genesis in the liver and the nitrogen released is excreted in
ported a range of weight gain of I 7-2 1 kJ/g (4-S kcal/g) with
urine.
40% of this considered to be fat tissue and 60% protein tissue.
They estimate the energy cost of synthesizing I g lost protein
Protein to be 3 1 kJ (7.5 kcal) and that for replacing 1 g fat to be 48.5
To describe the effect of infection on protein losses, Pow- kJ (11.6 kcal).
anda ( 1 3) summarized data from a wide variety of acute infec-
Vitamin A
tious diseases by adding the total nitrogen losses and dividing
them by the number of days oven which these losses occurred. The capacity of infections to precipitate xerophthalmia and

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For all infections, the average loss of 0.6 g protein kg . d keratomalacia in individuals already marginally deficient is
is equal to the mean estimated total protein requirement for well established and the effect is particularly severe with mea-
adults. Diseases associated with diarrhea or dysentery pro- sles and also noted for chickenpox. A significant drop in serum
duced an average loss of 0.9 g protein kg . d . Higher vitamin A concentrations has been observed in children with
losses were observed with typhoid fever and other severe acute respiratory infection. gastroentenitis. and measles. with
infections, reaching I .2 g protein kg ‘ ‘ d ‘ ( I 3). concentrations returning to normal after recovery. Vitaniin A
With use of urinary 3-methylhistidine as a measure of mus- blood concentrations also have been reported to be reduced in
cle protein catabolism in septic patients, losses from 1 2 to 30 pneumonia, rheumatoid arthritis, acute tonsillitis, and infec-
mg/d were detected during the peak fever response (14). By tious hepatitis. Lower serum carotene and vitamin A concen-
this measure, the average additional loss in the urine during trations also have been found with hookworm disease.
sepsis was equivalent to I . 14 g protein kg . d . Such cal-
culations are underestimates of the metabolic cost of infections, Ascorbic acid
however, because they do not include energy expended for the Ascorbic acid concentrations decrease in plasma and in-
multiple anabolic responses described below. crease in the urine of infected individuals compared with
noninfected persons living under comparable conditions. This

Lipids is seen even with vaccination against smallpox and measles and
for the common cold.
Infections affect plasma lipids but the changes are highly
variable and depend on the duration and severity of infection. B vitamins
the degree of fever, and age. Effects include changes in tniac-
The classic nutritional diseases of beriberi and pellagra were
ylglycenol. fatty acids, ketone bodies, and the products of fatty
known to be precipitated in vulnerable individuals by a variety
acids partially oxidized in the liven.
of infections. Riboflavin status is also adversely affected by
infection. Beisel et al ( I 6) showed marked increases in nibo-
Carbohydrates flavin excretion with sandfly fever in well-nourished male
The catabolic responses described above have as a principal volunteers.
function the provision of amino acid substrates for gluconeo-
Iron
genesis. Thus, a continual conversion of alanine carbon to
glucose carbon occurs with acute infection. even when exog- One metabolic consequence of infection is a decrease in
enous carbohydrate is adequate. It appears to be the rate of serum iron because of its being sequestered in the reticuloen-
release of glycogenic amino acid substrates from peripheral dothelial system. In addition. lactoferrmn, with a higher iron
tissues that determines the rate of hepatic gluconeogenesis. All binding capacity than bacterial siderophores. released
is by
of the hormones that regulate carbohydrate metabolism partic- phagocytes. The net effect is to deprive the infectious agent of
ipate in host responses to infection. Several groups have doc- iron for its replication and inhibit the spread of infection.
umented an increased fasting concentration of both glucagon
Other minerals
and insulin in serum. Despite the initial stimulation of glucone-
ogenesis, the body may eventually become severely hypogly- Infections decrease both serum copper and zinc. Careful
cemic. Lethal hypoglycemia can develop in septic neonates metabolic studies by Castillo-Dunan et al (17) documented the
with severe viral infections of the liver such as fulminating effect of diarrhea on zinc and copper status. Metabolic balances
hepatitis on, as shown in monkeys, yellow fever. of these minerals were strongly negative during periods of
466S SCRIMSHAW AND SANGIOVANNI

acute diarrhea. These losses cannot be predicted from serum blood loss with Se/zistosonia he11h’)tO/iU11l also increases iron
concentrations because copper concentrations often increase requirements. as does the sequestering of iron pigment by the
during infection as a result of stimulation of the hepatic pro- reticuloendothelial system in malaria.
duction of ceruloplasmin. Note that in this study serum copper
concentrations were significantly lower in subjects with diar-
rhea than in control subjects. Conversely, plasma zinc concen- RELATION BETWEEN NUTRITION AND IMMUNITY
trations often decline during acute infections because of an
Reasons for malnutrition are multiple and complex, but, as
internal redistribution of the metal to the liver. The reduced
reviewed above. infection is a common precipitating factor.
retention of zinc during diarrhea thus interacts with the redis-
Ironically, malnutrition is also a major factor in the occurrence
tnibutional influence of the infection.
of infection and the two interact, in many cases, making each
Anabolic losses other worse. The striking decrease in infectious disease mor-
bidity in preschool children in Teozonteopan, Mexico, given
During infection. amino acids are diverted from normal
additional milk is shown in Figure 1 (20).
pathways for the synthesis of immunoglobulins. lymphokines.
To complete the overview of this synergistic interaction, the
C-reactive proteins, and a variety of other proteins including
remainder of this paper summarizes the mechanisms responsi-
key liver enzymes (10).
ble for decreased resistance to infection and the specific nutni-
ent deficiencies that affect them. These potential mechanisms
Fever
include interference with the production of humoral antibodies
Fever increases the basal metabolic rate 1 3% for each I #{176}C. and of mucosal secretory antibodies, cell-mediated immunity.
During’ a period of high fever, metabolism may increase by bactericidal capacity of phagocytes, complement formation.
nearly one-third ( I 8). Additional nitrogen and amino acids are numbers of thymus-dependent T lymphocytes and T cell sub-

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lost in sweat. sets (helper. suppressor-cytotoxic, and natural killer cells), and
nonspecific defense mechanisms. These nonspecific defense
Additional intestinal losses
mechanisms include intestinal flora: anatomical barriers (skin,
Protein-losing enteropathy has been described for measles mucosa, and epithelium); secretory substances such as ly-
and diarrhea, especially when due to shigellosis. In studies by sozymes. mucus, and gastric acid; the febnile response; endo-
the International Center for Diarrheal Disease Research-Ban- crine changes: and binding of serum and tissue iron.
gladesh. nearly two-thirds of patients with enterotoxigenic E. Antimicrobial systems in the neutrophil. all of which are
co/i and 40% of those with notavirus diarrhea had excessive potentially affected by malnutrition, are listed in Table 1.
losses of protein in feces. In patients with shigellosis, between These include both oxygen-dependent systems, such as those
100 and 5(X) mL serum was lost with feces each day as a result responsible for the respiratory burst, and oxygen-independent
of’ protein-losing enteropathy (4). systenis, such as lactofernin, lysozymes, hydrolase, and pro-
Bleeding into the intestine from Sdzi.s’tosoina inansoni, on teases. Some of the still fragmentary evidence for the role of
hookworm. also results in significant losses of iron and energy. specific nutrients in each of the mechanisms is summarized
Each adult hookworm causes the loss of 4.2 kJ/d ( 1 kcal/d) below.
and 0.03-4)26 g blood depending on the species (19). Less than The 1968 WHO monograph on nutrition and infection (I)
one-half of iron lost in this way is reabsonbed. Chronic urinary summarized conclusions from experimental animal and human

60

IL.
I
I-,

I I
It-
I
I
I
I I
: I I

fir
I I
II I I I
I I

--E-- I

:iiH
I I
I If

i: . Li _ - ----
12 18 24

Fl(;URE I. Percentage of days sick per semester fr children in the maternal supplementation and complementary feeding group (solid bars) compared
with children breast-fed by unsupplemented mothers who received no complementary ftod from the program (dashed bars). Values are for the first 30 wk
of the supplementation program. .t ± SD. Reproduced with permission from the International Nutrition Foundation (20).
 NUTRITION. INFECTION, AND IMMUNITY 467S

TABLE 1 not be synthesized without a balance of essential amino acids.

Antimicrobial systenis iii the neutrophil experimental amino acid deficiencies have the same effict.
Essentially all forms of immunity have been shown to be
Oxygen depetident
affected by protein-energy malnutrition in young children,
MPG dependent
depending on the severity of the protein deficiency relative to
MPO. halide. HO
MPO independent energy. Effects include impaired antibody formation (33-37).
H,O decreased serum immunoglobulin (38), decreased secretory
1-lydroxyl radical (OH) immunoglobulin A (39-42). decreased thymic function (43-
Singlet oxygen (‘O) SO) and splenic lymphocytes. delayed cutaneous hypersensitiv-
Superoxide anion (O) ity (51-60), decreased complement formation (53. 56. 57.
Oxygen independent 6 1-66), decreased interferon, and effects on nonspecific mech-
Acid environment
anisms that include anatomic barriers and secretory substances
Cationic proteins
such as lysozymes and mucus.
Lactoferriti
Chandra and Newberne (67) tabulated more than 1(X) refer-
Lysosomal hydrolases
ences on antibody response in malnourished subjects: 33% of
Lysozyme
Neutral protcases
the studies were performed in humans. Of all the studies.
Sequestration of phagocytic vacuole 63% showed depressed responses with malnutrition. Of the
studies in humans. 53% showed depressed responses. The
I MPO. myloperoxidase. Table adapted from Stinnert (21).
question that must be addressed for each situation is when and
whether the deficiency is sufficient to have a demonstrable
studies then available. Assembled for the first time. 325 of effect. For example, there is no doubt about the deterioration of

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these studies provided evidence that many infections were immunity in the severe protein deficiency of kwashiorkor (33-
increased in prevalence or severity by specific nutritional de- 37). However. the failure of antibody fbrmation is reversed
ficiencies. However, 93 studies, almost all of them in expeni- within a few days of protein therapy as amino acids become
mental animals, indicated that it was possible to produce defi- available for the synthesis of immune proteins as in the studies
ciencies that were sufficiently severe enough to affect of Fernandez (68) and Brown and Katz (69).
replication of the infectious agent. The monograph introduced The severely malnourished preschool children studied by
the terms synergism to describe the former and antagonis?n to Chandra and Newberne (67) in Hyderabdad showed most of
characterize the latter. the effects on immunity discussed above. In field studies,
At the time of this 1968 monograph there was already however, results depend on the degree of malnutrition, the
extensive evidence, mainly from studies in experimental ani- nature of the antigen, and the immune functions tested. For
mals, of the depressing effects of a variety of nutrient deficien- example. in studies of undernourished African preschool chil-
cies on antibody formation and leukocyte function. There was dren. response to typhoid and tetanus antitoxin was slightly
no corresponding body of information for effects on cell- reduced compared with that in well-nourished children but no
mediated immunity. There are. of course, now many more effect was observed with measles vaccine (70). This was pre-
published research studies and a series of books on the subject sumably because with the live virus vaccine the amount of
including ones by Stinnert (21), the Nestl#{233}Foundation (22), stimulating antigen was not limited by the initial amount in the
Gershwin et al (23). Bendich and Chandra (24), Chandra (25), vaccine. Low-birth weight babies were shown by Chandra in
and Cunningham-Rundles (26), as well as several reviews (12. his studies in India to have lower concentrations of cord blood
27-32). In addition. the quarterly Journal of Nutritional liii- tetanus antitoxin (67).
inunologv began publication in 1992. However, the overall The classical studies of Hodges with pains of adult volunteers
conclusions of the 1968 tabulation have not changed. given 0.1, 1.0, and 2.0 g protein/kg body wt for 10 wk fbund
The most important advances are 1) many more studies in poor antibody responses to tetanus and typhoid antigen in men
human subjects and the strengthened evidence for the damag- receiving the lowest amount of protein (7 1 ). The inability of
ing effects on immunity of iron and protein-energy deficiencies poorly nourished children in Narangwal. India, to produce C3
in children and 2) a veritable explosion in the sophistication of in response to infection is shown in Figure 2 (61, 62). Evi-
immunologic studies, including studies of the role of cytokines. dence for the immunologic effects of moderate malnutrition
Much of the evidence relates to deficiencies of specific nutni- comes from studies in Bangladesh in which children with low
ents, some of which are summarized below. Where specific weight-for-age had fewer positive skin reactions to common
references are not given they can be found in the books and bacterial antigens. The higher the proportion of anergy. the
reviews listed above. higher the diarrheal disease rate (72, 73). Immunoglohulin
concentrations in malnourished subjects vary with the specific
Protein
immunoglobulins, the presence and nature of concurrent infec-
More than 100 studies in experimental animals alone have tion, and the nature and severity of the nutritional deficiency
shown the adverse effects of protein deficiency on immunity (74, 75).
and the clinical and public health significance of these studies
Specific amino acids
has been confirmed by dozens of clinical and field studies. It is
not surprising that protein deficiency is so consistently ob- Any limiting deficiency of an essential amino acid can he
served to interfere with resistance to infection because most shown in experimental animals to result in the impaired im-
immune mechanisms are dependent on cell replication or the munity associated with protein deficiency. There has also been
production of active protein compounds. Because protein can- a great deal of interest in the possibility that adding certain
468S SCRIMSHAW AND SANGIOVANNI

200

150

0)
E
C,)
0
I- %WTSTD = 79.8
z 100
w
Ui

Q_

0
0
50

% WI STD = 50

2 4 6 8 10
FEVER PREVALENCE (% DAYS)
Fl(;URE 2. Serum C3 concentrations correlated with infection morbidity indicated by the number of days of fever. Three weight categories in reference
to the standard (ek WT STD) are shown. In well-nourished children, C3 concentrations increase with infection: in undernourished children. C3

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concentrations generally decrease. Reproduced with permission (61).

amino acids, particularly arginine (76). to the diet will improve lower production of interferon, impaired delayed cutaneous
the immune response. Arginine administered in clinical studies hypersensitivy, less effective fixed fat macnophage activity,
enhanced phagocytes of alveolar macnophages (77), depressed and lower lymphocyte response to stimulation by mitogens
T suppressor cells, and stimulated T helper cells (76). The (74). Phagocytic activity may also be affected. However, there
“nonessential” amino acid glutamine is necessary for, and has is no understanding of how vitamin A deficiency exerts its
a high flux in, lymphocytes and other rapidly growing cells. effect on human resistance (23).
This may be a factor in the diminished integrity of the immune Vitamin A is essential for maintaining epidermal and muco-
system with the reduced protein turnover associated with low sal integrity but this does not appear to be compromised in the
protein intakes. Leucine administered to sheep decreased anti- populations studied. Most clinical studies find no effects on T
body response (78). cell function (89). Dietary vitamin A increased T cell mitogen-
esis in lung patients and reversed postoperative immunosup-
Vitamin A pression (74). High intakes of vitamin A are mixed in their
Experimental animals made deficient in vitamin A generally effects, enhancing some immune infections and suppressing
have increased susceptibility to infection. There have now been others (74).
several studies, eight of which are summarized in Table 2, of
13-Carotene
the effect of vitamin A administration to preschool children. In
six of these studies, large drops in mortality ranging from 30% n-Carotene in vivo can stimulate rat lymphocyte mitogenesis
to 50% were observed. Two of the studies showed no effect, (90) and increase human natural killer cell (91) and T helper
perhaps because other deficiencies were limiting. Surprisingly, cell (92) numbers. The administration of a-carotene to elderly
morbidity was not affected (88). humans increased the ratio of CD4 to CD8 but had no effect on
Vitamin A-deficient experimental animals have decreased natural killer cells, virgin T cells, memory T cells, or cytotoxic
thymus and spleen sizes. reduced natural killer cell activity, T cells (93). a-Carotene added in vitro to human lymphatic
cultures stimulated natural killer cell activity but did not affect
other T cell subsets (94).
TABLE 2
Results of eight vitamin A intervention trials on mortality of young B vitamins
children’
Pynidoxine deficiency has been associated with reduced cell-
Site Percent effect mediated immunity in both experimental animals and in hu-
mans. Hodges et al (95) reported that subjects given a diet
()
deficient in pantothenate had a normal response to typhoid
Aceh. Indonesia (79) -27
Sudan (80) 4 antigen but a reduced response to tetanus toxoid. With pyri-
Hyderabad, India (81. 82) -6 doxine deficiency, formation of antibodies against tetanus and
Jumla, Nepal (83) -26 typhoid was slightly reduced (96). With combined pantothe-
Sarlahi. Nepal (84) -29 nate and pynidoxine deficiency, the immunologic response was
Ghana (VAST Study) (85) -20 almost completely inhibited but became excellent when these
Bogor. Indonesia (86) -30 vitamins were restored to the diet (97).
Tamil Nadu, India (87) -50
Folic acid and vitamin B-12 are so essential to cellular
I Mean relative risk: 0.77: 95% Cl: 0.68. 0.84. From Beaton et al (88). replication that the finding that experimental deficiencies of
 NUTRITION, INFECTION. AND IMMUNITY 469S

these vitamins interfere with both antibody formation and iron supplementation of iron-deficient populations results in
replication of stimulated leukocytes was expected. The vita- decreased frequency of infectious episodes. The reported ef-
mins are also associated with thymic atrophy, as is choline fects of iron deficiency on immune function are listed in Table
deficiency. In folic acid deficiency anemia, cell-mediated im- 5. Mechanisms clearly identified are impaired phagocytic kill-
munity is depressed (98). ing power. less response to lymphocyte stimulation, fewer
natural killer cells associated with reduced interferon produc-
Vitamin C tion, and depressed delayed cutaneous hypersensitivity. Appar-
The reported immunologic and related consequences of ently B cell and antibody formation are not affected. Bryan and
ascorbic acid deficiency are listed in Table 3. Decreased neu- Stone (147) provided an extensive review and analysis of the
trophil function, impaired delayed cutaneous hypersensitivity, immunologically related properties of the iron molecule.
and abnormal serum complement concentrations have been One of the most revealing animal studies is one conducted by
documented in studies in both experimental animals and human Baggs and Miller (144). who found more viable intracellular
subjects. Reduced phagocytic response and killing power as and extracellular bacteria in the macrophages and intestinal
well as reduced antibody response have been described in walls of iron-deficient rats with experimental salmonellosis
clinical studies. Studies of experimentally induced scurvy in than in iron-replete animals. This was paralleled by the con-
humans found normal lymphocyte stimulation response in vitro centrations in the intestinal wall of the iron-containing enzyme
to T cell mitogens and no change in lymphocyte subsets (1 1 1). myeloperoxidase, which mediates the iodination of proteins
There is not conclusive evidence to support the hypothesis that and the formation of hydrogen peroxide to kill microorganisms
ascorbic acid deficiency in humans leads to either altered within the cell.
cell-mediated on humoral immunity. The many claims of a Chandra et al ( 145) showed a relation in Indian children
favorable effect on infection of massive doses of vitamin C between hemoglobin status and the capacity of lymphocytes to

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have not been confirmed in studies with acceptable expenimen- react to antigenic stimulation (Figure 3. top). He also showed
tal designs and are not reviewed here. the reduced capacity of phagocytes from malnourished Indian
children to produce a respiratory burst (Figure 3, bottom) and
Vitamin D hence a decrease in phagocytic killing power (Figure 3, mid-
dIe) (145). There is extensive evidence for a direct relation
Vitamin D serves as both an immunoregulatory hormone and
between iron status and plasma T lymphocyte concentrations
a lymphocyte differentiation hormone in addition to its role in
(67, 147). Impaired delayed cutaneous hypersensitivity to
mineral homeostasis.
several ubiquitous antigens has also been described in iron-
Vitamin E deficient children (67).

Alterations in immunity reported with vitamin E deficiency

are listed in Table 4. Reduced lymphocyte and leukocyte Iron overload and infection
killing power has been shown in humans as well as in expen- Any discussion of the effect of dietary iron on immunity is
imental animals. In animals it was shown to interfere with incomplete without discussion of the biological mechanisms
antibody formation, plaque-forming cells, and other aspects of for withholding iron from invading organisms ( 148). Iron is
cell-mediated immunity. Vitamin E supplementation has been needed for a wide variety of biochemical functions not only by
reported to enhance both humoral and cell-mediated immunity the host but also by the infectious agent (149). Transferrmn is
and to augment the efficacy of phagocytosis in experimental found not only in blood but in all body fluids and is the normal
and farm animals and humans (23, 121, 129, 130). Vitamin E mechanism for withholding iron from the infectious agent. as is
is one of the few nutrients for which supplementation at higher lactoferrmn. Conalbumin and lactoferrin have stronger iron
than recommended levels has been shown to enhance immune binding properties than do most bacterial siderophores and are
response and resistance to disease ( 1 2 1). normally highly unsaturated.
Ferritin is the storage form of iron and as ferritin molecules
Iron
become saturated with iron, some is metabolized to the inert
Iron deficiency is the most widespread nutrient deficiency in intracellular femc ion, hemosidenin. When molecules of lacto-
the world today and in field studies is consistently associated ferrmn become ‘‘40% saturated with iron, they are assimilated
with increased morbidity from infectious diseases. Moreover. by macnophages that have been attracted to the site of infection

TABLE 3
Vitamin C deficiency causes the following decreases in immune function’

Decreased immune function Animal Human

T lyniphocyte response Guinea pig (99) Elderly subjects ( 1(8))
Delayed cutaneous hypersensitivity Guinea pig ( 101 . 102) Experimentally induced deficiency ( 103). elderly subjects ( 1(8). l04
Phagocytic function Guinea pig ( 101, 102. 105-107) -

Killing power Guinea pig (106, 107) -

Complement formation or function Guinea pig ( lOS. 109) Gupta (75). in Cunningham-Rundles (26). states: “Vitamin C deficiency
in humans is associated with . . . an impairment of complement activity”
Epithelial integrity Guinea pig ( I 10) Spongy gums, subcutaneous hemorrhages

, Vitamin C may also act by increasing iron absorption.

470S SCRIMSHAW AND SANGIOVANNI

TABLE 4
Vitamin E deficiency causes the following decreases in immune function

Decreased immune function Animal Human

Humoral response. B cell function Mice (I 12-I 15). rats (I 16) -

Inimutioglohulins Mice (I 13) -

T lymphocyte response Mice ( I 14. 1 15). rats ( I 16). pigs ( I 17). Severe vitamin E deficiency ( 120. 121 ). premature infants
sheep ( I IS). dogs ( I 19) respond to vitamin E supplementation ( l22
Delayed cutaneous hypersensitivity - Severe vitamin E deficiency ( I 20, 12 I).
vitamin E-deficient patients with tropical sprue (123)
Phagocytic function Mice ( I I 5). rats ( I 24-I 26). pigs ( I I 7) Severe vitamin E deficiency ( I 20, 1 2 1 ), glutathione-
deficient neonates ( I 27)
Hemmagglutination titers Mice ( I I 2. 1 1 3) -

Cytokine or lymphokine function or production Rats ( I 28) Severe vitamin deficiency ( I 20, 121)

and much of the iron is incorporated into ferritin. Ferritin zinc deficiency in animals is associated with the wide range of
functions as an iron-withholding rather than as an inon-trans- immunologically related consequences listed in Table 6.
port agent. These include extensive changes in T cell-related indexes. In
Lactoferrmn, known to be released during degranulation of the genetic disease acrodermatosis enteropathica-character-
leukocytes in aseptic areas, is a major component of human ized by reduced intestinal zinc absorption-thymic atrophy,

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milk and resists proteolytic destruction in the gastrointestinal impaired lymphocytosis. and impaired response to stimulation
tract. It is not difficult to show in vitro the protective effect of are observed. However, unlike the situation for iron, there is no
lactoferrmn. In an iron-deficient host with reduced immune evidence that zinc deficiency in the underprivileged human
function, lack of available iron for agent replication is protec- populations of developing countries is severe enough to affect
tive. Baggs and Miller (144) found that in rats exposed to a immunity. Nevertheless, the number of publications reporting
standard dose of Salmonella, a diet lacking in iron is almost as the effects of experimental zinc deficiency on immunity out-
protective as one meeting iron needs. number those on iron by a ratio of 20 to I . Excessive zinc
When individuals whose resistance to infection is compro- intakes also impair immune responses (201).
mised by iron deficiency are given parentenal iron or large
doses of oral iron, a disastrous exacerbation of the infection Other mineral deficiencies
and death may occur ( 150. 15 1 ). This happens because the The immune effects of copper deficiency in experimental
agent is supplied with iron for replication before the host animals are listed in Table 7. They include both B cell- and T
immune system has had time to recover. However, in field
cell-related deficiencies. Impaired antibody formation, inflam-
studies, supplementation of poorly nourished adults with phys- matory response, phagocytic killing power, and lymphocyte
iologic amounts of up to 100 mg Fe/d and proportionately less stimulation responses. as well as thymic atrophy. have been
for children, consistently results in decreased morbidity from well documented. The only clinical relevance of these obser-
infectious disease. It is important to recognize that there is a vations is to children with Menkes syndrome. a rare congenital
fairly large range of iron intakes over which the immune
disease resulting in copper deficiency. Among its symptoms
system can function normally. are increased bacterial infections, diarrhea, and bnonchopneu-
monia. Note that anemia and reduced serum iron are charac-
Zinc deficiency
teristics of copper deficiency in rats that are not corrected by
Zinc is a ubiquitous trace metal essential to the development iron administration.
and maintenance of the immune system and that influences Magnesium participates in all major metabolic pathways
both lymphocyte and phagocyte cell functions (152-155). and is an obligate cofactor for DNA synthesis (216). The
More than 100 metalloenzymes have been identified that are immune effects of magnesium deficiency in experimental
zinc dependent. It is not surprising, therefore, that experimental animals are listed in Table 8. Effects include the same range

TABLE 5
Iron deficiency causes the following decreases in immune function

Decreased inimune function Animal Human

Humoral response, B cell function Rats (131. 132) (131. 133. 134)
Immunoglobulins Rats ( I 3 1) -

Thyniic structure or function Rats (135-137) -

T lymphocyte response Mice (138) (61. 67. 133. 134. 139-142)

Delayed cutaneous hypersensitivity - (67. 141. 142)
Phagocytic function Rats ( 143) -

Killing power Rats (144 (145)

Cytokine or lymphokine function or production Rats ( 146) -
 NUTRITION. INFECTION. AND IMMUNITY 47 1S

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Fl(;tJRE 3. Lymphocyte proliferation ( top). intricellular bactericidal capacity of neutrophils ( middle I, and quantitative nitroblue tetrazoliuni I N BT ) test
(bottom) related to serutii transferrin saturation. The shaded areas represent the means and ranges of values obtained in iron-replete control subjects.
Reproduced with permission (145).

of altered T and B cell functions as described for copper and Overnutrition and infection
zinc deficiencies. For these minerals. there is no evidence of
any public health significance to these observations because Definitive studies on the effects of overnutnition on immune
they have been limited to experimental animals. Selenium systeni function in humans are lacking. Lower respiratory tract
deficiency can also affect all coniponents of the immune infections have been reported to be higher in obese than in
systeni (228). nonobese infants (229). Overfed and obese beagle dogs. chal-

TABLE 6
Zinc deficiency causes the following decreases in immune function’

Decreased immune function Animal Human

Humoral response. B cell function Rodents ( 156. rats (157) -

T cell-dependent antigens (SRBC) Mice (158-168) -

T cell-independent antigens (dextran) Mice (161. 166. 167. 169) -

Immunoglobulins Mice ( 163. 164. 166. 168. 170) (171)

Thymic structure or function Mice ( 158-160. 164. 165. 167. 170. 172-175. rats ( 176-178. pigs ( 169, l83-I85
( I 79. I 80), Holstein-Friesiati cattle ( I 81-183)
Cell-mediated immunity functions Mice ( 158. 168). rats ( 186) ( 184)
Tlymphocyteresponse Mice(l60. 165. 169. 170. 172. 173. 187).rats(157. 166. 178. 188) (171. 183. 189, 192
Delayed cutaneous hypersensitivity Mice (158. 169. 170. 193. I94 (169. 171. 83. 85)
Phagocytic function Mice ( 169, 187. 194-197 ( 199)
Killitig power Mice ( 195. 197. 198) -

Cytokine or lyniphokine function or production Mice ( I 65 . rats ( I 86. I 93 ) ( 2(X)

‘ SRBC. sheep red blood cells.

472S SCRIMSHAW AND SANGIOVANNI

TABLE 7
Copper deficiency causes the following decreases in immune function

Decreased immune function Animal

Humoral response. B cell function Rodents (202). mice (203-206). rats (207, 208)
Immunoglobulins Mice (204)
Thymic structure Mice (202)
Cell-mediated immunity functions Mice (203. 209), rats (208)
T lymphocyte response Rodents (202), mice ( 187. 203. 206, 210), rats (21 1, 212)
Phagocytic function Mice (202. 203). rats (212, 213). sheep (214). cattle (214, 215)
Cytokine or lymphokine function or production Mice (204)

TABLE 8 responsible. Iron deficiency and protein-energy malnutri-

Magnesiun deficiency causes the following decreases in immune tion, both highly prevalent, have the greatest public health
function importance. El

Decreased immune function Animal

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