Clinical Science (1984) 66, 241-248
I
241
EDITORUL R E m W
The influence of undernutrition on immunity
PAULINE S. DOWD A N D RICHARD V. HEATLEY
Department of Medicine, St James’s University Hospital, Leeds, U.K.
Undernourishment has been suggested to be the
most frequent cause of secondary immunodeficiency in man [l]. The main practical importance
of this is that both epidemiological and clinical
studies have indicated that nutritional deficiency
leads to a significant increased susceptibility to
infection 12-41. This is especially common in
developing countries where malnutrition and infection frequently coexist. The interaction between
nutritional state and immunological function is
complex, with many factors, in particular the
nature of disease, concurrent infection, type and
duration of malnutrition, age of the subject and
the presence of specific nutrient deficiencies,
affecting the interpretation of studies.
The majority of studies on the interrelationship
of nutrition and immunity have concerned themselves with paediatric protein calorie malnutrition
(PCM) in developing countries. However, PCM also
occurs in the Western world, particularly in hospital
patients [5-8].
Proteiu4orie malnutrition and immunity
The most severe effects of PCM on immune function appear to be related to cell-mediated immunity
[9-111. Severe thymic atrophy is a striking and
consistent finding in undernourished children and
similar, but less marked, changes in size and cellular
composition (particularly in T cell areas) of other
peripheral lymphoid organs are also seen [4].
Decreases in both the size of induration and incidence of positive responses have been reported in
malnourished children skin tested with a variety of
recall antigens [9,11,12] and one study supports
the concept of a threshold protein intake as an
indicator below which cellular immunity may be
impaired [121.
Lymphocyte transformation in response to T
cell mitogens in vitro have been found to be depressed in both severe and moderate malnutrition
[9,10,13] although some studies report normal
values [ 14, 151. Differences may be attributable to
the type of serum used since serum from patients
with PCM has been shown to depress proliferation
[16]. This could be because of low serum zinc
levels, a trace element required for optimal
lymphocyte transformation [17].
The depression of lymphoproliferation may
partially be attributed to the reduced numbers of
circulating T cells described in PCM [18, 191.
Alterations in T lymphocyte subsets have been
demonstrated with a depression of Tp (helper) cells
and a slight increase in T r (suppressor) cells [19].
The increase in T r cells is thought to account for
the increased lymphocyte mediated cytotoxicity
and antibody dependent cellular cytotoxicity
(ADCC), observed in malnourished children [20].
In contrast, natural killer (NK) cell activity, may
be reduced in malnourished children [21]. NK cell
activity is enhanced by interferon in normal individuals but this does not occur in undernourished
children [21]. The production of interferon (in
vifro) has also been shown to be decreased in
marasmic infants [22].
Alterations in humoral immunity [23], phagocytosis [24] and the complement system [25] have
also been described in PCM. The effects of PCM on
some of these aspects of immunity are outlined in
Table 1. Conflicting results from some of these
studies may be due to differences in experimental
technique, genetic influences, pathogen exposure,
differences in dietary patterns and overall balance
of nutrients. These factors may also explain some
of the differences between human and animal
studies of PCM.
In animal models of PCM the diet consists of
normal proportions of vitamins and trace elements,
which is rarely the case in human PCM where coexisting nutritional deficiencies are usually present.
In a study of malnourished Ghanaian children [9],
for instance, a significant association between
features of PCM (depressed anthropometric
measurements and serum proteins) and impaired
cellular immunity was shown. Furthermore, the
contribution of specific nutritional deficiencies in
P. S. Dowd and R. V. Heatley
242
TABLE1. Summary of the effects of protein-calorie malnutrition on immune function
PMN, Polymorphonuclear leucocyte; RES, reticuloendothelial system; N, normal;
4, depressed; ?, increased.
Lymphoid anatomy [ 4 ]
Thymus
Spleen
Lymph nodes
Other lymphoid tissue
Total circulating lymphocytes
Humoral immunity [23]
Circulating B lymphocytes
Serum Ig levels
Serum Ab. response to Ag.
Secretory IgA
Splenic plaque forming cell response
Cellular immunity [9-111
Circulating T lymphocytes [ 18,191
Delayed cutaneous hypersensitivity (9, 1 1 , 141
Allograft rejection
Tumour cytotoxicity
Immunity to intracellular organisms
Lymphocyte proliferation 19, 1 0 , 1 5 , 16,171
(a) Concanavalin A
(b) PHA
(c) PWM
Lymphokine production [22]
Phagocytic function [27]
Monocyte chemotaxis
PMN chemotaxis
PMN phagocytosis
RES function
lntracellular killing
Complement [25]
producing decreased cellular immunity was suggested by significant correlations between serum
iron and haemoglobin, carotene, vitamin C and
pyridoxine and measures of cellular immunity.
The results suggest that, in malnourished individuals, there may be differences in the relative
importance of certain micronutrients in inducing
immunological impairment.
Single nutrient deficiencies
Iron
Iron deficiency in experimental animals leads to
an increased susceptibility t o infection [26]. In
human studies, the association between iron
deficiency and infection is variable and inconclusive [27]. Humoral immunity is generally thought
to remain intact, although a decrease in antibody
production after immunization with tetanus
toxoid proportional to the degree of deficiency
has been shown [28].
In clinical studies conflicting results have been
reported on the effects of iron deficiency on cellu-
Human
Animal
3
1
+
1
+
1
+ or N
t orN
1.
+
1.
.I
+
+
+
+
+
+
+
+
N or t or
+
t
+
1 or N
+ or N
N or t or 3
t or N
+
+
N
N
+ or N
1
1.
t
t or
N
$
+
lar immunity [27,29,30]. Total circulating lymphocyte numbers have been variously reported as
being increased, normal or decreased in iron deficient children, whereas the proportion of T cells
is usually reduced [27].
Iron deficient young rats show lymphoid tissue
abnormalities, including a marked increase in
thymic cell numbers [31]. Altered mitogen
responses are also observed with splenic cells
exhibiting enhanced responses, whereas thymocytes showed depressed responses [32], suggesting
that iron deficiency may have a differential effect
on lymphoid populations.
Iron deficiency has also been shown to influence
phagocytic cell function, the primary defect being
a reduction in bacterial killing ability [27].
Zinc
Many studies recently have examined the effects
of zinc deficiency on immunological function,
focusing particularly on cell-mediated immunity.
In the hereditary zinc deficiency disease, acrodermatitis enteropathica, T cell numbers, mitogen
Nutrition and immunity
proliferation and delayed cutaneous hypersensitivity (DCH) responses are all depressed [33] and
are corrected by zinc administration. A similar
condition can develop after prolonged total
parenteral nutrition in the absence of sufficient
zinc, and impairment of cellular immunity has
been reported in a number of these cases [34-361.
An association between zinc deficiency and
impaired immune function has been documented
in a number of clinical conditions. In patients with
Down’s syndrome low serum zinc levels, impaired
DCH responses, lymphocyte transformation and
neutrophil chemotaxis, have been improved with
zinc supplementation [37]. Uraemic patients supplemented with zinc were found to have positive
responses to mumps skin test antigen, whereas the
majority of untreated patients did not [38]. In
haemodialysis patients, moderate zinc deficiency
was shown to result in lower granulocyte zinc
concentrations and reduced granulocyte motility;
however, lymphocyte zinc concentrations and
mitogenic responses were normal [39].
Animal studies have confirmed that cell mediated
immunity is depressed in zinc deficiency. Thymic
atrophy, a commonly described feature [40,41],
is reversed by zinc replacement even in adult mice
in whom thymic involution due to ageing has
already begun [41]. Lymphoid cells from the
spleen, thymus and peripheral blood of zinc deficient rats have impaired proliferative responses to
mitogens [42] and zinc deficient mice have impaired T cell killer activity in response to tumour
challenge in vivo [43,44].
NK cell activity and ADCC have been shown to
be depressed [43] or increased [40] in zinc deficient mice. Discrepancies in these results could be
explained by differences in the zinc content of the
test systems. The removal of zinc from media and
serum has been shown to depress lymphocyte
responses to mitogen stimulation in vitro by
40-60% [171. In addition to being necessary for
optimal blastogenesis, zinc ions themselves have
mitogenic properties in vitro at concentrations
higher than are normally found in serum [45].
Depression in the antibody-forming capacity
of splenic cells from zinc deficient mice after
immunization with sheep erythrocytes has been
described [40,41,43]. Gestational zinc deficiency
has been shown to lead to a reduction of this
response in the offspring, the impairment remaining detectable in the second and third filial generations in spite of adequate feeding [46].
Pyridoxine
In animal models of pyridoxine deprivation,
atrophy of lymphoid tissues, lymphopenia and a
243
reduction in the quality and quantity of the antibody produced in response to antigenic stimulation
are seen. Impaired delayed hypersensitivity
responses and the inhibition of skin transplant
rejection have also been described [47].
A number of studies have reported low vitamin
B6 levels in uraemic patients [48,49] and depressed
reactivity in mixed lymphocyte cultures from
uraemic patients was reversed by oral vitamin B6
supplementation [48].
Folate and vitamin B12
Deficiency of vitamin B12and folic acid induces
changes in a number of actively replicating tissues.
In patients with megaloblastic anaemia due to
folate deficiency, depression of cell-mediated
immune responses (in particular lymphocyte proliferation) has been described [30],
In patients with combined PCM and folate
deficiency depression in phagocytic and bactericidal polymorphonuclear leucocyte functions
occurs. Folate supplementation was associated
with recovery of phagocytosis but not bactericidal
function [50]. A report suggesting that monophosphate shunt and phagocytic activity was
depressed in patients with vitamin Bl2 deficiency
but not in patients with folate deficiency [5 11 has
not been confirmed [52].
Vitamin C
The high ascorbic acid concentration of leucocytes and in particular lymphocytes, and its rapid
expenditure during infection and phagocytosis,
suggest that this vitamin has a vital role in supporting immunological surveillance [53].
Enhancement of lymphoproliferation in response to mitogens has been shown in vitamin C
supplemented normal individuals [54] but no
depression in response to the mitogen phytohaemagglutinin (PHA) was shown in experimentally
deprived human subjects [ 5 5 ] . A depression in
response to stimulation with the mitogen concanavalin A was observed in malnourished patients
with ascorbic acid deficiency [56] and a significant
correlation between ascorbic acid and responses
to PHA was shown in malnourished children [9].
These studies suggest that depression of lymphoproliferation occurs only in combination with
deprivation of other nutrients.
NK cell activity is thought to play a role in
combating viral infections and a significant correlation between leucocyte ascorbic acid levels and
NK cell function has been observed in malnourished
hospital patients [56]. Interferon is produced in
response to viral infection and ascorbic acid has
244
I? S. Dowd and R. V. Heatley
been shown to enhance interferon levels produced
by human embryo skin and lung fibroblasts induced
by Newcastle disease virus and polyinosinic-polycytidylic acid [57]. Circulating levels of interferon
in mice have also been enhanced with ascorbic acid
supplementation [58].
Vitamin C influences phagocytic cell migration
and killing functions and vitamin C supplementation improves the phagocytic function in children
with the congenital neutrophil defect in ChediakHigashi syndrome [59].
Vitamin A
Deficiency of vitamin A leads to an increased
host susceptibility t o infection [60] due partly to
the importance of vitamin A in maintaining the
functional integrity of epithelial and mucosal
surfaces.
In vitamin A deficient animals depressed antibody responses to antigenic stimulation [61] and
impaired lymphocyte proliferation [62] have been
reported. In contrast, human clinical studies of
vitamin A deficiency have shown no impairment
of humoral immunity or lymphocyte proliferation [63]. However, some vitamin A deficient
children do have impaired delayed hypersensitivity
responses t o recall antigens [29].
Immunocompetence in clinical states
In hospitalized patients malnutrition, infection
and decreased immunocompetence frequently coexist and for most patients establishment of the
primary causative factor is virtually impossible.
Impaired immunocompetence is important since it
is independently associated with a considerably
increased rate of sepsis and mortality [64]. However, many factors in hospitalized patients apart
from malnutrition may be responsible for producing diminished immune competence, including
drugs, infection, neoplastic disease, skeletal and
soft tissue trauma, burns, shock, uncomplicated
elective operation and anaesthetic agents [65-681.
Although the mechanisms generally are unclear, in
one of the above conditions nutrition has been
implicated since postoperative depression of
cellular immune responsiveness can be prevented
by pharmacological doses of vitamin A [69].
Infection and undernutrition
Nutrition appears to be a critical determinant
of susceptibility to infection. For instance. chronic
fungal infection and recurrent herpes labialis occur
in individuals with iron deficiency and impaired
cellular immunity and respond to iron admini-
stration [70, 711. Similarly, although serum
antibody responses to immunization with most
micro-organisms are generally normal in malnourished individuals, this may well not be the case
for the mucosal immune response to polio virus
or the cell-mediated response to BCG immunization [72].
Medical conditions
Undernutrition and depression of cellular
immunity have been reported to affect between
30 and 50% of all patients with medical conditions in hospital [6]. Patients most affected are
those with chronic liver disease, chronic renal
failure and some paediatric and geriatric populations. However, positive correlation between
nutritional deprivation and depressed immunocompetence is poorly documented except in
patients with liver disease and the elderly [8, 73751.
Surgical patients
Undernourishment of surgical patients undoubtedly impairs their resistance to infection
[76]. In hypoproteinaemic surgical patients there is
an increased incidence and severity of postoperative
and terminal infections [77,78]. Furthermore, the
most common complication in malnourished
patients is reported to be sepsis [79]. In undernourished patients undergoing surgical treatment
for peptic ulcers, for example, a 33% mortality
rate has been recorded in those with a pre-operative
weight loss of greater than 20% of their body
weight, many deaths being due to infection.
Patients with a better nutritional state experienced
a mortality rate of only one-tenth of this figure
[go].
Patients with cancer
In cancer patients, undernutrition and decreased
immunocompetence frequently occur. Cancer
patients appear t o be especially at risk from infection and fatal infections are a major cause of
death affecting about 50% of those dying with
solid wmours [81]. In patients with lymphoreticular malignancies, Pneumocystis carinii infection
most commonly occurs in those with low serum
albumin levels and the incidence of life-threatening
infection in childhood leukaemia appears to be
related to nutritional status and nitrogen losses
[72,82]. In cancer patients undergoing surgery,
septic complications are common and are probably
linked to immune competence. In one study, sepsis
occurred in 37% of patients who had normal fea-
Nutrition and immunity
tures of immune function, 46% of those with signs
of depressed immune function and 83% of patients
who were anergic [83]. Skin test reactivity to antigens is generally reduced in cancer patients and in
patients undergoing surgery for cancer. Tests of
cell-mediated immunity and complement levels
are also often reduced and correlate positively
with nutritional deficiencies [84,85].
Nutritional indices are predictive of immunological reactivity in cancer patients and both factors
have prognostic significance [86]. Patients with
significant nutritional depletion, reduced lymphocyte numbers and tests of cell-mediated immunity
have higher postoperative morbidity and mortality
[87]. In animal models the amount and composition of dietary intake significantly alters tumour
incidence and growth. This may be partly influenced by changes in cell-mediated immunity and
blocking antibody [88-901. In cancer patients,
correction of nutritional deficiency and attainment of positive nitrogen balance have been
reported in some studies to improve immune
competence and tumour responsiveness t o chemotherapy and reduce postoperative complications
[91,92].
Effects o f nutritional treatment
There have been a number of attempts to
return tests of immune function to normal by
nutritional repletion. In several studies, oral and
intravenous nutritional supplementation has proven
beneficial [66,85,93,94]. Since the most undernourished patients in clinical practice are usually
those with cancer, particularly that affecting the
gastrointestinal tract, many studies have concentrated on these patients. It has been claimed that
intravenous feeding restored skin-test reactivity in
50% of undernourished cancer patients undergoing
a variety of treatments [85]. In controlled studies
of pre-operative intravenous feeding in patients
with gastrointestinal cancer, postoperative infective
complications have been shown to be significantly
reduced with and without measurable improvement
in humoral and cellular immunocompetence [95,
961.
Infection is also a major complication of acute
renal failure and the morbidity and mortality of
this condition have been shown to be significantly
reduced, in a controlled trial, by intravenous
feeding [97].
In patients with Crohn’s disease undernutrition
is relatively common [98]. This results in diminished anthropometric measurements and serum
proteins and is also associated with a significant
reduction in circulating T-lymphocyte numbers,
monocyte function tests (phagocytosis and adher-
245
ence), mitogen-induced immunoglobulin production in vitro and increased circulating immune
complex levels [99]. In a controlled cross-over
trial these patients were given oral nutritional
supplements for treatment periods of 2 months.
Significant improvement in anthropometric
measurements, serum protein levels and tests of
immune function were observed during the course
of nutritional replenishment, implicating undernutrition as a prime factor in the original diminished immune competence [1001.
Nutritional influences on mucosal immunity
Although most evidence concerning the influence of nutritional deprivation on immune defences
relates to systemic immunity, undernutrition also
increases the frequency of infection at mucosal
surfaces, particularly in the intestinal and respiratory tracts [104]. In undernourished individuals
levels of secretory IgA (sIgA) and in some cases
lysozyme are reduced in many external secretions,
namely salivary, lacrimal, nasopharyngeal and
intestinal secretions and the numbers of IgA
secreting plasma cells are reduced in the jejunum
[101, 1021. Furthermore, nasopharyngeal sIgA
antibodies to viral antigens are significantly reduced
with live attenuated polio virus although normal
serum antibody responses occur [103].
Similar reductions in antibody levels occur in
the external secretions of protein-deprived animals
and it has been shown that PCM and vitamin A
deficiency inhibit the traffic of labelled mesenteric
lymph node cells to the small intestine [104].
In malnourished children, high titres of circulating food antibodies of the IgG and IgA classes
are often found. This may be due to increased
uptake of antigens from the small intestine, since
this has been demonstrated to occur in proteindeprived rats [105,106].
Conclusion
On a worldwide basis nutritional deprivation is one
of the commonest afflictions of mankind. Many of
the complications of undernutrition are ill-understood but the implications of its multitudinous
effects on the immune system are undoubtedly
far-reaching. In a clinical context, the picture is
often confused, since single nutrient deficiency
only rarely occurs. This is probably one of the
many reasons why data obtained from animal
experiments are often at variance with human
studies. Furthermore, most currently available
test systems of immune function in vitro are
dependent upon standard nutrient conditions,
which can only occasionally be reproduced when
examining samples from undernourished subjects.
246
P. S. Dowd and R. V. Heatley
We will increase our knowledge of the role of
nutrient status in the normal functions of the
body’s defence mechanisms only by conducting
carefully planned and executed studies. That
further understanding is a necessity is influenced
by the hope that even if it is impossible to replete
all nutritionally deprived individuals adequately,
specific nutritional supplementation may one day
alleviate some of the devastating accompaniments
of starvation.
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