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Institute of Parasitology, School of Dietetics and Human Nutrition, McGill University, Macdonald Campus, Ste-Anne de Bellevue, Quebec H9X 3V9, Canada
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONGALT in intestinal infectionsEvidence that zinc deficiency...Experimental model: H. polygyrus...Effect of zinc deficiency...Suggestions for future researchREFERENCES |
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KEY WORDS: • zinc deficiency • immunity • nematode infection • T helper cells • energy restriction • gut-associated lymphoid tissue
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONGALT in intestinal infectionsEvidence that zinc deficiency...Experimental model: H. polygyrus...Effect of zinc deficiency...Suggestions for future researchREFERENCES |
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,
Welsh et al. 1998
). Mucus secretion and formation of
tight cell junctions prevent the entry of bacteria and other pathogenic
antigens, and rapid mucosal turnover enables the repair of epithelial
or lymphoid cells damaged by parasitic infections.
Many nutritional deficiencies have been shown to cause atrophy of
lymphoid tissues, leading to lower numbers of immune cells and
functional defects during antigen-specific responses. Specifically,
zinc deficiency causes atrophy of lymphoid tissues (Keen and Gershwin 1990
, Shi et al. 1994
) and depressed
cutaneous delayed-type hypersensitivity reactions
(Sempertegui et al. 1996
, Shi et al. 1994
). In animals, experimental zinc deficiency reduces
antibody production, T cell proliferation and cytokine production in
response to mitogens and specific antigens (reviewed by Fraker 2000
, Harbige 1996
, Scrimshaw and San Giovanni 1997
). These findings, obtained from analyses of
thymus or spleen, reflect the essential requirement for zinc by
CD4+ helper T and B cells in systemic lymphoid
organs and presumably apply to lymphoid tissues in the intestine,
although information on the effects of zinc deficiency on the barrier
function and on specific immune responses in the GI tract is severely
lacking. The gut mucosa has one of the highest protein turnover rates
of all tissues in the body (McBurney 1993
,
Nakshabendi et al. 1995
), and therefore the GALT is
likely very sensitive to changes in nutritional status (Van der Hulst et al. 1998
, Wykes et al. 1996
). Zinc
deficiency has been associated with gross abnormalities in epithelial
structure (Moran and Lewis 1985
) and thus may weaken the
epithelial barrier, allowing greater penetration and establishment of
the larval stages of GI nematodes. It may interfere with the
recruitment and localization of immune cells to the intestinal
epithelium, thus impairing the host’s ability to effectively combat
parasitic infection.
Much of the recent work in our laboratory has concentrated on the effects of zinc deficiency on the host immune response to GI nematode infections; therefore, this review focuses on the impact of zinc deficiency on infection with a GI nematode parasite and the underlying host immune responses that control parasite growth, survival and reproduction. We will argue the following: (1) the efficiency of immunological responses against gastrointestinal nematodes depends on the zinc nutriture of the host; (2) initial immunological events occurring shortly after infection at the local intestinal level orchestrate subsequent events occurring both at the gut and at more distant systemic sites; (3) zinc deficiency impairs these processes, both because of its limited concentration and because of the limited energy intake that occurs concurrent with the ingestion of a zinc-deficient diet; (4) zinc deficiency impairs not only Th1-type responses, as hypothesized in the recent literature, but also Th2-type responses; and (5) because the immune response elicited to infectious agents normally includes many redundancies, the ultimate consequence of zinc deficiency in controlling infection needs to be established in an infected host.
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GALT in intestinal infections |
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TOPABSTRACTINTRODUCTIONGALT in intestinal infectionsEvidence that zinc deficiency...Experimental model: H. polygyrus...Effect of zinc deficiency...Suggestions for future researchREFERENCES |
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, Laissue et al. 1993
,
Regoli et al. 1994
); and (2) diffuse effector
sites (intraepithelium and lamina propria), where the outcome of an
effective immune response is elimination of the infectious agent
(Beagley and Elson 1992
). Luminal antigens are
transported across epithelial barriers either by specialized epithelial
M cells or by intraepithelial lymphocytes (mostly T cells) to the
organized lymphoid tissues within the mucosa (e.g., Peyer’s patches).
After epithelial transport, antigens are processed and presented by
antigen-presenting cells (APC) such as dendritic cells, B cells,
macrophages and other intestinal epithelial cells. Naive T lymphocytes
first interact with antigen-primed APC in aggregated Peyer’s
patches and single lymphoid follicles and then further differentiate in
the germinal centers of the lymphoid follicles. Thereafter, the
antigen-specific T and B cells leave the epithelial barrier to
collect in the mesenteric lymph nodes (MLN), which drain the mucosa and
supply the peripheral bloodstream with gut-derived or locally
activated immune cells, or both. From the blood, the lymphocytes
migrate to systemic lymphoid tissues such as the spleen and peripheral
lymph nodes, where the lymphocytes proliferate and mature either into
effector lymphocytes, which secrete cytokines and mediate T
cell–dependent humoral immunity, or into memory cells that can respond
rapidly to the infection on secondary encounter (Salmi and Jalkanen 1991
). Peripheral lymphocytes can preferentially leave
the blood vessels and move into the intestinal lamina propria and
intraepithelium (Kagnoff 1996
, Shanahan 1994
) by expressing adhesion receptors that are recognized by
specific endothelial molecules lining the gut mucosal lymphoid tissues
(Smith and Weis 1996
). As a result, most of the
antigen-committed and differentiated lymphocytes that enter the
effector sites of GALT are likely to have had prior contact with, and
specific activation by, parasite antigens located in the gut mucosa.
The continuous migration of lymphocytes from intestinal lymphoid
tissues to the bloodstream and back enables the GALT to carry out two
important roles in the defense against intestinal parasites. First, it
allows delivery of the parasite antigen to peripheral sites, initiating
a widely disseminated immune response, and second, it promotes
trafficking of gut-derived lymphocytes from the blood to effector
sites within the intestinal epithelium. Gut-associated lymphocytes
further contribute to host defense against GI parasites by secreting
cytokines that regulate the appropriateness, magnitude and phenotypic
expression of immune responses (Finkelman et al. 1997
,
Mosmann and Sad 1996
). Depending on the type of
antigenic stimulus, undifferentiated T helper (Th) cells transform into
either Th1 or Th2 cells (Fig. 1
). Bacterial, viral and protozoan infections usually stimulate a Th1
response, characterized by elevated levels of Th1 cytokines [i.e.,
interleukin (IL)-2, IL-12, interferon (IFN)-
] and effectors such as
macrophages, natural killer cells and neutrophils. In such Th1
responses, cell-mediated immunity involving phagocytosis is
responsible for the functional immunity. In contrast, the immune
response to intestinal nematode parasites depends on the production of
Th2 cytokines (e.g., IL-4, IL-5, IL-10), which mediate
antibody-dependent effector responses. These Th2 cytokines released
in the GALT attract progenitors of B cells, mucosal mast cells (MMC)
and eosinophils by chemotaxis to the mucosal epithelium, where they
proliferate and mature in response to the stimulatory signals of
cytokines and parasite antigens. Nematode infections of the GI tract
induce an up-regulation of gene expression for Th2 cytokines in MLN
and Peyer’s patches before changes in splenic mRNA levels
(Svetic et al. 1993
). Local cytokines in GALT also
promote mucosal mastocytosis, proliferation of IgE-secreting B
cells in situ, transport of systemic IgE into the intestinal lumen of
nematode-infected mice and IgE-mediated MMC degranulation and
release of cytotoxic inflammatory substances (Haig et al. 1984
, Ramaswamy et al. 1996
, Wahid et al. 1994
, Wastling et al. 1997
). Moreover, recent
evidence suggests that the cytokine milieu in GALT regulates peripheral
responsiveness in spleen and other peripheral organs during intestinal
parasitic infection (Shi et al. 1998b
). Taken together,
the gut-associated immune system stimulates host resistance to
intestinal parasites through its role in antigen presentation, cell
activation and trafficking, proliferation of immune effectors that
secrete regulatory cytokines and/or mediate protection and induction of
systemic immune responses.
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hypothesized that zinc
is very important in development of the Th1 immune response necessary
for protection against such important pathogens as human
immunodeficiency virus, leprosy and leishmaniasis, and that in zinc
deficiency, IL-1 is incapable of stimulating a strong Th1 response. He
therefore hypothesized that zinc deficiency caused a switch from a Th1
to a Th2 response. By implication, his report suggested that animals
are perfectly capable of mounting a Th2 response during zinc
deficiency. In fact, by far the majority of studies on the effects of
zinc deficiency on immunity have been undertaken using antigens or
mitogens, such as sheep red blood cells (Izdebska-Szymona et al. 1991
), yeast infections (Salvin and Rabin 1984
)
and protozoan infections (Humphrey et al. 1997
), that
normally stimulate either a Th1 response or a T cell–independent
response. If a Th2 response can function normally during zinc
deficiency, parasites that are normally controlled through a Th2
response should be relatively unaffected by zinc deficiency. Our
results demonstrate that this is not the case. |
Evidence that zinc deficiency impairs intestinal immunity |
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TOPABSTRACTINTRODUCTIONGALT in intestinal infectionsEvidence that zinc deficiency...Experimental model: H. polygyrus...Effect of zinc deficiency...Suggestions for future researchREFERENCES |
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). The improvements in the
growth of and reduction in diarrheal episodes in zinc-supplemented
children were most striking in children who were moderately or severely
malnourished (Tomkins et al. 1993
) although not
necessarily zinc deficient (Sazawal et al. 1995
). Viral,
bacterial and protozoan infections that cause diarrhea are likely to
elicit a Th1 response, and therefore the finding of reduced duration
and severity of acute diarrhea in association with zinc supplementation
is consistent with the hypothesis that zinc is required for a
Th1-dependent immune response. However, we note that this and related
studies have been conducted without knowledge of the specific
etiological agent responsible for the diarrhea, with the high
probability that several infections are concurrent, including nematode
infections that cause diarrhea (and stimulate a Th2 response), and with
the likelihood that multiple nutritional deficiencies are also present
in the children. In addition, we note that the authors did not provide
evidence of improved immunological functions, in response to zinc
supplementation.
Until recently, studies on the interaction between zinc deficiency and
intestinal nematode infections have been limited in number. In humans,
plasma zinc levels were shown to be significantly negatively correlated
with numbers of Trichuris trichiura in Jamaican children
(Bundy and Golden 1987
), although it was not clear
whether the low plasma zinc levels caused higher infection levels,
whether the higher infection levels caused a depression in plasma zinc
concentration or whether the association was related to some undefined
third factor. The only human study designed to test cause and effect
was undertaken in Guatemalan children from an urban primary school.
After drug treatment for intestinal worms, reinfection rates were
monitored in children receiving daily zinc supplements over several
months compared with placebo control subjects. No reduction in
reinfection rate was detected in the zinc-supplemented children
(Grazioso et al. 1993
). Zinc supplementation did improve
the plasma zinc concentration but did not alter the hair zinc content.
These two studies highlight the difficulties associated with designing
and interpreting human trials. In the first study, virtually 100% of
the children from a place-of-safety in Kingston, Jamaica, were infected
with hundreds to thousands of T. trichiura, and close to
50% of the children were zinc deficient. In contrast, the Guatemalan
study involved primary school children in an urban setting, where the
prevalence of infection was only 28% for T. trichiura, and
21% for Ascaris lumbricoides, where the authors did not
report the intensity of infection and where only 7% of the children
were considered to be zinc deficient at the beginning of the study.
Results from laboratory studies have been more illuminating.
The first set of laboratory studies on the effects of zinc deficiency
on intestinal nematodes examined whether parasites survived for longer
periods of time in animals fed a zinc-deficient diet. Not
surprisingly, the results varied depending on the level of dietary
zinc. Fenwick et al. (1990a)
reported delayed expulsion
and higher burdens of Trichinella spiralis in rats fed a
zinc-deficient diet (3 mg zinc/kg diet) compared with control
animals, Fenwick et al. (1990b)
showed a similar pattern
in rats infected with Strongyloides ratti and Boulay et al. (1998)
reported prolonged survival of
Heligmosomoides polygyrus in mice also fed a 3 mg zinc/kg
diet. In contrast, a dietary zinc intake of 5 mg/kg did not increase
the intensity of H. polygyrus infection in mice
(Minkus et al. 1992
). The results were also dependent on
the parasite under investigation and the type of infection protocol.
Although 3 mg zinc/kg diet prolonged the survival of T.
spiralis and S. ratti in rats and of H.
polygyus in mice, it had no effect on the number or size of
Nippostrongylus brasiliensis in rats (El-Hag et al. 1989
). Also, the effect of dietary zinc deficiency (3 mg
zinc/kg diet) on H. polygyrus was evident in naive mice
responding to the infection for the first time (a "primary"
infection) but not in previously immunized mice fed a "challenge"
infection (Boulay et al. 1998
). When the level of
dietary zinc was reduced to 0.75 mg/kg, H. polygyrus
survival was enhanced in both the primary and the challenge infection
protocols. From these studies, we conclude that dietary zinc deficiency
can improve the survival of intestinal nematode parasites in animal
models under controlled experimental conditions but that the effects
are dependent on both the severity of the deficiency and the nature of
the infection.
It is important to stress that the ultimate indicators of the impact of zinc status on host immune function are the intensity, duration and severity of parasitic infection and not the number or function of immune cells from uninfected animals or humans. Helminth infections elicit strong and diversified immune responses, which are now thought to include many redundancies. If our goal is to understand the effect of zinc deficiency (or other nutritional deficiencies) on functional immunity against parasitic infections, our experimental model must stimulate the full spectrum of immune responses, so we can determine whether the impact of the zinc deficiency exceeds the host’s capacity for a multidimensional response. Otherwise, we may observe many specific immunological defects during zinc deficiency yet never understand whether they make a difference in the host’s ultimate ability to resist or control infection.
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Experimental model: H. polygyrus in mice |
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TOPABSTRACTINTRODUCTIONGALT in intestinal infectionsEvidence that zinc deficiency...Experimental model: H. polygyrus...Effect of zinc deficiency...Suggestions for future researchREFERENCES |
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, 1995
, 1997
,
1998a
). Zinc-sufficient mice were fed a 60 mg
zinc/kg diet, and zinc-deficient mice were fed a 0.75 mg zinc/kg
diet. We controlled for the reduced food intake that normally
accompanies dietary zinc deficiency (Hambidge et al. 1986
) by using a pair-fed group of mice fed 80% of the
intake of the zinc-sufficient mice. This additional control group
not only serves to highlight those effects that are directly
attributable to zinc deficiency but also provides insight into the
importance of energy restriction, per se, on the host–parasite
interaction and on the host immune responses.
H. polygyrus–infective larvae are ingested by the mouse,
and they penetrate into the submucosal musculature of the small
intestine (for a general review of the biology of this parasite, see
Scott and Tanguay, 1994
). If the mouse has never been
previously infected with this parasite, the resulting fourth stage
larvae reside in the musculature for ~1 wk, and they then migrate
back into the intestinal lumen, where they mature as adult male and
female worms that live for several months in most strains of mouse.
This type of infection is considered a "primary" infection, because
the host "sees" the parasite for the first time. The fourth stage
larvae are highly antigenic, and they stimulate the host to initiate an
immune response. However, before this response becomes fully effective,
the larvae have moved into the lumen of the intestine, where they
mature into adult worms that release an immunosuppressive factor that
protects them against host immune responses (Monroy et al. 1989
). Thus, in the race between parasite development and host
immunity, the parasite wins in a primary infection and is able to
establish a long, chronic infection. The situation changes
dramatically, however, when the parasite enters a previously infected
host that has been treated with drugs to remove the first infection.
The host is able to mount a more rapid, specific Th2 response that
attacks the larvae while they remain in the submucosa. Larval
development is delayed, and those that do migrate back into the
intestinal lumen are rapidly expelled, so that within 3–4 wk, the
infection is cleared (Monroy & Enriquez 1992
). This
infection protocol is referred to as a "challenge" infection. Thus,
depending on whether we use a primary or challenge infection protocol,
we can establish a chronic infection without protective immunity or a
more acute infection with strong, effective immune response.
Figure 2
represents the course of immunological events known to occur during
H. polygyrus infection in well-nourished mice. During
the first 6–12 h after primary infection, Th2 cytokine mRNA is
detected in Peyer’s patches, leading to the activation of Th cells and
differentiation into the Th2 phenotype (Svetic et al. 1993
). Within 1–2 d, Th2 cytokine mRNA is detectable in the
MLN, and the respective cytokines are detectable in the MLN at 2–4 d
postinfection. Peripheral responses have first been reported at 6–8 d
postinfection, as evidenced by elevated levels of antibodies
(Slater and Keymer 1988
). These responses persist during
the primary infection, although the levels never increase to the levels
reached after a challenge infection. In the challenge infection, the
exact timing of initial mRNA or cytokine production in the intestinal
cells is unknown, but mastocytosis in the intestinal epithelium occurs
very rapidly (Dehlawi and Wakelin 1988
). As noted
earlier, there is considerable evidence to support the hypothesis of
redundancy in this immune response. Urban et al. (1991)
demonstrated that the host remains able to control H.
polygyrus infections if IL-5 activity is blocked by neutralizing
antibodies and in the absence of blood eosinophilia. In addition, host
protection against H. polygyrus does not appear to require
IgG1 responses (Katona et al. 1991
); that is, blockage
of a single effector (i.e., blood eosinophils or
IgG1) or cytokine (i.e., IL-5) does not prevent
the ability of the host to resist nematode parasites. It is clear,
however, that IL-4 and IgE must be present for an effective immune
response against H. polygyrus (Finkelman et al. 1997
, Urban et al. 1991
).
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Effect of zinc deficiency on immune response to H. polygyrus |
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TOPABSTRACTINTRODUCTIONGALT in intestinal infectionsEvidence that zinc deficiency...Experimental model: H. polygyrus...Effect of zinc deficiency...Suggestions for future researchREFERENCES |
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) (Shi et al. 1995
), perhaps because of a weakened local
inflammatory response or damage to the mucosal epithelial integrity.
This accelerated development may have consequences for the subsequent
immune response, given that antigens released by larval parasites in
the serosal musculature, not adults in the gut lumen, are responsible
for priming the cascade of immunological events leading to
parasite-specific immune effectors (Pritchard et al. 1983
, Wahid & Behnke 1992
). Therefore,
zinc-deficient mice may experience less antigenic stimulation by
larval parasites, and this may reduce the response to primary infection
as well as the priming for resistance to a challenge infection.
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) can be
summarized as follows. First, worm survival was highest in
zinc-deficient mice, intermediate in pair-fed mice and poor in
zinc-sufficient mice (Fig. 4
). Zinc deficiency was associated with reduced thymus and spleen
weights, lower delayed-type hypersensitivity (DTH) reactions to
H. polygyrus antigen, reduced production of IL-4 by spleen
cells restimulated with parasite antigen in vitro and decreased levels
of IgE, IgG1 and eosinophils in circulating blood (Fig. 5
). The reduced IL-5 production and reduced DTH response late in the
infection were attributed to the effects of restricted food intake
rather than zinc deficiency. Given that these specialized immune
responses are mediated by Th2 cells, we suggest that the prolonged worm
survival in zinc-deficient mice during the primary infection was
related to impaired Th2 response due to the direct effects of zinc
deficiency on number or function of Th2 cells and possibly to the
shortened period of antigenic stimulation during the larval stage of
infection.
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), and therefore we hypothesized that zinc
deficiency would also impair acquisition of protective immunity, which
is normally stimulated during challenge infection protocols. We
measured effectors in the peripheral circulation (see Fig. 5
) and found
that zinc deficiency, but not energy restriction, impaired IgE, total
IgG1 and parasite-specific
IgG1 responses throughout the challenge infection
(Shi et al. 1997
). Peripheral eosinophilia was reduced
by zinc deficiency early in the infection and by energy restriction at
21 d after challenge infection (Shi et al. 1997
).
These effector responses could have been the result of altered
proportions of spleen cell subpopulations or altered function of
splenic T cells or APC. Given that neither zinc deficiency nor energy
restriction significantly affected the phenotypic distribution of
splenic cells bearing CD3+,
CD3+CD4+,
CD3+CD8+,
B220+ or Mac 1+ markers
(Shi et al. 1998a
), we proceeded to examine the
functional capacity of APC and T cells. Spleen cells were harvested
from infected mice of each of the three dietary groups and separated
into T cell and APC populations. The two cell types were then paired in
vitro from the different dietary groups. To test T cell function, in
vitro assays included APC from zinc-sufficient mice, combined with
T cells from either the zinc-sufficient, the pair-fed or the
zinc-deficient mice. Similarly, we assessed the effect of zinc
deficiency on APC function by combining T cells from
zinc-sufficient mice with APC from one of the three dietary groups.
Our data indicated that the impaired effector responses were likely
associated with impaired proliferative response of T cells. The
depressed T cell proliferation was caused by effects of zinc deficiency
on T cell function but also by the effects of energy restriction on APC
function (Fig. 6
). This was interpreted as indicating a higher zinc dependency of T
cells than APCs for cell replication and DNA synthesis (Shi et al. 1998a
). The consequences of nutritional deficiencies on
cytokine production in response to parasite antigen were more complex
(Fig. 7
). Zinc deficiency caused a marked and dramatic reduction in IL-4
production when T cell function was evaluated. IL-5 production was also
significantly depressed, but whether this was entirely due to zinc
deficiency or in part also due to energy restriction was difficult to
assess. The results with IFN-
were clear, however. It was energy
restriction, not zinc deficiency, that reduced T cell function with
regard to production of this Th1 cytokine. When we evaluated the
effects of zinc deficiency (and energy restriction) on APC function, we
observed a predominant effect of energy restriction on IL-5 and IFN-
production and effects of both zinc and energy on IL-4 production.
Thus, impaired capacity for cytokine production by T cells and APC may
have been responsible for the lower antibody responses in the
zinc-deficient mice and the lower eosinophil responses in both the
zinc-deficient mice and the energy-restricted mice. These in
turn would account for the prolonged parasite survival in
energy-restricted mice and the even better survival in the
zinc-deficient mice.
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), and
schistosome worms have been shown to have particularly high uptakes of
zinc relative to host tissue, suggesting that they may have a
particularly high need for this molecule (Booth and Schubert 1968
). However, when we compared the zinc content of worms from
the three dietary groups (Shi et al. 1995
), we found no
significant differences.
From these experiments, a series of important observations arises.
First, the clearest, direct effect of zinc deficiency is that it
interferes with the ability of T cells to produce IL-4. IL-4 is the
most important, pivotal cytokine necessary to drive an effective Th2
response against H. polygyrus (Urban et al. 1991
). Without sufficient IL-4, production of IgE and
IgG1 is impaired, mucosal mast cell proliferation
and degranulation are prevented and IL-5 production is reduced. We
noted that zinc deficiency, possibly together with energy restriction,
also reduced levels of IL-5. It is possible that this effect is
secondary to the impaired IL-4 production seen in zinc-deficient T
cells, in which case we suggest that energy restriction exerts an
additional, direct effect on the ability of T cells to produce IL-5.
Second, energy restriction has important immunosuppressive effects in
this system. Well-designed experiments on zinc deficiency should
include controls for the concurrent reduced food intake, as a
confirmation that any observed effects are due to the lower zinc
intake, not the reduced energy intake. We have shown clear effects of
the reduced energy on APC function, on the ability of T cells to
secrete IFN- and, most importantly, on the actual rate of clearance
of infection. Given how common energy restriction is, with or without
zinc deficiency, we believe that this result has potentially important
implications that need to be pursued.
Third, our work raises interesting questions about how the phenotype of
the immune response (Th1 or Th2) alters the consequences of zinc
deficiency and the interpretation of the data. Although it has been
implied, if not directly suggested, that zinc deficiency impairs Th1
responses but not Th2 responses (Sprietsma 1997
), our
data very clearly demonstrate that the response to infections that
normally stimulate a Th2 response is diminished by zinc deficiency.
Zinc-deficient mice showed reduced proliferation of spleen cells,
their ability to produce IL-4 was markedly impaired and their levels of
IgE, IgG1 and eosinophils were reduced. Clearly,
zinc deficiency also influences Th2 responsiveness. This is of
particular importance in areas in which intestinal helminths are common
and coincident with dietary zinc deficiencies and other parasites.
Fourth, impaired IFN- production was observed as a result of energy
restriction on both APC and T cell function, and not because of zinc
deficiency. We suggest that some of the effects on Th1 responses
attributed to zinc deficiency may in fact be caused by the concurrent
energy restriction.
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Suggestions for future research |
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TOPABSTRACTINTRODUCTIONGALT in intestinal infectionsEvidence that zinc deficiency...Experimental model: H. polygyrus...Effect of zinc deficiency...Suggestions for future researchREFERENCES |
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We suggest that studies be conducted to investigate, in more depth,
mechanisms by which zinc deficiency impairs immunity (Fig. 8
). Considering the gut as an inductive site, we suggest that zinc
deficiency may impair antigen presentation and production of cytokines,
as it does in the spleen. We suggest that it may impair the priming of
Th2 cells and that its effects on gross epithelial structure and
function (Moran and Lewis 1985
) may also impair the more
nonspecific barrier function of the intestine. Changes in epithelial
barrier integrity, mucus secretion and intestinal smooth muscle
contractility may facilitate early worm migration and interfere with
mechanical processes involved in parasite expulsion from the intestine.
Impaired DNA synthesis for cell growth and replication may result in
reduced renewal of damaged epithelial cells and diminished clonal
expansion and proliferation of T cells. In addition, zinc is a cofactor
for protein kinase C, which is critical for proliferation of T cells
(Csermely et al. 1988
). Zinc is known to play an
important regulatory role in signal transduction pathways
(MacDonald 2000
) that influence gene expression and in
turn direct cell function. This may be partially responsible for the
observed disruptions in T cell and APC function. Impaired selective
trafficking of immune cells may lead to reduced recruitment of immune
progenitors or memory cells from the periphery into the GALT, lower
circulation of activated lymphocytes bearing parasite antigens to
systemic lymphoid organs and decreased localization of gut-derived
lymphocytes to the lamina propria and intraepithelial spaces where
effector cells mediate their antiparasitic activities. Finally, zinc
deficiency may prevent the degranulation of eosinophils and mast cells,
thus blocking their effector function. Any combination of these
mechanisms may explain the lack of systemic responsiveness and
increased survival of H. polygyrus observed during zinc
deficiency and energy restriction.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by grants from the Natural Sciences and Engineering Research Council of Canada and by the Fonds FCAR pour l’aide et le soutien à la recherche.
4 Abbreviations used: APC, antigen-presenting cell; ER, energy restriction; GI, gastrointestinal; GALT, gut-associated lymphoid tissues; IFN, interferon; IL, interleukin; MLN, mesenteric lymph nodes; MMC, mucosal mast cells; Th, T helper cell.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONGALT in intestinal infectionsEvidence that zinc deficiency...Experimental model: H. polygyrus...Effect of zinc deficiency...Suggestions for future researchREFERENCES |
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