THEMES
Mucosal Immunity and Inflammation
III. The mucosal antigen barrier:
cross talk with mucosal
cytokines*
Mary H.
Perdue
Intestinal Disease Research Program and Department of Pathology and
Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
L8N3Z5
 |
ABSTRACT |
We have known for many years that
mucosal responses to antigens are regulated by immune cells and their
molecular signals. More recently, it has become clear that epithelial
cells also synthesize and secrete chemokines and cytokines. A
sophisticated system of bidirectional cytokine signals is responsible
for immune activation in the case of enteropathogens vs. immune
suppression to food and commensal microbial antigens. A key factor in
determining antigen handling is the route taken by antigens across the
epithelial barrier. Cytokines and other mucosal messenger molecules
play a critical role in the regulation of transepithelial antigen transport.
epithelium; permeability; inflammation; stress; intestinal
hypersensitivity
 |
INTRODUCTION |
THE GASTROINTESTINAL MUCOSA is truly a unique
environment when it comes to antigen handling. The antigenic load
contained within the lumen is immense, and the mechanisms that have
evolved to deal with this load are extremely complex. For example, the gut content of commensal microbes is
~1013 organisms, and it has been
estimated that an individual consumes at least 2,500 kg of food
antigens during a normal lifetime. Yet, for the most part, these
foreign antigens do not elicit an inflammatory response. In addition,
numerous pathogenic organisms are ingested. It is clear that a
sophisticated system is required to discriminate between
enteropathogens and harmless food molecules or antigens from commensal
organisms. Only a single layer of epithelial cells separates the
luminal contents from effector immune cells in the lamina propria.
Intraepithelial leukocytes (IEL) are in even closer proximity to
luminal antigens, being located within the epithelial layer just below
the tight junctions that join adjacent epithelial cells. Regulation of
the epithelial barrier is critical to the maintenance of the low
reactivity state. Although there is now considerable information on the
influence of immune cell cytokines and mediators on epithelial
physiology, we are just beginning to understand the critical role of
epithelial cells in regulating the response to ingested antigens, that
is, in determining whether an immune response is activated or
suppressed. Oral tolerance is the term used to refer to the state of
unresponsiveness that exists for nonpathogenic antigens present within
the gut lumen. This state is not a passive lack of response; rather, it
is a specifically downregulated system essential for homeostasis. Over the past few years, much has been learned regarding mechanisms involved
in regulating mucosal immunity, particularly the importance of
bidirectional cytokine signals between epithelial cells and immune
cells. These and other messenger molecules direct the routes and nature
of transepithelial antigen transport and determine the consequences of
antigen uptake into the mucosa.
 |
THE EPITHELIAL BARRIER |
The gastrointestinal tract is lined by a single layer of epithelial
cells joined together at their apical poles by tight junctions. Tight
junctions used to be thought of as passive structures, barricades to
the paracellular pathway restricting passage of molecules beyond a
relatively small size. However, studies over the past few years have
documented that tight junctions are highly regulated gates that open
and close in response to events in the lumen, signals from the lamina
propria, and even messages from the epithelium itself. The transporting
enterocytes are the major cell type in the epithelium. However, other
cell types in the epithelium, such as goblet cells, enteroendocrine
cells, and Paneth cells, act in concert with enterocytes to enhance the
barrier properties of the epithelium to antigens. Paneth cells produce
defensins (molecules with secretagogue properties) that target
microorganisms; enteroendocrine cells secrete neuroendocrine molecules
that can act in a paracrine fashion to alter epithelial properties;
goblet cells synthesize mucus, a physical component of the barrier, and trefoil peptides needed for epithelial growth and repair. Epithelial cells are maintained on a scaffolding of myofibroblasts,
interdigitating cells that secrete basement membrane components and
also critical growth factors for the epithelium. In addition, ion
secretory responses of the epithelium can be amplified severalfold by
lipid mediators produced by myofibroblasts in response to
secretagogues. The barrier properties of the epithelium are influenced
by the enteric nervous system, with cholinergic neurotransmitters
clearly facilitating enhanced passage of macromolecules through tight junctions (5). In addition, mucosal mast cells are strategically located beneath the basement membrane in contact with nerve fibers, providing the potential for these cells to regulate epithelial functions. Other immune cells present in the lamina propria include T
and B lymphocytes, macrophages, eosinophils, neutrophils, and so forth.
Immune cell cytokines, both proinflammatory interferon-
(IFN-
)
and tumor necrosis factor-
(TNF-
), and anti-inflammatory interleukin (IL)-4 act on epithelial receptors to increase the permeability of tight junctions (4, 16). These and other cytokines have
been shown to affect epithelial physiology, altering barrier and/or
transport properties (Table 1).
Of course, the main role of epithelial enterocytes is absorption of
nutrients. Vectorial transport of nutrients and ions (and therefore
water) also depends on the epithelium being relatively tight, since
back diffusion would reduce or negate the direction and force of the
flow. However, when luminal concentrations of sugars are high, a degree
of absorption takes place via the paracellular pathway in response to
solvent drag. Although most nutrients are absorbed by epithelial
transporters in the form of small molecules (such as sugars, amino
acids, small peptides, and so forth), enterocytes can also sample
intact protein antigens. It was shown many years ago that endosomal
uptake of proteins occurs across the apical membrane of epithelial
cells, and small quantities of intact protein exit the basal cell
membrane after ~15-20 min. Most non-receptor-bound proteins
absorbed by this route are degraded by lysosomal enzymes following
fusion of endosomes with lysosomes. Binding to specific receptors
expressed on the apical membrane protects proteins/peptides from
degradation. Thus important growth factors such as epidermal growth
factor (EGF) in salivary secretions and breast milk are able to gain
access to the internal milieu of the body in an active form. However,
certain enterotoxins, including verotoxin (also known as Shiga toxin,
produced by enterohemorrhagic Escherichia coli), can make use of the endosomal route to gain
access to the body (21).
 |
ANTIGEN HANDLING AND ORAL TOLERANCE |
Intracellular processing of antigenic proteins within enterocytes
appears to be important for oral tolerance. Bypassing this route may be
detrimental. For example, enhanced intestinal epithelial permeability
has been demonstrated in humans with inflammatory bowel disease (IBD),
where it is thought to be a possible etiological factor. Theoretically,
luminal antigens crossing the epithelium through leaky junctions bypass
epithelial processing necessary for oral tolerance and activate
resident immune cells in the lamina propria. A similar mechanism may be
involved in the spontaneous gut inflammation that develops in the
E-cadherin gene-deficient mouse. In these mice, specific sites of
defective expression in the crypts are associated with local
inflammation (9). However, it is clear that regulation of tight
junctions occurs, and many factors can increase epithelial permeability
acutely with no long-term consequences. Therefore, it would appear that
chronic dysregulation of the epithelial barrier is required for
disease. Although epithelial uptake of luminal antigens may be
necessary for oral tolerance, invasion of epithelial cells by enteric
pathogens results in secretion of chemokines that recruit cells
involved in the inflammatory/immune response (10). Therefore, it is
obvious that epithelial interactions with antigens are critical to the
health and well-being of the host.
The mechanisms that account for oral tolerance are still not completely
understood, especially with respect to the role of the epithelium. The
cytokine profile (whether proinflammatory Th1 or anti-inflammatory
Th2) generated by mucosal T
cells varies depending on the nature of the antigen and its processing
and presentation. The key antigen-presenting cell may be the highly motile dendritic cell, as has been shown in the airways. Dendritic cells are present in large numbers in the gut mucosa and even within
the epithelium (14). Their long cellular processes might be able to
extend into the lumen and sample antigens and then transport these
antigens to sites of interaction with T cells such as the
local draining lymph nodes. However, in the airways where such a
mechanism has been convincingly demonstrated, the properties of
junctional structures in the multilayered epithelium may be quite
different from those in the gut. To my knowledge, no one has documented
extensions of dendritic cells penetrating through intestinal epithelial
tight junctions. However, there is evidence for a role for dendritic
cells in oral tolerance (26). M cells, specialized cells in the
epithelium covering Peyer's patches, can certainly take up antigens
and deliver them to professional antigen-presenting cells and T cells
in the lymphoid patch (19). M cells transport particulate antigens such
as bacteria and viruses and are undoubtedly important in the immune
response to enteric microbes. Immune cell signals appear to be
important for the development of M cells. There is considerable
evidence that lymphoid follicles are a key inductive site for the
generation of IgA-producing plasma cells that home to the
intestinal lamina propria; enterocytes then transport IgA into the
lumen via a membrane-bound receptor. However, an active role for M
cells specifically in antigen presentation and oral tolerance has not
been shown.
Enterocytes are capable of presenting antigens to T cells. It has long
been known that enterocytes can be stimulated to express major
histocompatibility (MHC) class II antigens, particularly during inflammation. IFN-
is an example of a proinflammatory cytokine that is a strong inducer of MHC II. It has been suggested that
MHC presentation of antigen by enterocytes to IEL may be important for
oral tolerance, with defective interactions in individuals predisposed
to IBD, although there is no conclusive evidence for this hypothesis.
However, with the use of CD1d (in association with gp180), a class Ib
molecule, epithelial cells obtained from humans were shown to activate
T cells, with cells from healthy humans preferentially stimulating
CD8+ suppressor T cells, whereas
cells from IBD patients stimulate CD4+ helper T cells (15).
Regardless of the nature of the antigen-presenting cell responsible for
oral tolerance, absorbed antigens in the circulation (plus other
factors?) have tolerizing properties, since oral tolerance can be
transferred to naive recipients in serum. In addition, cytokine
signals, particularly transforming growth factor-
(TGF-
), are
clearly involved in the generation of oral tolerance (25).
 |
ENTEROPATHOGENS STIMULATE CYTOKINES SIGNALS |
Complex cellular interactions and bidirectional messages occur in
response to enteropathogens. Invasion of the enterocyte by pathogenic
microbes, and in some cases by simply binding to epithelial cells,
stimulates production of epithelial cytokines and chemokines
[IL-8, TNF-
, lipid mediators, and so forth (Ref. 10, Table
1)], which recruit and activate inflammatory cells such as
neutrophils. Neutrophils penetrate through the tight junctions of
epithelial monolayers in response to bacterial products (13). In vivo,
neutrophil recruitment to gastric mucosa in allergic inflammation was
shown to be dependent at least in part on mast cell release of TNF-
(8). Microbial interactions with the apical membrane of epithelial
cells can cause rearrangements of F-actin and associated proteins via
phosphorylation of critical enzymes (myosin light-chain kinase, protein
kinase C), leading to increased permeability of tight junctions (22,
27). The situation becomes even more complex if one takes into account the responses of resident immune cells. For example, cells of the
monocyte/macrophage lineage are stimulated by microbial endotoxin and
tripeptides (f-Met-Leu-Phe) to release potent mediators including TNF-
, nitric oxide, oxygen radicals, and so forth, which can contribute to enhanced epithelial leakiness (28). This is true for
naive or blood-derived cells but not for gut macrophages, except in IBD
where these cells are reactive to commensal bacteria (7). However,
macrophages also synthesize IL-10 that may downregulate epithelial
permeability by reducing production of T cell proinflammatory cytokines
or possibly by acting directly on the epithelium. TGF-
, the cytokine
important in oral tolerance, acts directly on the epithelium to enhance
its barrier function (16). Growth factors, such as EGF, insulin-like
growth factor, and so forth, also have beneficial effects, and
glucagon-like peptide-2, a recently identified intestinotrophic factor,
appears to act specifically on intestinal epithelium to enhance its
barrier properties (1).
Different probe molecules have been used to identify changes in
epithelial barrier function. However, the size, shape, charge, and
other properties of the probe will alter the data obtained. For
example, decreased transepithelial resistance does not necessarily translate into increased permeability for all small probes, which theoretically cross the epithelium via the paracellular route, let
alone for macromolecules. Inert probes such as mannitol and 51Cr-labeled EDTA have provided
useful information on increases in permeability to small-sized
molecules, and sugars that can be digested before uptake can indicate
the location of the barrier defect (17). Results obtained in vivo may
be different from those obtained in vitro due to the effects of blood
flow. However, in vivo, increased permeability is important only if it
results in pathophysiology as a result of penetration of a bioactive
substance into the mucosa. Such substances include bacterial products
(e.g., endotoxins, enterotoxins, superantigens) and other luminal
macromolecular antigens capable of activating immune cells. Products of
activated immune cells act on the epithelium and can amplify uptake of
these molecules as well as bystander antigens. Therefore, epithelial permeability will continue to increase until protective factors restore
the barrier by acting both on the epithelium itself and on immune cells
to restore homeostasis. This scenario is likely to occur in response to
acute irritation of the epithelium or other short-term disruptive
events, including acute stress.
 |
MUCOSAL RESPONSE TO STRESS |
Exposure of humans or rodents to acute stress can alter epithelial
functions, stimulating secretion of ions, water, and mucus and
enhancing epithelial permeability. Rats that have a cholinergic hypersensitivity appear to be particularly sensitive to the effects of
stress (24). Recently reported studies in stressed mice demonstrated that acute stress alters brain expression of enzymes involved in the
metabolism of ACh (10). However, the mucosal abnormalities in the gut
after 2 h of restraint stress are relatively short lived, returning to
normal within 24 h (P. R. Saunders and M. H. Perdue, unpublished
observations). The barrier defect involves not only increased
permeability to small inert probes such as mannitol and
51Cr-EDTA but also bioactive
molecules, including a model protein antigen, horseradish peroxidase
(HRP). HRP was demonstrated by electron microscopy to cross jejunal
epithelium by both transcellular and paracellular routes (12). Atropine
pretreatment restored epithelial barrier function in stressed rats.
Mediators of the stress response include central and peripheral release
of corticotropin-releasing hormone as well as cholinergic and
adrenergic signals and mast cells (Refs. 6, 12, 23, and J. Santos and
M. H. Perdue, unpublished observations). However, the long-term
consequence of chronic stress-induced uptake of antigens on
gastrointestinal inflammation and pathophysiology in animal models has
not been reported. In humans, the intestinal effects of acute stress
have also been shown to be mast cell mediated, and, in fact, the
responses to stress were indistinguishable from those that occurred in
hypersensitivity responses to food antigens in allergic individuals
(23).
 |
INTESTINAL HYPERSENSITIVITY |
Intestinal hypersensitivity reactions occur following ingestion of food
antigens or infection with certain enteric parasites. Although such
reactions are beneficial in eliminating parasites, reactions to
normally innocuous food proteins serve no useful purpose to the host
and appear to be completely inappropriate. Reactions to food antigens
occur within minutes of ingestion of the offending food and include
edema and hyperemia of the mucosa followed by ion secretion and
increased motility. Immediate hypersensitivity reactions are initiated
by antigen cross-linking of IgE antibodies bound to the surface of
mucosal mast cells, releasing mediators that act on epithelial and
smooth muscle receptors to induce functional changes. In rodent models,
the intestinal ion secretory response to an antigen begins ~3 min
after luminal antigen challenge. The rapidity of the response suggests
that sensitization alters the nature of transepithelial antigen
transport. This was verified in rats sensitized to HRP, in which, 2 min
after luminal challenge, enterocytes contained a significantly greater
amount of HRP compared with intestine from naive control rats or those
sensitized to an irrelevant protein (2). In addition, the rate of
transport of HRP across the cell was enhanced ~10-fold. Studies in
mast cell-deficient Ws/Ws rats and normal littermate controls (3) showed that sensitization, but not the presence of mast cells, was
required for the enhanced transepithelial transport of specific antigens. Subsequently, antigen-induced mast cell activation initiated an increase in tissue conductance and enhanced mucosal-to-serosal flux
of HRP and the presence of HRP in the paracellular spaces and tight
junctions. Taken together, these findings suggest that mast cell
mediators (possibly interacting with nerves to release neurotransmitters) act on epithelial receptors to loosen tight junctions and facilitate passage of macromolecules between epithelial cells. The initial and mast cell-dependent phases of transepithelial antigen transport in sensitized rats are depicted in Fig.
1.

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Fig. 1.
Epithelial handling of antigen in intestinal hypersensitivity. The
paracellular pathway is normally impermeable to intact protein
antigens, which are taken up in small quantities by endocytosis and
cross the epithelial barrier via the transcellular route. In sensitized
rats, changes occur such that the initial phase (phase
I) of transepithelial transport involves enhanced
endosomal uptake and transport of specific antigen. Subsequent to
antigen-induced activation of mast cells (phase
II), the paracellular pathway becomes leaky to
macromolecules due to the action of released molecular signals from
immune (mast) cells and possibly nerves.
|
|
The studies described above suggest that the initial phase of antigen
transport involves specific recognition at the level of epithelial
cells, possibly mediated by immunoglobulin. Interactions between
intestinal epithelium and immunoglobulins are recognized to play an
important role in mucosal immunity. Transport of IgA across epithelial
cells into the intestinal lumen is protective against pathogens,
whereas epithelial uptake of IgG from the lumen is required for
transfer of maternal immunoglobulins in colostrum to neonatal rodents.
Both of these transport systems involve epithelial immunoglobulin
receptors (pIgR and FcRn for IgA and IgG, respectively). FcRn has also
been identified in human epithelial cells, but its role is not clear.
In addition, IgE is present in intestinal secretions during food
allergy reactions or following parasitic infection (18), suggesting the
possibility of an epithelial receptor for luminally directed transport
of IgE. However, to date, no evidence has been published describing an
immunoglobulin-mediated system for importing noxious antigens into the
body. Future publications will undoubtedly contain more information on
the mechanisms that account for the enhanced antigen transport and role
of cytokines in intestinal hypersensitivity reactions. Findings from
this research may provide novel strategies for interfering with uptake
of antigens into the body.
 |
CONCLUSIONS |
An increasing number of studies are demonstrating that the intestinal
epithelium is the critical interface in mucosal antigen handling.
Cytokines in the local environment can influence the route of
transepithelial antigen transport, that is, determine if an
antigen takes the transcellular or the paracellular pathway. Although the transcellular route may be beneficial in most instances, resulting in oral tolerance, this may not necessarily be the case if
the epithelial phenotype is altered, as in hypersensitivity. In
addition, the epithelium acts as a sentinel to summon inflammatory cells when it is invaded by pathogens. Cytokines and chemokines play a
key role in this multidirectional signaling. However, other molecules
derived from nerves, myofibroblasts, endothelial cells, and the
epithelium itself can alter the outcome or add amplification or
inhibitory effects.
In animal models of spontaneous intestinal inflammation, the common
features include a disrupted epithelial barrier and the requirement for
microbial flora for full expression of inflammation. The mechanism
responsible for the barrier defect can vary from abnormalities in
molecular components of the tight junction to dysregulation of its
function. It is clear that the balance of proinflammatory vs.
anti-inflammatory cytokines is critical, but overproduction of either
group can result in a disease if the dominant cytokine induces enhanced
uptake of immunogenic molecules into the mucosa. As stated earlier,
both IFN-
(Crohn's disease) and IL-4 (ulcerative colitis) are such
cytokines. On the basis of this hypothesis, one would predict that
defects or imbalance in the production of any of the critical factors
or elements involved in the regulation or maintenance of the epithelial
barrier would result in gut inflammation. Further studies will be
required to determine if this postulate is correct.
 |
FOOTNOTES |
*
Third in a series of invited articles on Mucosal Immunity
and Inflammation.
Address for reprint requests and other correspondence: M. H. Perdue,
HSC, 3N5C, McMaster Univ., 1200 Main St. West, Hamilton, ON, Canada
L8N3Z5 (E-mail: perdue{at}mcmaster.ca).
 |
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