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Regular Article |
From the Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A mixed cellular influx usually occurs in nasal cavity of allergic rhinitis patients during the late-phase reaction. The cellular elements include eosinophils, neutrophils. and mononuclear cells. Mast cells are typically activated in a biphasic manner in airway tissue after specific antigen challenge.3-5 In the intestinal tract of humans, inflammatory changes after antigen challenge are difficult to study because of the invasive techniques needed to obtain tissue samples. However, rodent models of intestinal anaphylaxis/food allergy have been studied for many years and have provided much information regarding the early phase of the allergic reaction.6 Mast cells have been shown to be the key effector cells, releasing mediators that alter mucosal physiology. Mast cell-dependent neutrophil infiltration of the stomach wall has been documented after antigen ingestion in mice.7 Another study described an increase in eosinophils in the mucosa of the small intestine that was related to the chemokine, eotaxin.8 However, little is known about functional changes in the intestine that may be related to the influx and activation of inflammatory cells occurring throughout several days after the acute reaction.
A continuous single cell layer of epithelial cells lines the
gastrointestinal tract. This epithelial lining acts as a barrier
limiting the uptake of noxious material and antigens from the gut
lumen. However, it is clear that a small quantity of intact protein
antigen is transported across the epithelium. Sensitized rats
demonstrate an increased rate and amount of antigen crossing the
epithelium, initially via a transcellular pathway.9
Once
in the lamina propria, antigen cross-links IgE antibodies bound to mast
cells releasing mediators that act on epithelial receptors to induce
ion secretion and enhance permeability of the paracellular pathway
(both of which contribute to diarrhea).6,9
In segments of
intestine studied in Ussing chambers, these events are indicated by
increased values for short-circuit current (Isc) and conductance,
respectively.9,10
Our previous studies have demonstrated
that the secretory response begins within 
3 minutes after antigen
challenge and continues for at least 2 hours.9-11
However, it is not clear if the epithelial dysfunction lasts for days
or resolves within several hours.
The aim of this study was to determine the pattern of functional changes, specifically ion secretion and permeability that characterize the late-phase reaction in rat intestine, and to examine the role of mast cells, both in the pathophysiology and in the recruitment of inflammatory cells into the jejunal mucosa.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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All experiments were approved by the Animal Care Committee at
McMaster University. Pathogen-free, male Sprague-Dawley rats (Charles
River Breeding Laboratories, St. Constant, Quebec, Canada), mean weight
300 g, were housed in cages equipped with filter hoods. Rats were
actively sensitized to a model protein antigen, horseradish peroxidase
(HRP, type II; Sigma Chemical Co., St. Louis, MO)9
by
injection of 1 mg of protein in 1 ml of alum and 50 ng of pertussis
toxin as previously described.11
Fourteen days after
sensitization, the rats were challenged intragastrically with 0.5 ml of
HRP (5 x 10-4 mol/L). The rats were
sacrificed at 0.5, 8, 48, or 72 hours after challenge. Control groups
included naive and sensitized unchallenged rats.
To determine the role of mast cells in the inflammatory and functional changes involved in the late-phase reaction, mast cell-deficient Ws/Ws rats and +/+ littermates were used. These rats were maintained in a breeding colony at McMaster University (original colony developed by Y. Kitamura, Osaka, Japan). Ws/Ws rats have a 12-base deletion in the tyrosine kinase domain of the c-kit gene and by 10 weeks of age no mast cells can be detected in their intestine, whereas +/+ rats have a normal number of mast cells.12 Early in life, Ws/Ws rats also have anemia, but this is primarily corrected in rats older than 10 weeks of age. Rats were sensitized and challenged with HRP as above, and studies were performed 48 hours after challenge.
Ussing Chamber Studies
Rats were anesthetized with urethane and a 10-cm segment of intestinal tissue was excised from the jejunum (beginning 5 cm distal to the ligament of Treitz). The external muscle with adherent myenteric plexus was carefully stripped off. From each rat, four adjacent pieces of intestine were mounted in Ussing chambers (WPI Instruments, Narco Scientific, Missisauga, Ontario, Canada), exposing 0.6 cm2 of serosa to Krebs buffer containing (in mmol/L): 115 NaCl, 8 KCl, 1.25 CaCl2, 1.2 MgCl2, 2.0 KHPO4, 25 NaCO3 (pH 7.35 x 0.02).9 The serosal buffer included 10 mmol/L of glucose as an energy source osmotically balanced with 10 mmol/L of mannitol on the luminal side. A circulating water bath maintained the buffer at 37°C. The electrical current crossing the tissue was measured in the voltage-clamp mode (zero volts potential difference (PD)) and expressed as short-circuit current (Isc, in µA/cm2). At intervals, the circuit was opened to record the PD and conductance (in mS/cm2) was calculated according to Ohm’s law. Baseline measurements of Isc and conductance were recorded at equilibration, 15 minutes after mounting.
Permeability
The inert probe,
51Cr-ethylenediaminetetraacetic acid (EDTA) (6
µCi/ml) (Radiopharmacy, McMaster-Chedoke Hospital, Hamilton, Canada)
was added to the luminal buffer of the Ussing chambers, balanced by an
equivalent concentration of unlabeled Cr-EDTA in the serosal buffer.
Four 1-ml samples were taken from the serosal buffer at 20-minute
intervals after equilibrium (30 to 90 minutes), whereas duplicate
0.05-ml samples were obtained from the luminal buffer at the beginning
and end of the experiment to calculate specific activity. The
radioactivity of 51Cr-EDTA was measured in a 
counter.13
The transepithelial flux was calculated and
expressed as nmol/cm2/hour.
Light Microscopy
Segments of jejunum were excised immediately after the rats were sacrificed. Tissues fixed in 4% formaldehyde were processed and stained with hematoxylin and eosin. The morphology of the epithelium, villi, and subepithelial layer were assessed, and the number of eosinophils, neutrophils, and mononuclear cells were counted in 10 random fields (magnification, x200) for each rat (40/rat group). To determine mast cell numbers, tissues were fixed in Carnoy’s fixative and stained with 0.5% toluidine blue. Mast cells were counted in 25 fields for each rat (100/rat group). Cell numbers were expressed per mm2 of mucosa. All sections were coded to avoid observer bias.
Electron Microscopy
Segments of jejunal tissue were fixed in 2% glutaraldehyde/cacodylate buffer (pH 7.4) and processed for routine transmission electron microscopy. Tissues were cut to obtain longitudinal sections of epithelial cells. Ultrathin sections were placed on copper grids, stained with uranyl acetate and lead citrate, and observed with a transmission electron microscope. Photomicrographs were prepared and evaluated using a computerized image analysis system. The total area of granules (area bounded by granule membrane) within 1,000-nm2 regions of mast cells were measured; 20 photomicrographs were analyzed for each rat (80/rat group).
Other Measurements
Serum samples were obtained from rats at time of sacrifice, and the concentration of rat mast cell protease (RMCP II) was measured using an enzyme-linked immunosorbent assay kit (Mordun Animal Health Ltd., Glasgow, Scotland). IgE antibody titers in serum were measured by passive cutaneous anaphylaxis.
Statistical Methods
Data are expressed as mean ± SEM. Differences between groups were tested by analysis of variance, with post hoc analysis by Newman-Keuls test or Student’s t-test when appropriate. P values less than 0.05 were accepted as significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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There was no difference in net active ion transport of jejunal
tissues from naive versus sensitized unchallenged (time 0)
Sprague-Dawley rats, as indicated by the similar values for baseline
Isc in both groups (Figure 1A)
. However,
intestine from sensitized rats challenged orally with HRP demonstrated
a significant (P < 0.001) increase in baseline
Isc at 0.5 hours after antigen challenge, and another small but
significant rise at 48 hours. The Isc remained elevated for at least 72
hours after challenge (the last time point in our study). Previously,
we showed that the antigen-induced Isc elevation is because of
secretion of Cl- ions.10,14
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. There was no
obvious phasic pattern to the conductance change. Mucosal Structure (Light Microscopy)
The morphology of the jejunal mucosa was essentially normal in
sensitized rats compared with controls (Figure 2, A and B)
. However, on closer
observation increased cellularity was apparent (Figure 2B)
. This was
confirmed by counting specific cell types at higher magnification (see
below). The mucosa was noticeably altered after antigen challenge of
sensitized rats. At 0.5 hours, some swelling of the villi was observed
(not shown) and by 8 to 72 hours, there was obvious edema and abnormal
villus architecture (Figure 2C)
. In some sections, the epithelial cells
were observed to be detaching from the underlying tissue.
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. The numbers of mast cells,
eosinophils, neutrophils, and mononuclear cells were greater in
sensitized/challenged rats compared with naive controls, although the
pattern of change differed for the various cell types. Mast cell
numbers were greater in the mucosa of sensitized rats compared with
naive rats and demonstrated a further biphasic increase after antigen
challenge, with peaks at 0.5 and 72 hours and lower values between 8 to
48 hours (Figure 3A)
. Similarly, the numbers of eosinophils,
neutrophils, and mononuclear cells were already elevated in jejunal
mucosa of sensitized rats compared with controls (Figure 3, B–D)
. The
number of eosinophils dipped at 0.5 hours and peaked at 48 hours
(Figure 3B)
. Neutrophil numbers were greatest at 0.5 hours (Figure 3C)
,
although compared with other cell types, neutrophil numbers were
relatively low. The most striking observation in tissues from
challenged rats was a dramatic increase in the infiltration of
mononuclear cells (Figure 3D)
. Thirty minutes after antigen challenge,
the cell number had doubled, and by 48 hours it was 10-fold that in
controls, reaching 300 per mm2
(versus a maximum of 70 for mast cells, 120 for
eosinophils, and 14 for neutrophils). At 72 hours, the number of
mononuclear cells in the mucosa had decreased toward the baseline value
but was still significantly greater than the control value.
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Changes were also evident at the ultrastructural level. Compared
with enterocytes in control rats (Figure 4A)
, enterocytes in sensitized/challenged
rats at 48 hours contained abnormal mitochondria (Figure 4B)
, many with
autophagosomes (insert).15
The basement membrane was often
disrupted (Figure 4C)
, frequently associated with immune cell
infiltration into the epithelial layer (Figure 4, D and E)
. The
majority of infiltrating cells were lymphocytes (Figure 4D)
and
eosinophils (Figure 4E)
. Large spaces were observed between invading
cells and epithelial cells (Figure 4D)
. Electron microscopy also
confirmed the exfoliation of epithelial cells (Figure 4F)
.
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Mast cells and their granules were evaluated in electron
photomicrographs of intestinal sections from naive versus
sensitized/challenged rats (Figure 5
,
Table 1
). In sensitized/challenged rats,
signs of mast cell activation were obvious, including haloing (spaces)
around the granule core and empty granules (Figure 5C)
, compared with
mast cells in naive controls (Figure 5A)
. Some changes were apparent in
sensitized rats even before challenge (Figure 5B)
, such as enlarged
granules and granules with decreased density. There was a significant
increase in the proportion of mast cells showing signs of activation
(threefold) at time 0 and this increased with time (12-fold by 72
hours) (Table 1)
. In addition, activation of eosinophils was observed
between 48 and 72 hours, as indicated by a decrease in the core density
of their granules (Figure 4E
and Figure 5D
).
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. After antigen challenge, a biphasic
pattern of further increase occurred with peaks at 0.5 and 72 hours.
This pattern mirrored that seen for mast cell accumulation in the
mucosa.
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To determine the role of mast cells in the functional and
structural changes observed after antigen challenge in sensitized rats,
we conducted experiments using Ws/Ws mast cell-deficient
rats and their +/+ normal littermates. Rats were sacrificed 48 hours
after oral antigen challenge, when abnormalities in epithelial
physiology and changes in infiltrating mononuclear cells were maximal.
Intestine from sensitized unchallenged Ws/Ws rats had
similar baseline values for Isc and conductance at 48 hours after
challenge compared to control rats (data not shown). However, in
contrast to the significant elevation of these parameters after antigen
challenge in sensitized +/+ rats, the Isc and conductance values were
unaffected by antigen challenge in Ws/Ws rats (Figure 1, A and B)
. To further evaluate the role of mast cells in the
antigen-induced permeability change, we measured the flux of
51Cr-EDTA across the tissues. The flux of this
standard permeability probe was significantly increased (approximately
fourfold) in tissues from sensitized/challenged +/+ rats compared with
sensitized unchallenged rats, but no flux change occurred in tissues
from sensitized Ws/Ws rats after antigen challenge (Figure 7)
.
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. In addition, no
RMCP II was detectable in serum of Ws/Ws rats (Figure 6)
.
With respect to other types of inflammatory cells in the mucosa, there
were normal numbers of resident eosinophils, neutrophils, and
mononuclear cells in the mucosa of naive rats (not shown), and no
increases greater than control values at 48 hours after challenge
(Figure 2, A–D)
. In addition, no epithelial damage was observed by
electron microscopy. However, anti-HRP antibody production was normal
in Ws/Ws rats (mean serum titer of 1:512 at 48 hours
versus 1:256 in +/+ rats). Heat treatment of the serum
abolished the passive cutaneous anaphylactic reaction, confirming that
the antibodies were of the IgE isotype. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The principal roles of the epithelial lining of the gastrointestinal tract are the exclusion of luminal macromolecules from the body (barrier function) and the selective absorption/secretion of ions and nutrients (transport function). These functions are perturbed during food allergic reactions and intestinal inflammation. For example, in vivo studies in sensitized rats showed that perfusion of small intestine with a food antigen stimulates ion and fluid secretion resulting in diarrhea.16,17 The Ussing chamber technique provides an instant readout of the immediate hypersensitivity reaction because ion secretion is indicated online by a rise in Isc that occurs within 2 to 3 minutes of antigen challenge of tissues from sensitized rodents.10 Enhanced permeability of the epithelium is also a consequence of intestinal anaphylaxis, and has been documented both in vivo and in tissues studied in the Ussing chamber where conductance and probe flux values increase.9,11,18 Therefore, here we used this apparatus to examine epithelial ion transport and permeability abnormalities during the late phase of the allergic reaction, recording electrical parameters at times from 0.5 to 72 hours after oral antigen challenge.
Baseline values for Isc and conductance were similar in naive control
and sensitized rats. However, oral antigen resulted in an 50%
increase in baseline Isc and 60% increase in conductance at 0.5
hours. There was an additional small but significant increase in Isc at
48 hours. The secretory and permeability changes persisted for at least
3 days after a single antigen challenge with no signs of decrease
toward normal values.
The epithelial pathophysiology was associated with ultrastructural abnormalities. Specifically, at 48 hours epithelial mitochondria appeared swollen with loss of cristae, and autophagosomes were present in many mitochondria. A reduction in ATP production from the mitochondria has previously been demonstrated in association with epithelial dysfunction.19 The basement membrane was frequently disrupted and eosinophils and lymphocytes were observed penetrating into the epithelial layer. Spaces appeared in these regions with actual sloughing of epithelial cells in some sections. It is not clear from our study if the invading inflammatory cells were responsible for the damage; however, the eosinophils were shown to contain hypodense granules typical of activated cells. Both eosinophils and T cells can release bioactive mediators/cytokines with the potential to induce tissue damage.20-23
Infiltration of inflammatory cells into the mucosa was also documented by counting numbers of specific cells within a defined area of the lamina propria. Sensitization alone resulted in greater numbers of mast cells, eosinophils, neutrophils, and mononuclear cells in the intestinal mucosa. An increase in mucosal mast cells after sensitization has been reported previously in our rodent model of food allergy.11 This finding is interesting because the model does not involve any local administration of antigen, suggesting that mast cells spontaneously accumulate at mucosal sites, as well as at other locations, after systemic sensitization. The mechanism directing mast cell traffic to the gut is not clear. However, the gut is a large immune organ, containing resident T and B cells as well as mast cells and nerves, which are stimulated by sensitization to synthesize Th2 cytokines (eg, interleukin-3, interleukin-4, interleukin-5) and/or possibly other factors that attract and stimulate cell growth (ie, stem cell factor, nerve growth factor).22-25
After antigen challenge, a biphasic pattern of increased mast cells was demonstrated, with peaks at 0.5 hours and 72 hours. This pattern correlated with release of RMCP II, suggesting that the number represents activated cells. However, this approach may not present the entire profile of events with respect to this cell type. Although we were using high-power light microscopy, and therefore were able to see partially degranulated cells, our numbers reflect only the number of mast cells with sufficient granule contents to stain. Experiments in progress (to be reported separately) indicate that several phenomena are occurring simultaneously: recruitment, maturation, activation, and resynthesis of granule contents after antigen-induced degranulation. Neutrophil numbers followed a similar but less obvious pattern to that of mast cells, with the first peak at 0.5 hours and a second wave of elevation at 48 to 72 hours. The number of eosinophils decreased after antigen exposure and then increased again with the greatest number being present at 48 hours. In contrast, mononuclear cells continued to accumulate in the mucosa, reaching a peak at 48 hours when the number was 10-fold greater compared with controls.
Our results are consistent with and expand findings from the few other studies reporting gut inflammatory changes in the late-phase allergic reaction. For example, several hours after antigen challenge of mice, infiltration into jejunal mucosa of mast cells, eosinophils, and intraepithelial lymphocytes was described.26 Wershil and colleagues7 reported neutrophil and mononuclear cell infiltration in the stomach of mice after antigen challenge, with neutrophils peaking at 2 hours and mononuclear cells rising several fold at 12 to 24 hours. In another study, mast cell influx was observed at 1 hour, villus edema at 3 hours, eosinophil infiltration at 6 hours, and villus atrophy associated with increased numbers of lymphocytes at 24 hours,27 although exact counts were not performed. Increased permeability was documented at 1, 6, and 24 hours with decreases between the peaks. No structural or functional analysis was performed at later times in those studies. In our investigation, the most severe morphological, ultrastructural, and physiological changes were documented at 48 to 72 hours, the time of greatest inflammatory cell accumulation within the tissues.
In other organ systems, the late-phase reaction involves similar cell types, although the pattern of accumulation may vary. In nasal mucosa, eosinophil accumulation begins within minutes after the immediate allergic reaction.2,3,28 These cells are followed by neutrophils, then by basophils, mast cells, and macrophages. In the skin, a nonmucosal site, early skin swelling is caused by released mast cell mediators, whereas the delayed reaction has peaks at 2 hours and 24 to 48 hours, the latter probably because of T cell activation.3,4,29 In asthma, the late-phase response occurs 6 to 10 hours after allergen exposure and is characterized by infiltration of inflammatory cells in the airway mucosa, mainly eosinophils, but also other cell types (mast cells, lymphocytes, and macrophages).30,31
Mast cells seemed to be critical for recruiting (and possibly activating) the other inflammatory cells because no inflammatory cell infiltration occurred in mast cell-deficient rats. Ws/Ws rats have a 12-base deletion in the tyrosine kinase domain of the c-kit gene that results in the lack or deficiency of melanocytes and erythrocytes as well as mast cells, although the anemia repairs in early life.12 The ideal experiment to determine the role of mast cells in a particular response is to specifically reconstitute mast cell populations in deficient animals. Mast cells have been reconstituted in mast cell-deficient mice by injection of precursor cells derived from +/+ bone marrow,32 but because of the heterogeneous genetic background of the Ws/Ws and +/+ rats (F2 generation of two inbred rat strains), reconstitution is not feasible in Ws/Ws rats because of cell rejection. Therefore, we cannot rule out other phenotypic abnormalities as contributors to the lack of observed responses to antigen challenge in Ws/Ws rats. However, Ws/Ws rats have normal intestinal epithelial responses to carbachol and forskolin (M. C. Berin and M. H. Perdue, unpublished data). In addition, these deficient rats have been used to determine the role of mast cells in mucosal changes induced by sensitization and the immediate hypersensitivity reaction in the gut and airways.33,34
Mast cells synthesize and secrete a host of bioactive factors, many of
which have chemotactic properties, such as tumor necrosis factor-
,
interleukin-5, leukotriene B4, platelet-activating factor, complement
C5a, and various other cytokines/chemokines.35
We found
evidence for a degree of mast cell activation even before antigen
challenge, with changes in granule size and density and an 15%
increase in the concentration of RMCP II in the circulation. In
addition, the numbers of inflammatory cells in the mucosa were
increased above control values. However, no physiological abnormalities
were documented. In contrast, oral antigen administration resulted in
more dramatic morphological and functional changes, including depletion
of mast cell granules associated with epithelial pathology and
pathophysiology. Release of different types of mast cell mediators
after sensitization (eg, chemokines) versus antigen
challenge (eg, typical mediators of immediate hypersensitivity such as
histamine) might account for the disparate affects. In addition,
cross-linking of the IgE receptor stimulates synthesis of additional
mediators and cytokines/chemokines35
that are likely to be
involved in the late-phase reaction. This would account for the
additional inflammatory cell recruitment that occurred after antigen
challenge, with somewhat distinct patterns for each cell type. The most
unique pattern was the 10-fold increase in numbers of mononuclear cells
at 48 hours, which was relatively transient because the value was
decreased to threefold 24 hours later. We are unable to explain this
effect. However, lymphocytes are highly motile cells known for their
trafficking characteristics.
Mast cells have been shown to be required for neutrophil accumulation
in the stomach after local antigen challenge of sensitized mice, with
tumor necrosis factor- playing a major role.7,36
Thus,
there is evidence for mast cell-dependent recruitment of inflammatory
cells into the gastrointestinal tract. Data from both in
vivo and in vitro systems suggest that mast cells may
serve a gatekeeper function by regulating leukocyte migration at the
level of microvascular endothelium that is a key step in initiating the
late-phase reaction.37-40
In addition, tumor necrosis
factor-, RMCP II, histamine, and other mast cell mediators have been
shown to induce pathophysiological changes in the gastrointestinal
tract.6,18,41,42
The role of other inflammatory cells in
the epithelial dysfunction during the late-phase reaction cannot be
determined from this study, but the most severe pathophysiology
coincided in time (at 48 hours) with the presence of the greatest
numbers of cells in the mucosa. Studies in progress suggest that at
these cells do contribute mediators that compound the injury.
In summary, our study has shown that both functional and morphological abnormalities persist after the immediate phase of the intestinal allergic reaction. During the late phase, epithelial dysfunction included on-going ion secretion and increased permeability. The mucosal barrier defect can result in greater nonspecific uptake of luminal antigens/microbial products with the potential to exacerbate the inflammatory response. Epithelial cell loss further contributed to the tissue damage. Our findings implicate mast cells as critical to the late-phase reaction, although influx of other inflammatory cells correlated with more extensive injury. Further studies will be required to determine the precise role of eosinophils, neutrophils, and T cells in the intestinal pathophysiology of the late-phase allergic reaction in the gut.
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Footnotes |
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Supported by the Canadian Institutes for Health Research.
Accepted for publication October 17, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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to selectively enhance endothelial cell adhesiveness for T cells. J Immunol 1991, 146:592-598[Abstract]
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