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,
Departments of
*
Pathology,
Molecular Biology and Pharmacology, and
Medicine, and
Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-/- mice with H.
felis resulted in high levels of colonization, but no
detectable gastric pathology. Conversely, infection of B cell-deficient
µMT mice resulted in severe gastric alterations identical with those
seen in immunocompetent C57BL/6-infected mice, including gastric
mucosal hyperplasia and intestinal metaplasia. These results
demonstrate that the host T cell response is a critical mediator of
Helicobacter-associated gastric pathology, and that B
cells and their secreted Abs are not the effectors of the
immune-mediated gastric pathology seen after H. felis
infection. These results indicate that in addition to specific
Helicobacter virulence factors, the host immune response
is an important determinant of Helicobacter-associated
disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One potential host factor is the adaptive immune response, as the gastric inflammatory infiltrate associated with Helicobacter infection is predominantly IgG- and IgA-producing B cells and CD4 and CD8-positive T cells (9, 10). Initial studies in immunodeficient (C.B-17 SCID) mice indicated that the adaptive immune response was not required to maintain chronic gastric inflammation after Helicobacter infection (11). However, recent reports have now shown that several mouse strains, including the strain used above, do not develop gastric pathology after Helicobacter infection. Specifically, the inbred mouse strain C57BL/6 develops a severe chronic active gastritis and intestinal metaplasia, whereas BALB/c mouse strains exhibit only mild gastritis after infection with the H. pylori strain SS1 (Cag-A+) and the closely related Helicobacter felis (Cag-A-) (12, 13, 14, 15). Due to the availability of this new C57BL/6 mouse model of Helicobacter-associated gastric disease, we reevaluated the hypothesis that the host adaptive immune response initiated by Helicobacter infection is responsible for subsequent gastric pathology.
We established gastric infection with H. felis in C57BL/6 wild-type and induced mutant mice. H. felis infection in C57BL/6 mice mimics human disease in many aspects, including a predominant CD4+ T cell response (9, 16) that is associated with an increased epithelial cell proliferative index and hyperplasia (12, 13, 17). However, H. felis does not express the cag pathogenicity island or the vacuolating toxin (vacA), and thus does not itself damage the gastric epithelium (18). Induced mutant mouse strains deficient in both B and T cells, or in B cells or T cells alone were infected with H. felis, and the subsequent gastric pathology was evaluated. In this report, we demonstrate that the T cell response is crucial for Helicobacter-induced gastric pathology, and that post-Helicobacter infection gastric destruction and hyperproliferation are not mediated by B cells or their secreted products.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6J-Rag-1tm1Mom, C57BL/6-Igh-6tm1Cgn, and C57BL/6J-Tcrbtm1MomTcrdtm1Mom breeder pairs were purchased from The Jackson Laboratory (Bar Harbor, ME). The strains were maintained by mating homozygous siblings. C57BL/6J control mice were purchased from The Jackson Laboratory. Mice were housed in a specific pathogen-free facility in microisolator cages under a strictly controlled light cycle and given a standard autoclaved chow diet ad libitum. All mice were maintained in accordance with the guidelines of the Animal Studies Committee of Washington University.
Generation of H. felis-induced gastritis
H. felis (ATCC 49179; American Type Culture Collection, Manassas, VA) was grown on moist ATCC 260 medium (trypicase soy agar (BBL 11043; Fisher Scientific, Pittsburgh, PA)) supplemented with defibrinated calf blood (5% v/v; Colorado Serum Company, Denver, CO), trimethoprim (5 mg/L; Sigma, St. Louis, MO), vancomycin (6 mg/L; Sigma), and Fungizome (1% v/v; Life Technologies, Gaithersburg, MD) under microaerophilic conditions at 37°C for 2 days. Confluent plates of H. felis were harvested, and the number of bacteria were determined by adsorption at OD450, with one OD unit corresponding to 109 bacteria. Bacteria were stored in a mixture of brain heart infusion broth (BHI; Difco 0037; Fisher) and glycerol (31 ml glycerol/100 ml broth) at -70°C. Per os (p.o.) infection of H. felis was accomplished using a 200-µl pipette tip. Mice were inoculated twice over a 3-day period with 0.05 ml of bacterial suspension. Mock infected animals were inoculated with the BHI/glycerol suspension medium.
Assessment of H. felis colonization and histopathology
Mice were sacrificed and their stomachs rapidly removed. Ninety minutes before sacrifice, animals received an i.p. injection of 5-bromo-2'-deoxyuridine (BrdUrd; Sigma) (dose, 120 mg/kg) to label cells in S phase (19). Tissue samples were fixed in methacarn solution (60% methanol, 30% chloroform, 10% glacial acetic acid) and embedded in paraffin, and 5-µm-thick sections were prepared. Colonization was established by evaluation of immunohistochemical staining of the H. felis organisms in histologic sections of the entire greater and lesser curvatures of the stomach. A semiquantitative determination (H. felis (HF) colonization score) of the organism load was made based on the number of bacteria observed per gastric glandular unit (0 = no bacteria, 1 = 1–2 bacteria, 2 = 3–10 bacteria, 3 = 11–20 bacteria, 4 = >20 bacteria). Sections were evaluated by two pathologists blinded to the experimental status of the mice.
Gastrointestinal inflammation and destruction were assessed by microscopic examination of hematoxylin/eosin-stained gastric tissue. The stomachs were transected along the greater and lesser curvature to obtain two halves, with each half subsequently embedded in paraffin. Gastric pathology was evaluated by two pathologists blinded to the strain and experimental status of the mice. The scoring system used was modified from Ermak et al. (20) and is based on a grade of 0–3 in each of three categories: longitudinal extent of inflammation (0 = no inflammation, 1 = patchy, 2 = <50%, 3 = >50%); vertical extent of inflammation (0 = no inflammation, 1 = basal lamina propria only, 2 = transmural, 3 = both mucosa and submucosa involvement); and histopathological changes (0 = none, 1 = mild alterations in differentiated epithelial cells, 2 = moderate alterations in differentiated epithelial cells, 3 = severe alterations in differentiated epithelial cells). The total histological score (0–9) was determined by summation of each subscore. All zones of the stomach were examined: squamous zone, zymogenic zone (parietal cells, zymogenic cells, surface and neck mucous cells), mucoparietal zone (parietal cells, surface and neck mucous cells), and mucous zone (surface and neck mucous cells).
Immunohistochemistry
To assess the proliferative state of the gastrointestinal tract,
as well as the infiltrating leukocytes, a polyclonal Ab against BrdUrd
was used (21, 22). Immunohistochemical methods were also
used on stomach sections to assess parietal and zymogenic cell density,
and inflammation (23). Specifically, a panel of lectins
and Abs was used as previously described to define alterations in the
proliferation and differentiation programs of gastric epithelial cell
lineages (23, 24, 25). Briefly, 5-µm-thick sections were
deparaffinized, nonspecific staining blocked using PBS containing 1%
BSA, 0.2% powdered skim milk, and 0.3% Triton X-100 (PBS-BB), and
then incubated with the appropriate primary Ab diluted in PBS-BB
overnight at 4°C. After extensive PBS washes, cyanine (Cy)-3 or
fluorescein (FITC)-conjugated secondary Abs and/or
fluorescent-conjugated lectins were added, incubated on the sections
for 1 h at room temperature, washed and coverslipped with
PBS/glycerol (1:1), and examined using a Zeiss (Oberkochen, Germany)
Axioskop fluorescent microscope. The methods used for single- and
double-label immunohistochemistry have been described previously
(26). Abs and lectins used were: goat anti-BrdUrd
(final dilution, 1:1000; kindly supplied by Dr. Steven Cohn, University
of Virginia, Charlottesville, VA) (21, 22); rabbit
anti-rat intrinsic factor (1:1000) (27); rabbit
anti-rat pepsinogen (1:500, kindly supplied by Michael Samloff,
University of California, Los Angeles, CA) rabbit
anti-H+/K+-ATPase
-subunit (1:250, kindly supplied by Michael Caplan, Yale University,
New Haven, CT); rabbit anti-H. pylori (1:1000, Dako,
Carpinteria, CA); Griffonia simplifolica II lectin (specific
for mucous neck cells; final concentration, 5 µg/ml, EY Laboratories,
San Mateo, CA) (24); Dolichos biflorus
agglutinin (specific for parietal cells; final concentration. 20
µg/ml; Sigma) (24); cholera toxin B-subunit (specific
for surface mucous (pit) cells; final concentration, 5 µg/ml; List
Biological Laboratories, Campbell, CA) (24).
Stastical analysis
Data analysis using a standard Student’s t test or Mann-Whitney test was performed using GraphPad Prism (San Diego, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To assess the contribution of the adaptive immune response to the
gastric epithelial pathology seen after Helicobacter
infection, C57BL/6 and C57BL/6J-Rag1tm1Mom
(RAG-1-/-) were infected p.o. with H.
felis. RAG-1-/- mice have no mature B or T
lymphocytes and consequently do not mount any Ag-specific immune
responses (28). Infected mice and control mock-infected
mice were sacrificed 4, 6, 8, 14, and 22 wk after inoculation (14 total
C57BL/6 and 15 RAG-1-/-). After 4 wk of
infection, the RAG-1-/- mice had similar levels
of Helicobacter organisms in their gastric glands as
C57BL/6, with colonization initially occurring in the pure mucous zone
(corresponding to the antral region of the human stomach) (Fig. 1
). However, at all time points examined,
they displayed minimal immune infiltrates, no alterations in their
gastric morphology (Fig. 2,
A–C) and no proliferative abnormalities (data not
shown). This was in contrast to the C57BL/6 immunocompetent mice, which
as early as 4 wk after infection displayed gastric infiltrates
consisting primarily of mononuclear cells and scattered neutrophils.
This infiltrate was accompanied by dramatic gastric epithelial changes,
including a marked reduction in the number of parietal and zymogenic
cells in the gastric epithelium by 14 wk after inoculation with
H. felis (Fig. 2, C, D, and F).
These severe alterations in differentiated gastric epithelial cells are
reflected by the high histopathological changes subscore as seen in
Table I. The differentiated gastric
epithelial cells appear to be replaced by two cell types. One is a
rapidly proliferating cell that does not display any characteristics of
gastric epithelial cell differentiation (see Fig. 5B). The
second is a mucous-producing goblet-like cell that results in a
histologic picture characteristic of intestinal metaplasia (see Fig. 3, E and F). The
absence of gastric pathology in H. felis infected
RAG-1-/- mice was consistently seen at all time
points examined, even though all RAG-1-/-
animals maintained high levels of H. felis colonization
(Fig. 1). These findings indicate that in the C57BL/6 inbred mouse
strain, the host adaptive immune response generated after infection
with Helicobacter was causally responsible for the
subsequent gastric pathology.
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Recent reports have demonstrated that infection with H.
pylori can lead to the production of anti-H. pylori
Abs that cross-react with human gastric mucosal Ags
(29, 30, 31, 32, 33, 34). These autoantibodies have the potential to play
a crucial role in the pathogenesis of gastric diseases, as Negrini et
al. (29) demonstrated that mice bearing hybridomas
secreting a H. pylori cross-reactive mAb caused gastric
abnormalities similar to gastritis. To analyze the role of B cells and
their secreted products (cytokines and Abs) in the development of
Helicobacter-associated gastric pathology, we used C57BL/6
mice with an isolated deficiency in the B cell compartment caused by a
targeted disruption in the heavy chain of IgM
(C57BL/6-Igh-6tm1Cgn, µMT)
(35). This disruption results in B cell maturation arrest
at the pre-B cell stage and the absence of mature B cells. The
pathology seen after H. felis infection of B cell-deficient
mice was identical with that seen in wild-type C57BL/6 (Fig. 2
, E, H, and I). As early as 4 wk after
inoculation with H. felis, a severe inflammatory infiltrate,
consisting of both monocytes and neutrophils, was seen. This infiltrate
was accompanied by dramatic epithelial changes, including a marked
reduction in zymogenic and parietal cells (Fig. 3, A and
D, and data not shown). The differentiated gastric
epithelial cells were replaced by a hyperplastic epithelium, which
included large areas of intestinal metaplasia containing
mucin-producing goblet cells (Fig. 3E). These epithelial
cell alterations were seen in both the C57BL/6 and µMT mouse strains
and were maintained throughout the length of infection (20 wk, a total
of 32 µMT and 29 C57BL/6 mice were examined). Both mouse strains
appeared to drastically reduce their levels of H. felis
colonization by 12 wk after inoculation (Fig. 1), demonstrating that B
cells and/or Abs are not essential for this reduction in bacterial
colonization levels.
H. felis infection of TCR (TCR) double knockout mice
(n = 28;
C57BL/6J-Tcrbtm1Mom
Tcrdtm1Mom) (36, 37, 38) did not
result in any significant histological changes when compared with
mock-infected control TCR-/- mice. Mice
examined 4–12 wk after H. felis inoculation had high levels
of bacterial colonization (Fig. 1), but demonstrated minimal gastritis
and no significant gastric epithelial pathology (Fig. 4 and Table I). It should be noted that
mock-infected control TCR-/- have a low,
but consistent level of gastric inflammation and histological changes.
As these TCR mutant mice have been previously described to develop
spontaneous inflammatory bowel disease, this low level gastric
inflammation is not surprising (37). Although H.
felis infection significantly increases the total histology score
in the TCR-/- mice; this elevated score is due to
an increase in the level of inflammatory infiltrate, as the
histopathological changes subscore is not significantly different
(Table I). These data indicate that T cells and/or their secreted
products are the crucial mediators of the gastric pathology seen after
Helicobacter infection.
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Intestinal-type gastric cancer develops over decades from
superficial to chronic gastritis, followed by the development of
atrophy, intestinal metaplasia, dysplasia, and finally cancer
(39). We have now demonstrated that the initial stages of
this pathway—gastritis and atrophy (defined as the loss of parietal
and chief cell populations)—are a result of the T cell response to
Helicobacter infection. As gastritis and atrophy are
associated clinically with an increase in mucosal cell proliferation
(40, 41), we wanted to directly assess the levels of
gastric epithelial cell proliferation in our mouse model of
Helicobacter gastritis. The mice were injected i.p. with
BrdUrd (120 mg/kg) 90 min before sacrifice. This thymidine analogue is
incorporated into the DNA of dividing cells. Cells in S phase during
the injection period can subsequently be immunohistochemically detected
in tissue sections using an Ab specific for BrdUrd (19, 21). In normal murine stomach, BrdUrd labeling was limited to a
narrow band of positive cells in the previously well described isthmus
progenitor cell zone (42). In contrast, H.
felis-infected C57BL/6 stomachs demonstrated a dramatic increase
in the number of BrdUrd-positive cells and in the width of the
proliferative zone (Fig. 5, A
and B, and Table II). The
marked proliferative abnormalities were seen as early as 6 wk after
infection in C57BL/6 mice and continued throughout the length of our
experiment (20 wk). Note, that after 12 wk, there were very few
detectable Helicobacter organisms in the stomach (Fig. 1);
thus, direct effects of H. felis itself on gastric
proliferation is unlikely. Epithelial cell hyperplasia was not
dependent on the presence of B cells, as a marked expansion of the
number of gastric epithelial cells in S phase as well as the size of
the proliferative zone was observed in infected B cell-deficient µMT
mice (Fig. 5, C and D, and Table II). In
contrast, there was no proliferative abnormality seen at any time after
infection in the RAG-1-/- mouse strain or in
uninfected control mice (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-/-,
and µMT to evaluate the contribution of the adaptive immune response
to the gastric epithelial hyperproliferation, altered glandular
differentiation, and intestinal metaplasia seen after
Helicobacter infection. C57BL/6 mice demonstrated severe
chronic active gastritis with increased epithelial cell proliferation
and loss of specialized parietal and zymogenic cells after infection
with H. felis. Strikingly, C57BL/6 mice with either no
mature B or T cells (RAG-1-/-) or specifically
no mature T cells (TCR-/-) do not develop
gastric epithelial pathology after H. felis infection.
Although immune responses have been postulated to be involved in
the progression from Helicobacter infection to gastric
atrophy, metaplasia, and cancer, this is the first demonstration of the
crucial role of the T cell response in this progression. The
hyperplastic epithelium and altered glandular differentiation seen in
the C57BL/6 mouse are all features of preneoplastic lesions seen in the
recently described Mongolian Gerbil model of
Helicobacter-induced gastric cancer (43).
These results confirm and extend our previous report that targeted
microbial attachment in a novel transgenic mouse model of H.
pylori infection results in increased gastric infiltration and
gastric pathology (44). These data also serve as a
potential explanation for the observation of an unexpectedly low
prevalence of H. pylori-associated gastric histopathology in
immunocompromised patients with AIDS (45). However, our
findings are in contrast with a previously reported H. felis
SCID model, which concluded that the host adaptive immune response
played a limited role in control of Helicobacter
colonization (11). In the SCID study, immunodeficient
(SCID) mice and immunocompetent C.B-17 congenic mice (identical with
the BALB/c strain except at the Ig heavy-chain locus (Igh))
(46) were both infected with H. felis. No
statistical difference between the two mouse strains in the number of
H. felis organisms or the intensity of inflammation was
seen; however, this study did not evaluate
Helicobacter-associated gastric pathology. We and others
have now shown that the BALB/c inbred mouse strain does not develop
extensive gastric pathology after Helicobacter infection
(histological score = 2.05 ± 0.43, 4–28 wk after infection,
n = 10), whereas the C57BL/6 mouse strain develops
hyperplasia and parietal and zymogenic cell destruction (see Fig. 2)
(12, 13). Therefore, to stringently test our hypothesis
that the host adaptive immune response initiated by
Helicobacter infection is causally responsible for the
subsequent gastric pathology, it was necessary to infect
immunodeficient mice that were of the C57BL/6 background. The different
interpretation of our results and the previously published data is
almost certainly due to our ability to detect and quantitate gastric
mucosal abnormalities in the C57BL/6 strain, as these abnormalities do
not occur in the C.B-17/BALB/c inbred strain.
It has been clearly shown that human infection with H. pylori induces autoantibodies reactive with gastric parietal cell Ags, specifically to H+/K+-ATPase, which is also known to be a key autoantigen in autoimmune gastritis (34, 47). It is unknown whether these autoantibodies are directly pathogenic for the gastric epithelium or are in response to gastric epithelial cell destruction caused by Helicobacter virulence factors such as cytotoxins (48). The significance of autoantibodies to Helicobacter-induced gastric pathology has proven difficult to experimentally address in human subjects. To assess the contribution of host B cells and their products in Helicobacter-induced gastric pathology, we have infected the B cell-deficient mouse strain, µMT. Our results showed that the µMT and C57BL/6 mice exhibited identical gastric pathology after H. felis infection, with mucosal inflammation, gastric epithelial cell hyperproliferation, parietal and zymogenic cell destruction, and metaplastic changes. This demonstrates for the first time that B cells and their secretion of potentially autoreactive Abs are not critical to the development of gastric epithelial cell destruction and hyperplasia after H. felis infection.
The finding that the adaptive immune system, specifically T cells, are critical mediators of H. felis-associated gastric pathology does not allow for the discrimination between direct Ag-specific and indirect non Ag-specific effects of T cells. There are at least two major potential mechanisms of T cell-dependent gastric pathology. One mechanism would be based on the postulate that specific immune recognition events are critical for the resulting gastric epithelial pathology. This Ag-specific event, where a T cell with a TCR specific for gastric self-proteins could be stimulated to develop by molecular mimicry of a H. felis protein, or by exposure to a previously sequestered gastric Ag, could result in the development of a gastric autoimmune disease. A second potential mechanism is based on an indirect effect of T cells and the factors they secrete in response to a gastric infection. In this scenario, the T cell response to H. felis infection results in a cytokine/chemokine milieu that modifies the differentiation of gastric epithelial cells from the gastric epithelial stem cell. This altered milieu could be due either to the infiltration of H. felis-specific T cells or to the influx of a polyclonal T cell population into the gastric epithelium. This modified gastric epithelial cell differentiation program would result in an increase in proliferating undifferentiated epithelial cells and mucus-producing intestinal-like epithelial cells, and a decrease in zymogenic/parietal cells. As there is currently a very limited knowledge of the factors involved in gastric epithelial differentiation from the gastric stem cell, it is unclear whether lymphocyte-derived factors could have this effect on gastric epithelial cell differentiation.
There is now evidence in human H. pylori infection of an altered gastric epithelial cell turnover early in the course of the disease (49, 50, 51). Both increased epithelial cell apoptosis and proliferation have been described. The lack of epithelial cell hyperproliferation in the RAG-1-/--infected mice indicates that in the absence of the adaptive immune response, factors are missing that crucially affect epithelial cell proliferation. These data suggest that future investigations of the infiltrating adaptive immune response will further our knowledge of the mechanisms by which Helicobacter infection results in hyperplastic changes in the gastric epithelium.
In summary, our studies have demonstrated that the host T cell response initiated by Helicobacter infection is causally responsible for subsequent gastric pathology. Future studies of the interplay between the host cellular immune response and Helicobacter infection should provide insights into the key immune mediators responsible for the Helicobacter-associated gastric pathology.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to: Dr. Robin G. Lorenz, Department of Pathology (Box 8118), Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address:
3 Abbreviations used in this paper: cag, cytotoxin associated gene; BrdUrd, 5-bromo-2'-deoxyuridine; RAG, recombinase activating gene.
Received for publication December 3, 1998. Accepted for publication April 15, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and block thymocyte development at different stages. Nature 360:225.[Medline]
gene mutant mice: independent generation of T cells and programmed rearrangements of 
TCR genes. Cell 72:337.[Medline]
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K. A. Eaton, M. Mefford, and T. Thevenot The Role of T Cell Subsets and Cytokines in the Pathogenesis of Helicobacter pylori Gastritis in Mice J. Immunol., June 15, 2001; 166(12): 7456 - 7461. [Abstract] [Full Text] [PDF]
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K. A. Eaton and M. E. Mefford Cure of Helicobacter pylori Infection and Resolution of Gastritis by Adoptive Transfer of Splenocytes in Mice Infect. Immun., February 1, 2001; 69(2): 1025 - 1031. [Abstract] [Full Text] [PDF]
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 J. V. Solnick and D. B. Schauer Emergence of Diverse Helicobacter Species in the Pathogenesis of Gastric and Enterohepatic Diseases Clin. Microbiol. Rev., January 1, 2001; 14(1): 59 - 97. [Abstract] [Full Text] [PDF]
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D. G. E. Smith, S. C. Mitchell, T. Nash, and S. Rhind Gamma Interferon Influences Intestinal Epithelial Hyperplasia Caused by Lawsonia intracellularis Infection in Mice Infect. Immun., December 1, 2000; 68(12): 6737 - 6743. [Abstract] [Full Text] [PDF]
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L. E. Smythies, K. B. Waites, J. R. Lindsey, P. R. Harris, P. Ghiara, and P. D. Smith Helicobacter pylori-Induced Mucosal Inflammation Is Th1 Mediated and Exacerbated in IL-4, But Not IFN-{gamma}, Gene-Deficient Mice J. Immunol., July 15, 2000; 165(2): 1022 - 1029. [Abstract] [Full Text] [PDF]
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V. B. Young, C. A. Dangler, J. G. Fox, and D. B. Schauer Chronic Atrophic Gastritis in SCID Mice Experimentally Infected with Campylobacter fetus Infect. Immun., April 1, 2000; 68(4): 2110 - 2118. [Abstract] [Full Text] [PDF]
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8 wk with H. felis