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Clinical Investigations |
Departments of Medicine [S. F. M., E. M. S., A. M. A., V. M., P. R. H.] and Pathology and Laboratory Medicine [E. M. S., Z. H.], St. Luke’s-Roosevelt Hospital Center, New York, New York 10025, and Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, Tennessee 37232 [G. I. P-P., M. J. B.]
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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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How H. pylori increases the risk for gastroduodenal disease is not well understood. Some of the mechanisms that may contribute to disease include altered gastric secretory physiology (5) or gastric growth factor secretion (6) , interference with antioxidant defenses (7) , and the inflammatory response associated with the presence of H. pylori infection (8) .
Several studies have also shown evidence of increased cell proliferation, both in humans carrying H. pylori (9, 10, 11, 12, 13, 14, 15, 16) and in animal models of Helicobacter infection (17 , 18) . After eradication therapy, increased proliferation returns to normal levels, which suggests that H. pylori or the associated inflammatory response is responsible for the increased proliferation observed (9 , 11, 12, 13, 14, 15) . Because of the increasing realization that cell turnover is dependent not only on proliferation but also on apoptotic cell loss (19) , and because it is now appreciated that many pathogenic bacteria are capable of interacting with the apoptotic program of epithelial cells (20) , the effect of H. pylori on gastric epithelial cell apoptosis also has been recently investigated. H. pylori induces apoptosis in gastric epithelial cells in cell culture (21, 22, 23, 24, 25, 26, 27) . Furthermore, using TUNEL3 as a marker of apoptotic cells in gastric biopsy sections, the presence of H. pylori has been associated with a 2- to 5-fold increase in gastric epithelial apoptosis in vivo that returns to normal levels after eradication of the organism in most studies (24 , 26 , 28, 29, 30, 31, 32, 33, 34, 35, 36, 37) . However, in other studies, apoptosis was reported as unchanged (38) , or even decreased (39) . in the presence of H. pylori.
Because current models of homeostasis predict that clinical outcome may be determined by an imbalance between proliferation and apoptosis (40) , and in view of the epidemiological evidence in Western populations implicating the cag island in the pathogenesis of H. pylori (3 , 4) , perhaps related to insertion and phosphorylation of the CagA protein into gastric epithelial cells after H. pylori attachment (2) , the effect of cag status on gastric epithelial turnover has also been evaluated. Heterogeneous patient populations, both with and without peptic ulcer disease, have been studied by our group (31) and by others (36) . The results of these studies indicate that cag-positive strains are associated with increased proliferation but not with increased apoptosis (31 , 36) . These findings are consistent with the hypothesis that an imbalance favoring proliferation over apoptosis in cag-positive strains predisposes to cancer. However, this model is at variance with other evidence that apoptosis is increased significantly in patients with duodenal ulcer disease, nearly all of whom carry, or would be predicted to carry, cag-positive strains (28 , 34 , 35 , 37 , 41) .
Because of these discrepancies, the aim of the present study was to examine prospectively the effect of H. pylori cag status on gastric epithelial apoptosis and proliferation in a relatively homogeneous cohort of patients with a diagnosis of nonulcer dyspepsia, undergoing endoscopy at a single hospital. In view of the suggestion that H. pylori may mediate gastric damage and apoptosis through the induction of antigastric autoantibodies (32 , 42 , 43) , a secondary aim was to assess the relationship between the presence of gastric autoantibodies and parameters of cell turnover in these patients.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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18 years, and ability to give
informed consent. Exclusion criteria were evidence of active bleeding;
previous gastric surgery; use of nonsteroidal anti-inflammatory drugs,
proton pump inhibitors, Histamine (H2)-receptor
antagonists, bismuth compounds or antibiotics within the previous 3
months; pregnancy; and endoscopic findings of ulcers, masses or
bleeding lesions. The study was approved by the Investigational Review
Board of St. Luke’s-Roosevelt Hospital Center. Informed consent was obtained from each subject prior to the endoscopy, and 10 ml of blood was taken for ELISAs to measure total anti-H. pylori IgG and anti-CagA IgG, performed as described previously (3) , and for autoantibodies (see "Autoantibodies"). The presence of serum antibodies to the CagA protein of H. pylori was used as a marker of H. pylori strains carrying the cag island. Five gastric biopsies were obtained during endoscopy using disposable forceps with a cup diameter of 9 mm (Microvasive, Watertown, MA); three were from the antrum [two fixed in formalin for histology and one for the biopsy urease test (CLOtes; Tri-Med Inc, Lenexa, KS)] and two were from the corpus (for histology). Histological examination of sections stained by H&E was performed by a single pathologist (Z. H.), who was blinded to the clinical data, serology, and biopsy urease test data. Biopsies from one patient were excluded because the formalin-fixed tissues could not be located. In three additional patients, there were too few well-oriented glands in the corpus biopsies for this site to be evaluated. Gastritis was scored according to the updated Sydney system (44) .
Patients were considered positive for H. pylori if two or more of the following tests were positive: biopsy urease test, histology, total anti-H. pylori IgG, or anti-CagA IgG.
Measurement of Apoptosis.
Apoptotic epithelial cells were identified in 4-µm thick
formalin-fixed biopsy specimens by the use of TUNEL as described
previously (31)
. Apoptotic cells were counted only in
complete, well-oriented gastric glands for both antrum and corpus. The
mean number of apoptotic cells per gland for each individual patient at
each anatomical subsite was determined after evaluating all of the
well-oriented glands in both biopsies taken at each anatomical subsite.
The mean number of gastric glands scored in the antrum was 43.3 (range,
7–113) and for the corpus was 32 (range, 7–64). Assessment of the
reproducibility of an observer to score apoptotic cells in this study
was tested by randomly rescoring 20% of the slides. Thus, in 11 cases,
the block was recut, and sections were restained and counted on two
separate occasions. For another 13 cases, the same stained slides were
counted on two separate occasions. From these data, the intraclass
correlation coefficients for cell counting reliability was calculated
to be 0.922 using the method described by Shrout and Fleiss
(45)
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Measurement of Proliferation.
Proliferating epithelial cells were identified by immunostaining for
the Ki-67 antigen using the Mib-1 monoclonal antibody and a microwave
accentuation technique (31)
. The method for counting cells
was as described for apoptotic cells above, and the data were expressed
as the average number of positively labeled cells per gland. The mean
number of glands counted in the antrum was 14.3 (range, 4–22) and for
the corpus 11.2 (range, 4–20). Proliferation reproducibility data were
tested in 24 (20% of the total number examined) randomly chosen slides
from the antrum and corpus. The intraclass correlation coefficient for
cell-counting reliability was 0.90.
Autoantibodies.
Antiparietal cell antibodies were determined by a standardized,
semiquantitative indirect fluorescent procedure (46)
using
mouse stomach/kidney substrate (Kallestad, Sanofi Pasteur), in
comparison with positive and negative control sera (known patient
samples) and commercial (Kallestad) controls. Sera were considered
positive for antiparietal cell antibodies if fluorescent staining of
the parietal cells, but not the cytoplasm and luminal border of the
kidney tubules, was observed. Initial screening for reactivity was
performed on sera diluted 1:20 in PBS. Sera that produced a specific
pattern of fluorescence were considered positive, and serial 2-fold
dilutions of each positive sample were retested to determine the
autoantibody titer.
Statistical Analysis.
Comparisons between groups were analyzed by the Mann-Whitney
U test, and evaluation of correlation was assessed by
Spearman’s ranked correlation. Differences between proportions were
evaluated by 
2 with Yates correction. In all
cases, a 2-tailed value of P < 0.05 was used
to signify statistical significance.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Proliferation.
The proliferation labeling index was significantly increased in
H. pylori-positive compared with H.
pylori-negative patients (Figs. 1
and 2)
. In the antrum, the mean number of proliferating cells per gland in
the negative patients (± SD) was 9. 6 (± 3.9) compared with 15.9 (±
6.8) in patients with cagA+ H. pylori, and 17.7
(± 5.0) in patients with cagA- H. pylori
(P < 0.05 for each comparison). In the
gastric corpus, the mean number of proliferating cells per gland in the
negative patients was 8. 6 (± 4.2) compared with 14.6 (±9.5) in
patients with cagA+ H. pylori, and 15.7
(±7.3) in patients with cagA- H. pylori
(P < 0.05 for each comparison). Differences
between the scores in persons carrying cagA-negative and
cagA-positive strains were not statistically significant in
either antrum or corpus. Scores for proliferation were positively
correlated with the degree of histological gastritis (classified as
none, mild, moderate, or severe) for both antrum
(r2, 0.57; P < 0.0001) and corpus (r2, 0.37;
P < 0.005).
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and 4)
. The mean number of apoptotic cells per antral gland in H.
pylori-negative patients was 1.5 (±1.5), compared with 3.0
(±3.3) in patients with cagA+ H. pylori
(P < 0.05), and 2.5 (± 3.0) in patients
with cagA- H. pylori. Similar data were obtained
for the gastric corpus. In the corpus, the mean number of apoptotic
cells per gland in H. pylori-negative patients was
1.1 (±1.3), compared with 1.8 (±2.0) in patients with
cagA+ H. pylori (P < 0.05), and 1.3 (±1.1) in patients with cagA- H.
pylori. The difference between H. pylori-negative
patients and patients with cagA- organisms was not
statistically significant. Scores for apoptosis were not correlated
with the grade of histological gastritis.
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Relationship between Autoantibodies, H. pylori
Presence, and Parameters of Gastric Epithelial Cell Turnover.
Classical antiparietal cell antibodies were found in the serum of three
H. pylori-negative patients, of four patients with
cagA+ H. pylori, and of two patients with
cagA- H. pylori strains. The proportion of
patients with H. pylori (either cagA+ or
cagA-) who had antiparietal antibodies was not
significantly different from the proportion in the H.
pylori-negative patients. To evaluate whether the presence of
antiparietal cell antibodies was associated with increased cell
turnover, apoptosis, proliferation, and the proliferation:apoptosis
ratio were compared in patients with antiparietal cell antibodies and
patients who did not have antibodies. Apoptosis in the antrum was
statistically significantly lower, and the proliferation:apoptosis
ratio in the antrum was significantly higher, in the 9 patients with
antiparietal cell antibodies than in the 51 patients without such
antibodies (Table 1)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our results confirm previous positive associations between parameters of epithelial proliferation and gastric inflammation scores (16 , 31) . Previous studies have reported positive (31 , 36 , 37) , inverse (39) , or no (28 , 30 , 33 , 34 , 38) association between inflammation scores and apoptosis. These inconsistencies are not explained by study designs, nor by the endoscopic findings or clinical details of the patients studied. This lack of a clear correlation between inflammation and apoptosis, therefore, suggests either that the inflammatory response is not important in determining the extent of epithelial apoptosis in response to H. pylori in vivo or that the measurement of the inflammatory response to H. pylori by histological criteria alone does not adequately reflect proapoptotic inflammatory stimuli present in the H. pylori-colonized gastric mucosa.
Epithelial apoptosis is considered to be essential for the maintenance of gastrointestinal homeostasis and health (47) . It has been suggested that H. pylori colonization stimulates the production of autoreactive antigastric antibodies (42 , 48) , thus causing accelerated epithelial apoptosis and subsequently gastric atrophy (32) . Such a model is supported by the increased frequency of serum antigastric antibodies in persons colonized by H. pylori (32 , 42 , 43 , 49) and by their rapid disappearance after H. pylori eradication therapy (50) . However, the control antigens for these studies have not been standardized nor described sufficiently to rule out artifactual autoreactivity. Nevertheless, even using conventional rodent antigens, Steininger and colleagues (32) reported antigastric antibodies more frequently in H. pylori-positive infected patients (6 of 84) than in controls (0 of 32). Our failure to confirm an increased frequency of classical antiparietal cell autoantibodies could be attributable to the different ethnic background of our patients (African-American and Hispanic) compared with the northern Europeans, or to differences in assay methodology. Overall, however, our results show no evidence to support the involvement of autoimmune-mediated apoptosis in the pathogenesis of H. pylori-associated gastritis in African American and Hispanic patients with nonulcer dyspepsia.
In the present study, the presence of cagA-positive strains was associated with increased apoptosis. This result challenges the hypothesis initially suggested by our group (31) and supported by the results of Rokkas et al. (36) , that cagA may play a role in abrogating the apoptotic response to H. pylori. Are these discrepancies regarding the effect of H. pylori cag status on gastric cell turnover attributable to methodological differences? All previous studies of apoptotic gastric epithelial cells have used the TUNEL stain, with similar protocols. However, several different methods have been used to assess proliferating cells including immunohistochemistry using antibodies directed against Ki-67 (Ref. 31 and the present study) or PCNA (33) and by the quantitation of silver-stained nucleolar organizing regions (36) . Although there is no standardized methodology for the measurement of gastric epithelial proliferation, Ki-67 is superior to PCNA as an endogenous marker of cells in S phase in gastric mucosal biopsies (51) and in the human colon is more reproducible than PCNA (52) .
Similarly, there is no standardized method of counting and quantifying positively stained cells, nor a minimum number of glands to evaluate (53) . To minimize potential gland to gland variability, we examined the maximum number of glands cells possible, representing at least 3000 cells for apoptosis and 2000 for proliferation, numbers far in excess of the previous studies. Documentation of the high reproducibility of cell counts for each patient adds confidence to the findings of the present study. We consider that the methods used to measure cell turnover in this study are the currently available optimum for endoscopic biopsies. Another advantage of the present study is that we were able to examine apoptosis and proliferation in biopsies taken from both antrum and corpus. The corpus only has been examined once previously, in a study of patients with duodenal ulcers (35) , in whom corpus involvement by H. pylori is generally mild.
What other reasons can explain the differences between the present results and those of our earlier collaborative study (31) , in which carriage of cagA-positive strains was not associated with increased epithelial apoptosis? One major difference is the ethnicity and clinical status of the patient populations that were examined. The patients in the present study were mainly Hispanic and African-American, and had no ulcers at endoscopy. This contrasts with the population in the previous study who were recruited at a Veterans’ Affairs Medical Center (31) and were almost entirely Caucasian males, almost one-half of whom had peptic ulcers.4 In both human colonization and animal models, the epithelial and inflammatory responses to H. pylori depend not only on the type of infecting strain but also on the genetic background of the host (54, 55, 56, 57) . Thus, the most likely explanation for the discrepant results in these two clinical studies is the varying genetic compositions of the populations studied.
It should be emphasized that although cagA status is defined as positive or negative for any given individual, there is no widely used standard method to determine cag status. In the present study and a previous one (36) , H. pylori cag status was determined by the presence of serum antibodies to the highly immunogenic CagA protein. In contrast, in our earlier study, the presence of the cagA gene was determined by PCR of bacteria cultured from gastric biopsies (31) . Both methods are indirect compared with immediate PCR of an endoscopic biopsy (58) . A further complexity is the coexistence of multiple H. pylori strains in a single host, including both cagA-negative and -positive variants (59) . Because deletion of all or part of the cag island may occur in H. pylori subpopulations in vivo or in vitro, the detection of circulating antibodies to the CagA protein indicates colonization by cag-positive strains but does not rule out mixed infections. Because there is no widely accepted standard for the diagnosis of H. pylori infection, we defined patients as H. pylori-positive in this study if at least two of four tests were positive. Using these criteria, one patient was classified as H. pylori-positive based on serology alone but with negative rapid urease test and histology. Whether this single patient was truly H. pylori-positive (with false negative biopsy tests) or had undergone spontaneous or antibiotic-induced clearance of H. pylori is not known, but even if this patient were reclassified as H. pylori-negative, the overall conclusions of our study would not be altered.
In addition to genes within the cag pathogenicity island, several other bacterial factors may be markers of clinical outcome. These include expression of the vacuolating cytototoxin (VacA), products of the iceA gene, and the babA2 gene, which determines binding to the Lewisb blood group antigen (4 , 60, 61, 62) . Although the possible relationship between these markers and epithelial cell turnover is worthy of further study, in practice it may be difficult to separate their effects from those of the cag pathogenicity island because there is often cosegregation of cag, babA2, and the vac s1a genotype in H. pylori strains in Western populations (60) .
In conclusion, the evaluation of proliferation and apoptosis in this study has been the most extensive to date. We found that epithelial cell proliferation was higher in H. pylori-positive persons, irrespective of cagA status, and that genes within the cag pathogenicity island may play a role in the induction of apoptosis. Furthermore, we found no evidence for the involvement of antigastric antibodies in the stimulation of apoptosis. Because in some populations, cagA-related genes are associated with an abrogated apoptotic response, whereas in the current study they are associated with increased apoptosis, we speculate that host factors may be at least as important as bacterial factors in determining gastric mucosal responses to H. pylori.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by Astra Merck, now AstraZeneca, (to
S. F. M.), by NIH Grant RO1 DK 53707, and by the Medical Research
Service of the Department of Veterans Affairs. This study was presented
in part at Digestive Disease Week, New Orleans, May 1998, and was
published as an abstract in Gastroenterology. 
2 To whom requests for reprints should be
addressed, at Department of Medicine, Division of Gastroenterology,
Rhode Island Hospital, APC 445, 593 Eddy Street, Providence, RI 02903.
Phone: (401) 444-6713; Fax: (401) 444-2939; E-mail: smoss1{at}pol.net
3 The abbreviations used are: TUNEL,
terminal uridine deoxynucleotidyl nick end labeling; PCNA,
proliferating cell nuclear antigen.
4 R. M. Peek, personal communication.
Received 8/18/00. Accepted 12/15/00.
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