Helicobacter pylori cagA+ strains and dissociation of gastric epithelial cell proliferation from apoptosis.
BACKGROUND
Infection with Helicobacter pylori induces chronic gastritis in virtually all infected persons, and such gastritis has been associated with an increased risk of developing gastric cancer. This risk is further enhanced with cagA+ (positive for cytotoxin-associated gene A) H. pylori strains and may be a consequence of induced gastric cell proliferation and/or alteration in apoptosis (programmed cell death) in the gastric epithelium.


OBJECTIVE
To determine whether the H. pylori cagA genotype and another virulence-related characteristic, the vacA (vacuolating cytotoxin A) s1a genotype, differentially affect epithelial cell proliferation, apoptosis, and the histologic parameters of inflammation and injury, we quantitated these characteristics in infected and uninfected persons.


METHODS
Fifty patients underwent upper gastrointestinal endoscopy, and biopsy specimens were taken. Apoptotic cells in the specimens were quantitated after terminal deoxynucleotidyl transferase labeling of DNA fragments with digoxigenin-deoxyuridine triphosphate; epithelial cell proliferation was scored by immunohistochemical analysis of the proliferation-associated antigen Ki-67. Antibodies directed against H. pylori and CagA protein were measured in the serum of patients by means of enzyme-linked immunosorbent assays. Analysis of H. pylori genomic DNA, by use of the polymerase chain reaction, was performed to determine the cagA and vacA genotypes. Acute and chronic inflammation, epithelial cell degeneration, mucin depletion, intestinal metaplasia, glandular atrophy, and vacuolation were each scored in a blinded manner. Reported P values are two-sided.


RESULTS
Persons harboring cagA+ strains (n = 20) had significantly higher gastric epithelial proliferation scores than persons infected with cagA-strains (n = 9) or uninfected persons (n = 21) (P = .025 and P<.001, respectively), but the difference in cell proliferation between the latter two groups was not statistically significant. The number of apoptotic cells per 100 epithelial cells (apoptotic index) in persons infected with cagA+ strains was lower than in persons infected with cagA-strains (P = .05). Apoptotic indices in the cagA+ group were similar to those in the uninfected group (P = .2). Epithelial cell proliferation was significantly correlated with acute gastric inflammation, but only in the cagA+ group (r = .44; P = .006). The cagA+ and vacA s1a genotypes were found to be concordant, confirming the close relationship between these virulence-related genotypes.


CONCLUSIONS
Gastric mucosal proliferation was significantly correlated with the severity of acute gastritis in persons infected with cagA+ vacA s1a strains of H. pylori. This increased proliferation was not accompanied by a parallel increase in apoptosis.


CONCLUSIONS
Increased cell proliferation in the absence of a corresponding increase in apoptosis may explain the heightened risk for gastric carcinoma that is associated with infection by cagA+ vacA s1a strains of H. pylori.
Peek
R M
RM
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2279, USA.
Moss
S F
SF
Tham
K T
KT
Pérez-Pérez
G I
GI
Wang
S
S
Miller
G G
GG
Atherton
J C
JC
Holt
P R
PR
Blaser
M J
MJ
D000942:Antigens, Bacterial; D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics*; D001427:Bacterial Toxins / Q000235:genetics*; D002455:Cell Division; D003603:Cytotoxins / Q000235:genetics*; D015342:DNA Probes; D004797:Enzyme-Linked Immunosorbent Assay; D005753:Gastric Mucosa / Q000382:microbiology* / Q000473:pathology*; D005838:Genotype; D016481:Helicobacter Infections / Q000235:genetics* / Q000473:pathology*; D016480:Helicobacter pylori / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012306:Risk
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D003603:Cytotoxins; D015342:DNA Probes; C074689:VacA protein, Helicobacter pylori; C080866:cagA protein, Helicobacter pylori