Faculty Bibliography

Two major markers of virulence have been described in H. pylori. The first is a secreted protein (VacA) that is toxic to human cells in tissue culture. This cytotoxin causes vacuolation of epithelial cells in vitro and induces epithelial cell damage in mice. The second is a 40-Kb pathogenicity island for which the gene cagA (cytotoxin-associated gene A) is a marker. Approximately 60% of H. pylori isolates in Western countries are cagA+. The protein encoded by cagA+ has a molecular weight of 120-140 kDa and exhibits sequence heterogeneity among strains isolated from Western and Eastern countries. Although no specific function has been identified for CagA, there is increasing evidence that cagA+ strains are associated with increased intensity of gastric inflammation and increased mucosal concentration of particular cytokines including interleukin 8. Inactivation of picB (Hp 0544) or any of several other genes in the cag island ablates the enhanced IL-8 secretion of human gastric epithelial cells in tissue culture. Furthermore, persons colonized with cagA+ strains have an increased risk of developing more severe gastric diseases such as peptic ulcer and distal (non-cardia) gastric cancer than those harboring cagA- strains. We investigated the role of cagA status in both gastroduodenal and extragastroduodenal disease with H. pylori. Among the diseases limited to the antrum and body of the stomach and the duodenum, we demonstrated a correlation between CagA seropositivity and peptic ulcer disease. We also showed correlation between distal gastric cancer rated and CagA prevalence in populations in both developed and developing countries. In addition, we found that for several Asian populations, the relationship between CagA seropositivity and gastroduodenal diseases was complex. For extragastroduodenal diseases, our results confirmed previous reports that demonstrated that CagA status did not play a role in diseases such as rheumatoid arthritis and hyperemesis gravidarum. However, we found a clear negative association between the presence of a positive response to CagA and esophageal diseases. Therefore, CagA seropositivity (and thus gastric carriage) is associated with increased risks of certain diseases (involving the lower stomach and duodenum) and decreased risks of GERD and its sequelae. This apparent paradox can best be explained by differences in the interaction of cagA+ and cagA- strains with their hosts

The incidence rates of gastric cardia and esophageal adenocarcinomas are increasing, but data suggest that carriage of cagA(+) Helicobacter pylori strains may protect against development of Barrett's esophagus and esophageal adenocarcinoma. Our aims were to examine the relationship between pre-malignant and malignant lesions in the gastric cardia and serum antibodies to H. pylori antigens in patients with and without complications of Barrett's esophagus. The prevalence of carditis was 40% in controls compared with 13% in patients with complicated or uncomplicated Barrett's esophagus and cardia adenocarcinoma (p < 0.001). Cardia intestinal metaplasia (IM) and atrophy were present and concordant in 28% of controls but less frequent in patients with Barrett's alone or with dysplasia/adenocarcinoma (0% for each, p < 0.001). Carriage of cagA(+) strains was present in 34% of patients with carditis and significantly associated with increased frequency and severity of cardia inflammation, IM, and atrophy but not with adenocarcinoma. IgA and HspA seropositivity were significantly increased in H. pylori-colonized patients with carditis compared to persons with normal cardia histology (p </= 0.005) but not in persons with esophageal disease or cardia adenocarcinoma. We conclude that carriage of cagA(+) H. pylori strains and induction of particular serological responses are significantly associated with marked histological findings in the gastric cardia but not with adenocarcinoma of either the gastric cardia or esophagus

Several different families of vacuolating toxin (vacA) alleles are present in Helicobacter pylori, and they encode products with differing functional activities. H. pylori strains containing certain types of vacA alleles have been associated with an increased risk for peptic ulcer disease. In this study, we tested serum samples and gastric juice from 19 H. pylori-negative and 39 H. pylori-positive patients for enzyme-linked immunosorbent assay reactivity with two different types of VacA antigens (types s1/m1 and s2/m2), which were purified from H. pylori 60190 and 86-338, respectively. Both antigens were recognized better by serum immunoglobulin G (IgG) from H. pylori-positive persons than by serum IgG from H. pylori-negative persons (P < 0.01). The s1/m1 VacA antigen was better recognized by sera from patients carrying vacA type s1/m1 strains than by sera from patients carrying vacA type s2/m2 or s1/m2 strains (P < 0.01). Conversely, the s2/m2 VacA antigen was better recognized by sera from patients carrying type s2/m2 or s1/m2 strains (P = 0.03). Serum IgG anti-VacA antibodies were present more frequently in patients carrying type s1/m1 strains than in other H. pylori-positive patients (P = 0.0002). In addition, the highest levels of IgA anti-VacA antibodies were detected in the gastric juice of patients carrying type s1/m1 strains. These data indicate that different VacA isoforms have distinct antigenic properties and that multiple forms of VacA elicit antibody responses in H. pylori-positive humans

Helicobacter pylori synthesizes an unusual GroES homolog, heat shock protein A (HspA). The present study was aimed at an assessment of the serological response to HspA in a group of Chinese patients with defined gastroduodenal pathologies and determination of whether diversity is present in the nucleotide sequences encoding HspA in isolates from these patients. Serum samples collected from 154 patients who had an upper gastrointestinal pathology and the presence of H. pylori defined by biopsy were tested for an immunoglobulin G (IgG) serologic response to H. pylori HspA by an enzyme linked immunosorbant assay. HspA-encoding nucleotide sequences in H. pylori isolates from 14 patients (7 seropositive and 7 seronegative for HspA) were analyzed by PCR and direct sequencing of the PCR products. The sequencing results were compared to those of 48 isolates from other parts of the world. Of the 154 known H. pylori-positive patients, 54 (35.1%) were seropositive for HspA. The A domain (GroES homology) of HspA was highly conserved in the 14 isolates tested. Although the B domain (metal-binding site unique to H. pylori) resembled that in the known major variant, particular amino acid substitutions allowed definition of an HspA variant associated with isolates from East Asia. There were no associations between patient characteristics and HspA seropositivity or amino acid sequences. We confirmed in this study that the clinical outcomes of H. pylori infection are not related to HspA antigenicity or to sequence variation. However, B-domain sequence variation may be a marker for the study of the genetic diversity of H. pylori strains of different geographic origins

Helicobacter pylori urease is required to counteract acidity during colonization of the stomach, and has been suggested as a major immunodominant antigen. The aim of this study was to determine the anti-urease response in a representative national serologic survey in Mexico. The population surveyed included persons 1-90 years of age from all socioeconomic levels and geographic zones of the country. Helicobacter pylori status was determined by ELISA serology. The IgG anti-urease was studied by ELISA using a recombinant apoenzyme. We found that 2,930 of the 7,720 infected patients (38%) were seropositive for IgG urease. The rate of IgG anti-urease positivity increased with age; in children < 10 years old it was < 20% and in persons > 40 years old it was > 50%. Age and a region with a high level of development were risk factors for seropositivity, whereas gender, educational level, crowding, and socioeconomic level were not associated with seropositivity. In conclusion, in natural infection with H. pylori, the response to urease is poor, mainly during the first years of infection. This inconsistent immune response to the enzyme may favor persistence of infection. A vaccine eliciting a consistent anti-urease response might overcome immune evasion and enhance clearance of bacteria after exposure

BACKGROUND & AIMS: The specificity of colonization by Helicobacter pylori and complex host-bacterium interactions cannot be readily examined in humans. The aim of this study was to perform such analyses in rhesus monkeys. METHODS: Four animals that had been cured of natural H. pylori colonization were challenged with a mixture of 7 strains of human origin, and bacteria recovered during periodic videogastroscopy were DNA fingerprinted. RESULTS: Three animals carried mixtures of several strains for 4 months, after which strain J166 predominated. In the fourth animal, only strain J238 was isolated from the earliest phase of colonization through 7 months, but strain J166 again became predominant by 10 months after the challenge. Gastritis scores and plasma gastrin and anti-H. pylori immunoglobulin G titers reached levels observed in naturally colonized animals by 4 months after the challenge; however, no plasma immunoglobulin A response was observed up to 10 months. CONCLUSIONS: These results show that (1) natural colonization does not elicit protective immunity against subsequent H. pylori challenge; (2) individuals differ in susceptibility to different H. pylori strains during initial stages of colonization; and (3) certain strains are better suited than others for long-term survival in different hosts. These observations show the complexity of H. pylori-host interactions

Helicobacter pylori strains possessing the Cag pathogenicity island have been associated with increased gastric inflammation and with duodenal ulcer. In contrast, studies on the association of cagA+ H. pylori infections and gastric cancer have shown conflicting results. The aim of our study was to determine whether H. pylori and CagA status are associated with gastric cancer in Mexico. We selected serum samples from 3 geographic areas with gastric cancer mortality rates per 100,000 inhabitants of 2.5 (low risk), 4.5 (medium risk) and 6.4 (high risk). H. pylori infection was determined by the detection of antibodies to H. pylori whole cell antigen by an enzyme-linked immunosorbent assay (ELISA). To study the prevalence of infection with cagA+ strains, serum IgG antibodies to CagA were determined by ELISA using a recombinant CagA antigen. Of the 2,775 individuals studied, 1,931 were H. pylori seropositive and 1,710 had antibodies against CagA. The risk for gastric cancer in the 3 populations studied increased proportionally as infection with cagA+ strains increased (p < 0.001 for trend). H. pylori infection also showed association with gastric cancer (p < 0.05). Individuals seropositive for CagA, but seronegative for H. pylori whole cell antigen, were more frequent in areas with higher gastric cancer rates (p < 0.01). These results support the possible role of CagA(+) status as predictor of risk for gastric adenocarcinoma in Mexico; this is in agreement with results in European and American populations, but contrary to studies in some Asian countries

A nationwide community-based survey for Helicobacter pylori infection had not been done. This study sought to determine the seroprevalence of infection in Mexico, and the socioeconomic and demographic variables that are risk factors for infection. The survey assessed 11,605 sera from a sample population representing persons ages 1-90 years from all socioeconomic and demographic levels and from all regions of Mexico. Antibodies against H. pylori were studied by ELISA using whole cell antigen. Among the findings were that 66% of the population was infected and that age was the strongest risk factor for infection. By age 1 year, 20% were infected and by age 10 years, 50% were infected. Crowding (odds ratio [OR], 1.4), low educational level (OR, 2.42), and low socioeconomic level (OR, 1.43) were risk factors for infection. Prevalence was similar in urban and in rural communities (OR, 0.95). This study is the largest community-based seroepidemiologic study of H. pylori to date

OBJECTIVE: Little is known about Helicobacter pylori infections and the immune response to urease and CagA in pediatric populations. Our aims were: 1) to validate serological assays for antibodies against whole cell extract, CagA, and urease of H. pylori; 2) to examine their role in diagnosis of infection in children with recurrent abdominal pain (RAP); and 3) to examine the antibody responses to CagA and urease in children. METHODS: An enzyme-linked immunosorbent assay (ELISA) for diagnosis of H. pylori infection using whole cell extracts was validated in 50 children with biopsy-confirmed infection. The IgG and IgA antibody responses against recombinant CagA and urease were compared by ELISA in 82 children with RAP and in 246 age- and sex-matched healthy children. RESULTS: The whole-cell extract ELISA had a sensitivity of 85 % and specificity of 87%. Children with RAP were more infected with H. pylori than were healthy control subjects; however, IgG and IgA CagA seropositivity was lower among those with RAP than among asymptomatic children (34% and 23% vs 76% and 55%, respectively; p < 0.0001). In both groups of children, the immune response to urease was low. CONCLUSION: A serodiagnosis of H. pylori infection using native strains was developed. The difference in the immune response between children with RAP and control subjects suggests that RAP occurs during the acute phase of H. pylori infection. Our results also suggest that urease is a poor immunogen

BACKGROUND & AIMS: The role of Helicobacter pylori in the pathogenesis of gastroesophageal reflux disease (GERD) is unknown. We determined the prevalence of cagA-positive (cagA+) H. pylori strains in patients with GERD or its complications compared with controls of similar age. METHODS: A total of 153 consecutive patients with GERD, Barrett's esophagus, and Barrett's esophagus complicated by dysplasia or adenocarcinoma were compared with 57 controls who underwent upper endoscopy for reasons other than GERD. H. pylori infection and CagA antibody status were determined by histology and enzyme-linked immunosorbent assay. RESULTS: H. pylori prevalence was lower (34%) in patients with GERD and its sequelae than in the control group (45.6%)(P = 0.15). Regardless of the group, increasing age was associated with higher prevalence of H. pylori (P = 0.003). When compared with controls (42.3%), the prevalence of cagA+ H. pylori strains decreased (P = 0.008) in patients with more severe complications of GERD (GERD, 36.7% [nonerosive GERD, 41.2%; erosive GERD, 30.8%]; Barrett's esophagus, 13.3%; and Barrett's with adenocarcinoma/dysplasia, 0%). CONCLUSIONS: Prevalence of H. pylori in patients with GERD and its sequelae was lower but not significantly different than that of a control group. However, patients carrying cagA+ strains of H. pylori may be protected against the complications of GERD, especially Barrett's esophagus and its associated dysplasia and adenocarcinoma