Genetic polymorphisms of NOD1 and IL-8, but not polymorphisms of TLR4 genes, are associated with Helicobacter pylori-induced duodenal ulcer and gastritis

BACKGROUND: Intracellular pathogen receptor NOD1 is involved in the epithelial cell sensing Helicobacter pylori, which results in a considerable interleukin (IL)-8 production. The aim of this study was to evaluate the relationship between NOD1 and IL-8 genetic polymorphisms and the development of H. pylori-induced gastritis and duodenal ulcer (DU), as compared with TLR4 polymorphisms. MATERIALS AND METHODS: Eighty-five patients with DU and 135 patients with gastritis were enrolled in the study. Seventy-five serologically H. pylori-positive subjects without gastric or duodenal symptoms served as controls. The G796A (E266K) NOD1 polymorphism was determined by restriction fragment length polymorphism, and the -251 IL-8 polymorphism by amplification refractory mutation system method. The TLR4 (ASP/299/Gly and Thr/399/Ile) gene polymorphisms were examined by melting point analysis. RESULTS: AA homozygote mutant variants of NOD1 were detected in 20% of the H. pylori-positive patients with DU versus 7% of H. pylori-positive patients with gastritis and versus 6% of the H. pylori-positive healthy controls. The IL-8 heterozygote mutant variant was detected with a significantly higher frequency among the DU patients and those with gastritis than among the H. pylori-positive controls. However, no significant correlation concerning the frequency of the TLR4 gene polymorphism could be revealed between any group of patients and the controls. CONCLUSION: E266K CARD4/NOD1, but not the TLR4 gene polymorphism increases the risk of peptic ulceration in H. pylori-positive patients. The -251 IL-8 polymorphism was significantly associated with either gastritis or DU in H. pylori-infected subjects. Host factors including intracellular pathogen receptors and IL-8 production play an important role in H. pylori-induced gastric mucosal damage.     

Toll-like receptor (TLR2, TLR4 and TLR5) gene polymorphisms and Helicobacter pylori infection in children with and without duodenal ulcer

Helicobacter pylori infection is mainly acquired in childhood, and polymorphisms in the host genes coding for Toll-like receptors (TLRs) may influence the innate and adaptive immune response to the infection, affecting the susceptibility to H. pylori or the disease outcomes. Our aim was to investigate whether TLR4, TLR2, and TLR5 polymorphisms were associated with H. pylori susceptibility and risk for duodenal ulcer in children. Gastric biopsy specimens were obtained at endoscopy for evaluation of H. pylori status, TLR4, TLR2 and TLR5 polymorphisms from 486 children (254 H. pylori-negative and 232 H. pylori-positive: 72 with and 160 without duodenal ulcer). cagA status of H. pylori infection was investigated by PCR. The levels of gastric cytokines were detected by ELISA. H. pylori-positivity or duodenal ulcer were not associated with TLR2, TLR4 or TLR5 polymorphisms. Otherwise, the presence of TLR4 polymorphic allele was associated with infection by cagA-positive strains and with increased gastric levels of interleukin-8 and interleukin-10. TLR4 polymorphism might ultimately contribute to more severe consequences of the infection in adulthood since it was associated with susceptibility to cagA-positive H. pylori infection early in life.     

The prevalence of peptic ulcer not related to Helicobacter pylori or non-steroidal anti-inflammatory drug use is negligible in southern Europe

BACKGROUND AND AIM: Helicobacter pylori is the major cause of peptic ulcer disease, but the proportion of H. pylori-negative peptic ulcers seems to be increasing in developed countries. We investigated the frequency of H. pylori-negative peptic ulcer without intake of nonsteroidal anti-inflammatory drugs (NSAIDs) in a Mediterranean European country. MATERIALS AND METHODS: We prospectively collected consecutive patients with an endoscopically verified active peptic ulcer over 6 months from different areas of Spain. Helicobacter pylori infection was assessed by rapid urease test and histologic examination (corpus and antral biopsies). A (13)C-urea breath test was performed if H. pylori was not detected with the invasive test. Patients were considered H. pylori-negative if all three tests were negative. NSAID use was determined by structured data collection. RESULTS: Of 754 consecutive peptic ulcer patients, 16 (2.1%) were H. pylori-negative and had not used NSAIDs before the diagnosis. Of the 472 patients who had duodenal ulcers, 95.7% (n = 452) were H. pylori-positive and only 1.69% (n = 8) were negative for both H. pylori infection and NSAID use; 193 patients had benign gastric ulcers and 87% (n = 168) of them were infected by H. pylori (p <.001 vs. duodenal ulcers). NSAID intake was more frequent in gastric ulcer patients (52.8%) than in duodenal ulcer patients (25.4%; p <.001). Consequently, the frequency of H. pylori-negative gastric ulcer in patients not using NSAID was 4.1% (n = 8). CONCLUSION: Peptic ulcer disease is still highly associated with H. pylori infection in southern Europe, and only 1.6% of all duodenal ulcers and 4.1% of all gastric ulcers were not associated with either H. pylori infection or NSAID use.     

Helicobacter pylori-induced immunological responses in patients with duodenal ulcer and in patients with cardiomyopathies

The interaction between the bacteria and the host is a key factor determining the clinical consequences of H. pylori infection. The immune system plays an important role in either promoting or preventing the disease. The mucosal production of TNF-alpha, IL-6, IL-8 and IL-10 and the CagA status were investigated in H. pylori-positive patients with duodenal ulcer (DU). The concentrations of these cytokines in gastric antral mucosal specimens from patients infected with H. pylori (n = 40) were determined by ELISA and compared with data on mucosal specimens from H. pylori-negative patients (n = 12). The local TNF-alpha, IL-6 and IL-8 concentrations in the antral biopsy samples were significantly higher (p < 0.001) in the patients infected with H. pylori than in the samples from the H. pylori-negative subjects. CagA positivity was demonstrated in 39 (97.5%) of the 40 patients with DU, and in 41 (70.7%) of H. pylori-positive (58 of 100) healthy blood donors. In complementary studies focusing on extragastric disease, it was found that 57% of patients with ischaemic heart disease were seropositive as concerns H. pylori, and 91% of them had antibodies against human heat shock protein 60, too. This study suggests that, besides the bacterial virulence factor, the host response of an increased mucosal production of inflammatory cytokines can be relevant to the gastric pathophysiology in H. pylori-induced DU. At the same time, in ischaemic heart diseases the role of autoimmune processes induced by H. pylori cannot be excluded.     

Helicobacter pylori stimulates a mixed adaptive immune response with a strong T-regulatory component in human gastric mucosa

BACKGROUND: Host factors play an important role in the pathophysiology of Helicobacter pylori infection and development of gastritis and related disease. The established opinion is that the T-cell-mediated immune response to H. pylori infection is of Th1 type. Our earlier immune cell phenotype studies indicate a mixed Th1-Th2 profile of the effector cells. Therefore, an extensive adaptive and regulatory cytokine gene expression profile was conducted by quantitative real-time polymerase chain reaction (qPCR). MATERIALS AND METHODS: Biopsies from gastric mucosa of 91 patients diagnosed as H. pylori negative, H. pylori positive with gastritis, or H. pylori positive with peptic ulcer were obtained by endoscopy. Gene expressions of nine cytokines and CagA status were measured by qPCR. RESULTS: All cytokine genes showed higher expression levels in the presence of H. pylori when compared to H. pylori-negative samples (fold increase: IL8: x 11.2; IL12A: x 2.4; TNF-alpha: x 5.2; IFN-gamma: x 4.3; IL4: x 3.6; IL6: x 14.7; and IL10: x 6.7). Patients infected with CagA-positive strains had higher expression of IL1-beta and IL18 compared to patients infected with CagA-negative strains (x 1.6 for IL1-beta and x 2.0 for IL18). Patients with duodenal ulcer had a lower antral Th1/Th2 ratio than other H. pylori-positive patients. CONCLUSIONS: The cytokine profile of H. pylori-infected gastric mucosa shows a mixed Th1-Th2 profile. Furthermore, a high IL10 expression may indicate that also regulatory T cells play a role in the chronic phase of H. pylori infection.     

Local and peripheral cytokine response and CagA status of Helicobacter pylori-positive patients with duodenal ulcer

The mucosal production of TNF-alpha, IL-6, IL-8, IL-10 and nitrotyrosine was investigated in H. pylori-positive patients with duodenal ulcer (DU). The concentrations of these cytokines in gastric antrum mucosal specimens from patients infected with H. pylori (n = 40) were determined by ELISA and compared with data on mucosal specimens from H. pylori-negative patients (n = 12). Nitrotyrosine was determined by ECL Western blotting. It was additionally investigated whether the tissue levels of the cytokines correlated with the peripheral cytokine levels, and the CagA status of the patients. The local TNF-a, IL-6 and IL-8 concentrations in the antral biopsy samples were significantly higher (p < 0.001) in the patients infected with H. pylori than in the samples from the H. pylori-negative subjects. There was a negative correlation between the TNF-alpha and IL-10 concentrations. Further more, in 23 of the 40 biopsy specimens, considerable nitrotyrosine production was detected by ECL Western blotting. There was no significant difference in peripheral TNF-a and IL-6 production between the DU patients and healthy blood donors (n = 100; 58% of whom were also H. pylori-positive). Only the in vitro IL-8-producing capacity was higher in the peripheral blood of the DU group after ex vivo induction with H. pylori. CagA positivity was demonstrated in 39 (97.5%) of the 40 patients with DU, and in 41 (70.7%) of the 58 H. pylori-positive, healthy blood donors. This study suggests that besides the bacterial virulence factor, the host response, with an increased mucosal production of inflammatory cytokines and reactive oxygen and nitrogen species could be relevant to the gastric pathophysiology in H. pylori-induced DU. There is no generalized cytokine overproduction in these DU patients, but the moderate increase in in vitro IL-8 production might be of pathophysiological importance.     

Pro- and anti-inflammatory cytokines gene polymorphisms and Helicobacter pylori infection: interactions influence outcome

The aim of this study was to evaluate whether there was any correlation between Helicobacter pylori-associated diseases and (1) H. pylori virulence genes or (2) IL-1B, IL-1RN, IFN-G, TNF-A, IL-10 genetic polymorphisms. Patients with non-cardia gastric cancer (NCGC, n=129) or benign gastroduodenal diseases (n=792) were studied. IL-1RN intron 2 VNTR polymorphism (PCR), IL-1B -31 C/T (RFLP), the SNPs of IFN-G (+874 A/T), TNF-A (-1031 C/T, -857 C/T, -376 A/G, -308 A/G, -238 A/G), IL-10 (-1082 A/G, -819 C/T, -592 A/C) (Taqman chemistry) were studied. cagA, s1 and m1 vacA, were PCR amplified. Duodenal ulcer was more frequent in TNF-A -857 TT and in IL-1RN 1,2 subjects. TNF-A -857 TT genotype was also correlated with gastric ulcer. IL-10 -819 TT genotype was associated with intestinal metaplasia and NCGC. Antral inflammation was associated with TNF-A -1031 TT, while corpus activity with IL-10 -819 CC. H. pylori infection was associated with TNF-A -308 AG genotype, while IFN-G +874 AA genotype was associated with cagA. In conclusion, among host genetic factors contributing to H. pylori disease outcome, IFN-G +874 AA genotype favors cagA positive infections, TNF-A -857 TT duodenal ulcer while IL-10 -819 TT intestinal metaplasia and NCGC.     

The effects of genetic polymorphisms of IL-1 and TNF-A on Helicobacter pylori-induced gastroduodenal diseases in Korea

OBJECTIVE: To evaluate whether or not genetic polymorphism of IL-1B, IL-1RN, and TNF-Alpha is an important factor in the different expression of gastroduodenal diseases after Helicobacter pylori infection. METHODS: This study consisted of 1360 subjects: control, gastric cancer (GC, intestinal type, and diffuse type), benign gastric ulcer (BGU), duodenal ulcer, and first-degree gastric cancer relative (GCR). IL-1Beta-511 and TNF-A-308 biallelic polymorphism were genotyped by 5' nuclease polymerase chain reaction (PCR) assays, and PCR-restriction fragment length polymorphism (PCR-RFLP). IL-1RN penta-allelic variable number of tandem repeats was genotyped by PCR. RESULTS: There was no difference in the genetic polymorphism of IL-1Beta-511, IL-1RN and TNF-A in the patients with gastric cancer regardless of H. pylori positivity compared with control. However, the frequencies of IL-1B-511 C/T (OR: 0.5, 95% CI: 0.3-0.7) and T carrier (OR: 0.6, 95% CI: 0.4-0.8) were lower in the H. pylori-positive BGU patients. The IL-1RN 2/2 was higher (OR: 5.5, 95% CI: 1.1-28.5) in the H. pylori-positive GCR. There was no significance in the polymorphism of TNF-Alpha-308 regardless of H. pylori-induced gastroduodenal diseases. CONCLUSIONS: The IL-1Beta-511 T-carrier polymorphism has a negative effect on the development of H. pylori-positive BGU, and high frequency of IL-1RN 2/2 was found in the H. pylori-positive relatives of GC patients, which suggest that this genetic polymorphism could play some role in the H. pylori-induced gastroduodenal diseases in Korea.     

MDR1 C3435T polymorphism has no influence on developing Helicobacter pylori infection-related gastric cancer and peptic ulcer in Japanese

AIMS: P-glycoprotein, the gene product of multidrug-resistant transporter-1 (MDR1), confers multidrug resistance against antineoplastic agents but also affects the kinetic disposition of some drugs and carcinogens. MDR1 C3435T polymorphism influences the development of colon cancer and adult acute myeloid leukemia by the association with transporting carcinogen. The aim of this study was to clarify the association of MDR1 C3435T polymorphism with susceptibility to gastric cancer and peptic ulcers in patients with Japanese H. pylori infection. MAIN METHODS: We assessed the MDR1 C3435T polymorphism in H. pylori-positive gastritis alone patients (n=150), gastric cancer (n=292), gastric ulcer (n=215), and duodenal ulcer (n=163) and H. pylori-negative subjects (n=168) as control by a PCR-based method. KEY FINDINGS: No significant difference existed in frequencies of MDR1 C3435T polymorphisms between H. pylori-negative controls and H. pylori-positive gastritis alone patients. Moreover, MDR1-3435 T allele carriage didn't affect the risk of gastric cancer or peptic ulcer development. The age- and sex-adjusted odds ratios (ORs) of MDR1 3435 T allele carriers relative to the C/C genotype group for gastric cancer, gastric ulcer and duodenal ulcer risk were 0.96 (95%CI: 0.56-1.66), 1.16 (95%CI: 0.72-1.84) and 1.00 (95%CI: 0.61-1.62), respectively. SIGNIFICANCE: In this preliminary data, the association with MDR1 C3435T polymorphism and risk for developing H. pylori-related gastric cancer and peptic ulcer in Japanese was low. P-glycoprotein might not be involved in the carcinogenesis of H. pylori-related gastric cancer.     

The interleukin-1 RN polymorphism and Helicobacter pylori infection in the development of duodenal ulcer

BACKGROUND: The host genetic factors that determine the clinical outcomes for Helicobacter pylori-infected individuals remain unclear. AIMS: To elucidate the relations among interleukin-1 locus polymorphisms, and H. pylori infection in the development of duodenal ulcers. MATERIALS AND METHODS: In a case-control study involving 168 control subjects and 147 patients with duodenal ulcer, biallelic polymorphisms of two interleukin-1 loci, IL-1B(-511) and IL-1B(+3954), as well as the penta-allelic variable number of tandem repeats of interleukin-1 receptor antagonist IL-1RN, were genotyped, and the H. pylori states of controls and patients were examined. RESULTS: Helicobacter pylori infection, male gender and the carriage of IL-1RN*2 independently increased the risk of duodenal ulcer with odds ratios of 6.4 (95% confidence interval, 3.7-11.0), 1.9 (95% confidence interval, 1.1-3.4) and 2.7 (95% confidence interval, 1.1-6.8), respectively. Statistical analysis revealed an interaction between IL-1RN*2 and H. pylori infection with the duodenal ulcer risk conferred by the H. pylori infection substantially increased (odds ratios, 22.6; 95% confidence interval, 5.9-86.5) by the carriage of IL-1RN*2. In addition, a synergistic interaction between IL-1RN*2 and blood group O existed. The combined risk of H. pylori infection, the carriage of IL-1RN*2 and blood group O for duodenal ulcer was 27.5 (95% confidence interval, 3.1-243.6). CONCLUSIONS: This work is the first to verify IL-1RN*2 as an independent factor that governs the development of duodenal ulcers. Our data indicate that H. pylori infection and IL-1RN*2 synergistically determine susceptibility to duodenal ulcer. The blood group phenotype is possibly a crucial determinant for the outcome of the impact of an interleukin-1 locus polymorphism on H. pylori-infected individuals.     

Helicobacter pylori virulence genes and host IL-1RN and IL-1beta genes interplay in favouring the development of peptic ulcer and intestinal metaplasia

Helicobacter pylori infection outcome might depend on genotypic polymorphisms of both the bacterium and the host. We ascertained: (1) the functionality of H. pylori oipA gene; (2) the polymorphism of the hostinterleukin (IL-1beta) gene (-31 C/T) and of the IL-1RN gene (intron 2 VNTR); (3) the association between the above genes and the histological and pathological outcome of H. pylori infection. One hundred and sixty-five H. pylori positive and 137 H. pylori negative subjects (23 gastric adenocarcinoma, 58 peptic ulcer, 221 gastritis) were studied. oipA was sequenced, IL-1beta was RFLP analysed. Antral and body mucosal biopsies were histologically evaluated. Functional oipA genes were correlated with cagA gene; both genes were significantly associated with gastritis activity, peptic ulcer and gastric adenocarcinoma. In these patients heterozygousIL-1RN 1/2 and IL-1beta C/T genotypes were more frequent than in gastritis patients. Intestinal metaplasia was associated with cagA, functional oipA and IL-1RN 2 allele. In conclusion, peptic ulcer and the preneoplastic intestinal metaplasia are associated with H. pylori virulence genes and with IL-1RN 2 host allele. An interplay between bacterial virulence factors and cytokines genotypes, is probably the main route causing H. pylori infection to lead to benign mild disease, benign severe disease or preneoplastic lesions.     

Helicobacter pylori and Nonmalignant Diseases

The incidence of peptic ulcer disease has declined over the last few decades, particularly in Western populations, most likely as a result of the decrease in Helicobacter pylori infection and the widespread use of proton-pump inhibitors (PPI) in patients with dyspepsia. The hospital admission rate for uncomplicated duodenal and gastric ulcers has significantly decreased worldwide. In contrast, admissions for complicated ulcer disease, such as bleeding peptic ulcers and perforation, remained relatively stable. Prophylactic H.?pylori eradication was found to be associated with a reduced risk of both gastric and duodenal ulcers and their complications, including bleeding in chronic users of nonsteroidal anti-inflammatory drugs. The recent Helicobacter Eradication Relief of Dyspeptic Symptoms trial presented important data relating to symptoms and quality of life of H.?pylori-positive patients with functional dyspepsia (FD) and also demonstrated significant benefits from eradication compared with the control group. The new Asian consensus report on FD recommended that dyspepsia accompanied by H.?pylori infection should be considered a separate disease entity from FD and that H.?pylori infection should be eradicated before diagnosing FD. The association of H.?pylori with gastroesophageal reflux disease (GERD) is still controversial. Treatment for H.?pylori does not seem to increase GERD symptoms or reflux esophagitis. However, documented eradication of H.?pylori appears to significantly improve GERD symptoms. Additional long-term intervention studies are needed to provide more information on which to base clinical decisions.     

The CD14-260 C --> T promoter polymorphism co-segregates with the tumor necrosis factor-alpha (TNF-alpha)-308 G --> A polymorphism and is associated with the interleukin-1 beta (IL-1 beta) synthesis capacity of human leukocytes

Genetic variations contribute to the interindividual variance in the cytokine response to endotoxin. The gene of tumor necrosis factor-alpha (TNF-alpha) carries a polymorphism at position -308 of the promoter, consisting of a G/A exchange. To further elucidate the inherited mechanisms influencing cytokine levels, healthy human blood donors were studied. Genotyping for the TNF-alpha -308 and the CD14 -260 C/T promoter polymorphisms was carried out by real-time polymerase chain reaction assay using specific fluorescence-labelled hybridisation probes. A human whole blood assay was used to study the leukocyte TNF-alpha and IL-1 beta synthesis capacity upon endotoxin stimulation. We found a linkage disequilibrium between the TNF-alpha -308 G/A and the CD14 -260 C/T polymorphisms (p = 0.043). The CD14 -260 polymorphism was associated with IL-1 beta levels (p = 0.033) and higher values were found in C homozygotes. No association was found between the CD14 -260 genotypes or the TNF-alpha -308 - CD14 -260 genotypes and the TNF-alpha response.     

Helicobacter pylori-induced IL-8 production by gastric epithelial cells up-regulates CD74 expression

CD74, or the class II MHC-associated invariant chain, is best known for the regulation of Ag presentation. However, recent studies have suggested other important roles for this protein in inflammation and cancer studies. We have shown that CD74 is expressed on the surface of gastric cells, and Helicobacter pylori can use this receptor as a point of attachment to gastric epithelial cells, which lead to IL-8 production. This study investigates the ability of H. pylori to up-regulate one of its receptors in vivo and with a variety of gastric epithelial cell lines during infection with H. pylori. CD74 expression was increased dramatically on gastric biopsies from H. pylori-positive patients and gastric cell lines exposed to the bacteria. Gastric cells exposed to H. pylori-conditioned medium revealed that the host cell response was responsible for the up-regulation of CD74. IL-8 was found to up-regulate CD74 cell surface expression because blocking IL-8Rs or neutralizing IL-8 with Abs counteracted the increased expression of CD74 observed during infection with H. pylori. These studies demonstrate how H. pylori up-regulates one of its own receptors via an autocrine mechanism involving one of the products induced from host cells.     

Helicobacter pylori and peptic ulcer disease.

Medical therapy for duodenal or gastric ulcer disease has traditionally involved gastric acid antisecretory therapy for 4 to 8 weeks to promote initial healing and indefinitely to prevent recurrences of ulcer. The discovery of Helicobacter pylori in most patients with peptic ulcer disease has led to a change in this approach. Therapy designed to eradicate H pylori may facilitate ulcer healing with acid antisecretory agents and, more important, may greatly reduce the incidence of ulcer recurrence, obviating the need for maintenance antisecretory therapy. Regimens designed to eradicate H pylori are difficult to comply with, however, and are associated with adverse effects in some patients. In this article we review the diagnosis and treatment of H pylori infection in patients with peptic ulcer disease and make recommendations regarding the use of conventional ulcer therapies and therapies designed to eradicate H pylori.     

Helicobacter pylori defines local immune response through interaction with dendritic cells

The bacterial pathogen Helicobacter pylori colonizes the human gastric and duodenal mucosa, evades clearance by the host response and is associated with peptic ulcer disease and an increased risk of gastric adenocarcinoma. Dendritic cells (DCs) are initiators of the immune response to H. pylori. The aim of the current study was to investigate the interaction between H. pylori with DCs. To determine the impact of H. pylori on the maturation and the activation of monocyte-derived DCs, the effect of 20 clinical H. pylori strains with different inflammatory backgrounds on adenocarcinoma gastric epithelial cells was investigated. The inflammatory background was defined according to the degree of lymphocyte and granulocyte infiltration and the bacterial density at the site of infection. DC maturation and activation varied after exposure to the different strains. While maturation appeared to be independent of any virulence factor tested, a significant increase in the average level of cytokine production was observed for the proinflammatory cytokines interleukin-12 (IL-12), tumour necrosis factor-α, IL-6 and IL-1β when comparing strains with low inflammatory backgrounds with those of the medium or high backgrounds. In conclusion, the DC response towards different strains in vitro was associated with the clinical outcome of the individual host, suggesting a major role of this cell type in modulating strain-specific H. pylori infection.     

Gastric mucosal cytokine responses in Helicobacter pylori-infected patients with gastritis and peptic ulcers. Association with inflammatory parameters and bacteria load

Helicobacter pylori is an important pathogen in gastroduodenal inflammation and ulceration. Several mechanisms have been proposed to explain its role. We studied the cytokine production patterns in situ in gastric mucosal biopsies from H. pylori-positive and H. pylori-negative patients with dyspepsia. Immunohistochemistry with monoclonal antibodies was used. The study showed enhanced expression of interleukin (IL) -8, IL-10 and interferon-gamma (IFN-gamma) in H. pylori infection and a significant association was found between these cytokines and the following parameters: bacteria load, chronic inflammation and activity. These parameters were significantly correlated with the cell markers CD19 and CD56. The study indicates a dual effect of H. pylori on the Th1 response, i.e. a stimulation of the response verified by increased IFN-gamma and a feed-back verified by an increase of the counterinflammatory IL-10, which may dampen the inflammatory and cytotoxic effect of the Th1 response. Furthermore, the study confirms the connection between increase of IL-8 and inflammatory activity in gastric mucosa in H. pylori infection.     

Long-term follow-up after eradication of Helicobacter pylori with omeprazole, clarithromycin, and tinidazole (OCT regimen) in a Japanese population

BACKGROUND: The long-term benefit of Helicobacter pylori eradication treatment that includes metronidazole on peptic ulcer disease in Japan is unclear. We investigated the rate of H. pylori re-infection and ulcer relapse after H. pylori eradication. MATERIALS AND METHODS: A total of 266 patients with endoscopically confirmed peptic ulcer disease and H. pylori infection were treated with triple therapy of omeprazole 40 mg (20 mg b.i.d.), clarithromycin 800 mg (400 mg b.i.d.), and tinidazole 1000 mg (500 mg b.i.d.) for 7 days. Endoscopy with gastric biopsy was performed before and 1 month, 6 months, 1.5 years, and 3.5 years after therapy. H. pylori status was determined by H. pylori culture, rapid urease test, and histopathology. 13C-urea breath test was done at 6 months after eradication therapy. Treatment was deemed successful when all tests were negative at 6 months after therapy by endoscopic biopsy. RESULTS: Successful H. pylori eradication was achieved in 262/266 (98.5%) patients with peptic ulcer. Total relapse of peptic ulcer occurred in 8/262 (3%) patients after eradication, with 3/262 (1.1%) occurring within 1.5 years after treatment and 5/262 (1.9%) within 3.5 years. All relapsed patients were found to be H. pylori-positive at the time of relapse. Of the 262 patients who experienced eradication, 20 (7.6%) were subsequently re-infected, six (2.3%) within 1.5 years and 14 (5.3%) within 3.5 years. CONCLUSION: Triple therapy with omeprazole, clarithromycin, and tinidazole (OCT) is useful for H. pylori eradication in Japan, but there is an appreciable re-infection rate in this population.     

Helicobacter pylori, T cells and cytokines: the "dangerous liaisons"

Helicobacter pylori infection is the major cause of gastroduodenal pathologies, but only a minority of infected patients develop chronic and life threatening diseases, as peptic ulcer, gastric cancer, B-cell lymphoma, or autoimmune gastritis. The type of host immune response against H. pylori is crucial for the outcome of the infection. A predominant H. pylori-specific Th1 response, characterized by high IFN-gamma, TNF-alpha, and IL-12 production associates with peptic ulcer, whereas combined secretion of both Th1 and Th2 cytokines are present in uncomplicated gastritis. Gastric T cells from MALT lymphoma exhibit abnormal help for autologous B-cell proliferation and reduced perforin- and Fas-Fas ligand-mediated killing of B cells. In H. pylori-infected patients with autoimmune gastritis cytolytic T cells infiltrating the gastric mucosa cross-recognize different epitopes of H. pylori proteins and H+K+ ATPase autoantigen. These data suggest that peptic ulcer can be regarded as a Th1-driven immunopathological response to some H. pylori antigens, whereas deregulated and exhaustive H. pylori-induced T cell-dependent B-cell activation can support the onset of low-grade B-cell lymphoma. Alternatively, H. pylori infection may lead in some individuals to gastric autoimmunity via molecular mimicry.     

Interleukin-6 genetic polymorphisms are not related to Helicobacter pylori-associated gastroduodenal diseases

Background. Polymorphisms in the promoter region of the proinflammatory cytokine, interleukin (IL)‐6 have been related to several chronic inflammatory diseases. Inter‐individual variation in the severity of gastric inflammation may be important in determining the clinical outcome of an Helicobacter pylori infection and relate to polymorphisms in this region. Materials and Methods. We studied H. pylori‐infected patients with duodenal ulcer or gastric cancer. In addition six gastric cancer cell lines, AGS, SNU‐668, MKN‐1, MKN‐7, MKN28 and KATOIII, were cocultured with both cag pathogenicity island‐positive and ‐negative H. pylori. Single nucleotide polymorphisms at positions ?174, ?572, and ?597 in the IL‐6 promoter region were identified by PCR‐RFLP. The IL‐6 production from the cancer cells was determined by ELISA. Results. Sixty patients with gastric cancer and 60 with duodenal ulcer were studied. The alleles at positions ?174 and ?597 were closely linked (?174G/?597G or ?174C/?597A) regardless of the ethnic group or disease presentation. There was no difference in the allele frequency at any of the sites among patient groups. H. pylori‐induced IL‐6 production from the gastric cancer cell lines was also independent of the IL‐6 polymorphisms or the presence of the cag pathogenicity island. Conclusions. The genetic polymorphisms in IL‐6 can be attributable to ethnicity and appear to be independent of the clinical outcome of an H. pylori infection.