Hussein, Nawfal Rasheed
(2009)
The pathogenesis of Helicobacter pylori associated diseases in Kurdistan region, Iraq.
PhD thesis, University of Nottingham.
Abstract
Helicobacter pylori is regarded as the most important risk factor for peptic ulcer disease and gastric cancer. In Kurdistan region, northern Iraq, gastric cancer is rare (5/100,000). To investigate some possible reasons for this, the prevalence of H. pylori infection, gastric mucosal histopathological changes in H. pylori infected subjects, and virulence factor genotypes (especially dupA) of colonising strains were studied. The immune response to H. pylori infection, focusing on genes associated with T-helper (Th) and regulatory T-cell (Treg) cells, was also investigated.
It was found that 79% of 163 adults and 37% of 120 children were seropositive for H. pylori (p<0.0001). For infected people, gastric lymphocyte infiltration was more prominent in the antrum (p=0.01).
71% of Iraqi H. pylori strains were positive for cagA and its presence was significantly associated with peptic ulcer disease (PUD) (p<0.01). cagA genes encoding four or more tyrosine phosphorylation motifs could not be found in any of the Iraqi strains. Isolates possessing the i1 form of vacA were significantly associated with GU (p<0.02). 32% of Iraqi H. pylori isolates were dupA-positive and presence of this gene was associated with PUD (p<0.01).
The levels of IFNγ, IL-12 p35, IL-10, IL-4 and FOXP3 mRNA were found to be elevated in gastric mucosal samples from H. pylori-infected patients compared to those from H. pylori-negative patients (median increase 7-fold p=0.001; 17-fold p=0.002; 1320-fold p=0.001; 1184-fold p=0.001; and 3-fold p=0.01, respectively), indicating a predominant IL-4 and IL-10 (Th2) response. Interestingly, IFNγ mRNA levels were 16-fold higher in tissues taken from 17 infected smokers than found in tissues taken from 18 infected non-smokers (p=0.009). IL-4 mRNA levels in tissues from 20 infected females were 40-fold higher than in tissues from 15 males (p=0.005).
Nucleotide sequencing of the dupA 3' region from 32 strains showed that dupA commonly had additional single base insertions or deletions that either truncated or extended the open reading frame (ORF). We have therefore classified dupA into two main groups: the common extended ORF within jhp0917-19 (dupA1), and dupA with an early stop codon to truncate the ORF (dupA2). ELISA performed on supernatants from H. pylori-infected gastric epithelial cell lines found no significant differences in IL-8 production between strains that possessed or lacked dupA. In comparison to wild-type H. pylori, disruption of dupA significantly reduced IL-12, IFNγ, TNFα and IL-8 production by peripheral blood mononuclear cells (PBMCs) in 2/4 strains. For the remaining 2 strains, where gene sequencing revealed a frame shift resulting in truncated dupA in the wild-type, the level of these cytokines was unchanged by dupA mutation.
H. pylori infection is common in Kurdistan region and acquired at a young age. The low cancer rate may be partially explained by a predominant lymphocyte infiltration in the antrum rather than the corpus, which has been reported to be associated with reduced risk of gastric adenocarcinoma. An absence of the more toxic cagA genotype with four or more tyrosine phosphorylation motifs in the Iraqi strains, and the predominance of Th2 cytokine expression rather than a more pro-inflammatory Th1 response to H. pylori could also contribute to a reduced incidence of cancer. dupA1 appears to play an important role in promoting the inflammatory response of leukocytes to H. pylori.
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