S2 Gut 1998;43 (suppl 1):S2–S5 Bacterial factors and immune pathogenesis in Helicobacter pylori infection Gut: first published as 10.1136/gut.43.2008.S2 on 1 July 1998. Downloaded from T Shimoyama, J E Crabtree Summary strains,5 m1 strains are associated with in- Virulent Helicobacter pylori strains which have creased gastric epithelial damage,6 and s1a been clinically associated with severe outcome strains are associated with increased mucosal induce increased gastric mucosal immune neutrophil and lymphocyte infiltration in vivo.6 responses. Although several bacterial patho- These results suggest s1a/m1 strains are the genic factors have been shown to have a most virulent allelic type. In fact in US popula- considerable role in H pylori infection, variabil- tions, infection with vacA s1 strain is more fre- ity in host immune responses may also contrib- quent in patients with ulcer disease than in ute to mucosal damage in H pylori associated those with chronic gastritis only (table 1).6 gastritis. However, the association between vacA diver- sity and clinical outcome is not as evident in Introduction Asian populations as it is in Western popula- Since the discovery of H pylori, many studies tions. Recent studies show that most H pylori have implicated infection with this bacterium strains in Japan have a s1a/m1 genotype even in in the pathogenesis of gastric and duodenal patients with chronic gastritis only (table 1).78 diseases. However, most patients with H pylori infection have chronic gastritis only and few cag PATHOGENICITY ISLAND develop peptic ulcers or gastric tumours. To The cytotoxin associated gene A (cagA)isthe date, the role of bacterial virulence factors such most studied non-conserved gene of H pylori. as vacA, cagA and lipopolysaccharide (LPS) in cagA, which encodes a high (120–140 kDa) the pathogenesis of H pylori infection has been molecular weight immunodominant protein, is extensively studied. The host’s mucosal im- present in approximately 60% of H pylori mune response, which includes activation of strains.9 In vitro studies have shown that the neutrophils, T cells and complement, has also ability of H pylori to induce chemokines in gas- been the subject of recent investigation. Both tric epithelial cell lines varies, the response bacterial and host factors are likely to play a being restricted to strains with the CagA critical role in the clinical outcome of H pylori phenotype.10–12 In vivo, infection with CagA http://gut.bmj.com/ infection. positive strains results in increased mucosal immune responses and more intense Bacterial virulence factors gastritis.13–15 Several studies have shown that Increasing evidence has shown that H pylori infection with CagA positive strains is highly strains are highly diverse and that strain diver- associated with peptic ulcer disease,15 16 sity is associated with greater gastric mucosal atrophic gastritis,17 18 and gastric cancer.19–21 inflammation and the clinical outcome of Recent studies show that cagA is part of a 40 on September 27, 2021 by guest. Protected copyright. infected patients. kilobase pathogenicity island (cag PAI) which contains over 30 genes.22 23 The importance of CYTOTOXIN gene products from cag PAI in the stimulation The vacuolating cytotoxin (VacA) which in- of epithelial chemokine responses has been duces cytoplasmic vacuolation in eukaryotic assessed using isogenic mutant strains. These cells was first described by Leunk et al.1 The studies have shown that the deletion of cagA cytotoxin is produced by approximately 50% of has no eVect on epithelial secretion of inter- H pylori strains2 and infection with toxin leukin (IL) 8,12 24 but deletion of many other producing strains is more common in patients genes in the cag PAI abolishes the ability of with peptic ulcer disease.3 Bernard et al showed the bacterium to stimulate IL-8 pro- that biological activity of VacA protein was duction.22 23 25 26 These studies show that the increased by exposure to acidic pH.4 The acid CagA is a phenotypic marker for virulent Molecular Medicine Unit, Level 7, Clinical activated VacA is currently considered to be an strains and the epithelial chemokine responses Sciences Building, St. important factor of increased mucosal damage depends on multiple genes in the cag PAI. The James’s University in H pylori infection. proteins encoded by cag PAI genes are thought Hospital, Leeds The vacuolating cytotoxin gene A (vacA), to function as a secretion system for the export LS9 7TF, UK which encodes VacA, is possessed by all H of bacterial factors involved in host epithelial J E Crabtree pylori strains. Atherton et al showed that there activation.22 23 5 First Department of are two divergent regions in vacA. One is in Internal Medicine, the second half of the signal sequence (s1a/s1b LIPOPOLYSACCHARIDE Hirosaki University and s2) and the other is in the mid-region of H pylori LPS has also been implicated in the School of Medicine, the gene (m1 and m2). Recent studies demon- pathogenesis of H pylori infection.27 The Hirosaki, Japan strate the association between diversity in this immunological activity of H pylori LPS has T Shimoyama gene and cytotoxin activity and increased been considered to be low.27 Early studies 56 Correspondence to: gastric inflammation. The s1/m1 strains pro- showed the lethal toxicity in mice of H pylori Dr Crabtree. duce higher toxin activity in vitro than s1/m2 LPS was 500-fold lower compared with that of Bacterial factors and immune pathogenesis in H pylori infection S3 Table 1 H pylori vacA gene signal sequence type in patients with peptic ulcer disease and Immune mediated damage chronic gastritis from the USA and Japan Histologically, the host’s response to H pylori 6 8 infection is characterised by infiltration of USA Japan Gut: first published as 10.1136/gut.43.2008.S2 on 1 July 1998. Downloaded from plasma cells, lymphocytes, neutrophils, and Signal sequence Peptic ulcer disease Chronic gastritis Both conditions monocytes into the gastric mucosa.39 The sla 17 1 84 inflammatory host immune response may play slb 8 6 1 a major role in the induction of gastric mucosal s2 2 8 0 damage by H pylori infection. This review Values presented as number of patients. focuses on cellular responses as the role of B salmonella LPS.28 Several studies also showed cells and autoantibodies is discussed elsewhere that secretion of the proinflammatory cy- in this supplement. tokines tumour necrosis factor (TNF) á, inter- leukin (IL)1 and IL-6 from human mononu- NEUTROPHIL ACTIVATION clear cells and IL-8 secretion from neutrophils In acute gastritis caused by infection with H following stimulation with H pylori LPS was pylori, neutrophils comprise the initial inflam- significantly lower than that induced by matory component of the response to the Escherichia coli and salmonella LPS.29 30 This pathogen. Activated neutrophils have many low biological activity of H pylori LPS is a result properties which may contribute to tissue of the phosphorylation pattern of its lipid A damage. Neutrophil chemotaxis and activation component and may prolong H pylori infection can be induced directly by products of H pylori and contribute to chronic inflammation in the and also indirectly through the inflammatory gastric mucosa.27 cytokine cascade.39 A water soluble neutrophil H pylori LPS may have an important role in activating 150 kDa protein, HP-NAP, has been autoimmune responses in the gastric mucosa. purified and extensively studied.40 41 The napA The structure of LPS O-specific antigen in dif- gene which encodes this protein is present in all ferent H pylori strains is similar to that of host H pylori strains but expression of HP-NAP var- 40 LewisX or LewisY blood group antigens31 32 ies in vitro. Recent studies suggest HP-NAP which are expressed in normal human gastric may have multiple functions, being induced in 42 mucosa.33 This molecular mimicry may ac- the bacterium by acid stress. H pylori LPS count for some of the gastric autoantibodies also aVects neutrophils; it does not stimulate neutrophils directly to release superoxide but it induced by H pylori. Appelmelk and 43 colleagues34 showed that the â chain of the H+, primes neutrophils to oxidative metabolism. K+ proton pump has LewisY epitopes and anti- Neutrophil infiltration and activation will Y also be stimulated indirectly by the cytokine Lewis antibodies induced by H pylori may 10–12 cascade induced by H pylori infection. The http://gut.bmj.com/ contribute to the development of atrophic gastric epithelium secretes chemokines which gastritis.35 Recent studies suggest that peptide have neutrophil attractant properties, such as epitopes on gastric H+,K+ ATPase may also be IL-8 and GROá in response to bacterial infec- the target of autoimmune responses in chronic tion. In vivo, increased IL-8 immunoreactivity gastritis.36 Lewis antigens are expressed more and increased IL-8 mRNA expression in H frequently on cagA positive than on cagA nega- 37 pylori infected mucosa have been tive strains. This suggests that cagA positive demonstrated.13 14 44 45 In vitro the expression of strains could potentially be more likely to IL-8 in gastric epithelial cells is up-regulated by on September 27, 2021 by guest. Protected copyright. stimulate autoimmune responses and contrib- the inflammatory cytokines such as TNF-á and ute to the association between cagA positivity 46 17 18 IL-1, which are produced in the gastric and atrophic gastritis. However, H pylori mucosa in H pylori infection.47 48 Inflammatory infected subjects without serum antibodies to X cytokines are increased in patients infected Lewis are at increased risk of atrophic with strains of the CagA phenotype.13 14 39 As 38 gastritis.