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Host, heredity and helicobacter
  1. J G NEDRUD
  1. Institute of Pathology
  2. Case Western Reserve University
  3. School of Medicine, Cleveland, Ohio, USA
  4. Department of Pediatrics
  5. Case Western Reserve University
  6. School of Medicine, Cleveland, Ohio, USA
  1. Dr Czinn, Department of Pediatrics and Pathology, Case Western Reserve University, RB&C Hospital, 11100 Euclid Avenue, Cleveland, Ohio 44106, USA.
  1. S J CZINN
  1. Institute of Pathology
  2. Case Western Reserve University
  3. School of Medicine, Cleveland, Ohio, USA
  4. Department of Pediatrics
  5. Case Western Reserve University
  6. School of Medicine, Cleveland, Ohio, USA
  1. Dr Czinn, Department of Pediatrics and Pathology, Case Western Reserve University, RB&C Hospital, 11100 Euclid Avenue, Cleveland, Ohio 44106, USA.

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Helicobacter pylori is considered one of the most common pathogenic infections of mankind. Despite its worldwide distribution, the pathogenesis of H pylori associated gastroduodenal disease remains poorly understood. What is clear is that only a minority of infected individuals develop severe inflammation leading to peptic ulcers or gastric cancer, the more severe manifestations of helicobacter infection. What are the factors which determine whether an infected individual will develop severe disease? It has been suggested that phenotypic or genotypic differences among bacterial isolates may be important in disease.1 There is evidence to suggest that individuals infected with strains of H pylori which express the cytotoxin associated gene product CagA, a marker for the presence of a “pathogenicity island”, are more likely to develop peptic ulcers or gastric cancer.2-5Recent observations suggest that polymorphism ofvacA genotypes may determine whether anH pylori infected individual develops gastritis or an ulcer.6 However, only a small fraction of the estimated 60% of all individuals infected with such strains ofH pylori develop severe gastroduodenal disease (peptic ulcers or gastric cancer). This suggests that the host is also a factor in determining the ultimate clinical outcome following helicobacter infection.

In fact, several laboratories have provided evidence that the host response is an important determinant in helicobacter associated disease processes. Mouse models of disease are among the most amenable to genetic analysis and of the available mouse models, theH pylori mouse model is limited by a delayed course of disease progression and consistently low inflammation scores. For instance, moderate to severe inflammation is present inH pylori infected C57BL/6 mice only after six months or more. An alternative model of helicobacter disease is theHelicobacter felis mouse model which has been used extensively to examine how the host response prevents and/or exacerbates helicobacter induced gastroduodenal disease.7-11 In the mouse H felis infection model, several inbred strains of mice, including C57BL/6, C3H/He, and SJL, exhibit severe inflammation/gastric atrophy (“high responder”) after infection whereas other inbred strains, including BALB/c, CBA/Ca, and C3H/HeJ, are low gastritis/atrophy responders to H felis infection. These results suggest that the nature of the host immune or inflammatory response to H pylori infection in humans may also be important in determining disease outcome.

The report by Sutton et al, in this issue (see page 335), represents an important next step in determining the basis for differential host response to helicobacter infections. These investigators used the H felis model, and infected several high responder mouse strains as well as a low responder strain and the F1 crosses between the low responder and high responder strains. They then examined the degree of bacterial colonisation, several parameters of the gastric inflammatory response and serum anti-H felis antibody responses in these populations of mice. For the most part, no significant differences in bacterial colonisation were observed. In contrast, both the low responder CBA/Ca strain as well as the F1 progeny from high and low gastritis/atrophy responsive strains always exhibited low inflammation. Thus, low inflammation was a “dominant” response.

The results of the antibody responses from data reported here as well as elsewhere are more complicated. The parental low inflammation strain, CBA/Ca, also exhibited low serum antibody responses as did the F1 mice between CBA/Ca and either C3H/He, C57BL/6, or SJL, three high inflammation parental mouse strains. This result alone could be consistent with a linkage of low antibody response to low atrophy/gastritis. However, although high inflammation C3H/He mice exhibited high levels of IgA, IgG1 and IgG2a serum antibodies, another high atrophy/gastritis parental mouse, the SJL strain, produced relatively low levels of serum IgA and IgG1 and has a genetic deletion of the IgG2a subclass. The other high atrophy/gastritis strain examined in this study, C57BL/6, produced high levels of serum IgA, low levels of serum IgG1 and is also unable to produce IgG2a. Furthermore, although the analysis was not as complete as reported by Suttonet al, another atrophy/gastritis unresponsive mouse strain, BALB/c, was previously reported by this group to produce moderate to high levels of H felis specific serum IgG.8 Also, the low inflammation C3H/HeJ mouse strain produced equivalent or even slightly higher serum and salivary antibody levels than high inflammation C3H/He mice,10 a situation which may be further complicated by the lipopolysaccharide non-responsiveness of C3H/HeJ mice. Finally, local gastric IgA and IgG antibody production, which were not examined in this study, may be more relevant to gastric inflammation than serum antibodies.

Thus, although a state of low atrophy/gastritis in response toH felis infection seems to be a dominant trait, the linkage of this phenomenon to antibody production seems to be less firm and much more complicated. This is an important point because the authors speculate, largely on the basis of low antibody responses in their H felis infected F1 mice, that a dominant low response may actually represent active suppression of the host immune/inflammatory response to helicobacter infections. Active suppression has been hypothesised by others to result in a state of low inflammatory/immune responsiveness in humanH pylori infections. Thus, although the studies reported by Sutton et al are not definitive in all respects, they do reveal the somewhat unexpected dominance of a low inflammatory response to H felis infection. They also point out the usefulness of genetic quantitative trait analysis in probing the mechanisms of helicobacter associated diseases. Additional studies using similar methods have the potential to provide exciting new information on helicobacter–host interactions.

Acknowledgments

The authors laboratories are supported by grants DK-46461 and AI 40701 from the National Institutes of Health.

See article on page 335

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