Helicobacter pylori-induced cytokines. Relation to gastritis and duodenal ulcer disease

Abstract

Helicobacter pylori causes antral gastritis and peptic ulcers and is associated with development of gastric cancer. It is unclear why only a few of the infected subjects develop duodenal ulcers whereas the majority remains asymptomatic. Both bacterial factors as well as the nature of the host immune response might be important for the outcome of disease. The aims of this thesis were to characterize the local inflammatory response in human H. pylori infection and to study the relation of the local cytokine response to gastritis and peptic ulcer disease. Furthermore, the inflammatory properties of different putative virulence factors of H. pylori were examined.The cytokine, secretory component (SC) and immunoglobulin (Ig) A expression in antral biopsies from H. pylori infected duodenal ulcer (DU) patients and asymptomatic (AS) carriers as well as from healthy volunteers was studied by immunohistochemistry. The cytokine response in DU patients as well as in AS carriers was of the T helper 1 type. Furthermore, the levels of proinflammatory cytokines were increased in the H. pylori infected subjects. The gastric epithelial cells contributed substantially to the increased expression of several of the cytokines. However, none of the studied cytokines was correlated with peptic ulcer disease since the levels in DU patients and AS carriers were comparable. Also the antibody-mediated immune response, i.e. IgA producing cells and SC, to H. pylori infection was of the same magnitude in DU patients and AS carriers. Locally produced IFNg, but not IL-4, was correlated with increased SC expression.Acute gastritis induced in healthy volunteers by aspirin treatment allowed studies of the role of inflammation in the dysregulation of gastric secretory function, which is associated with H. pylori infection. The aspirin and the chronic H. pylori-induced gastritis shared common features, i.e. increased levels of IL-1b, IL-6, and IL-8 in the antral mucosa. Antral distention normally inhibits acid secretion and gastrin release. Components of the gastric inflammation, possibly cytokines, seemed to dysregulate the acid secretion, since antral distension failed to inhibit the acid secretion after aspirin therapy. However, the inhibition of gastrin release in response to antral distension was preserved, indicating another underlying mechanism of the H. pylori associated hypergastrinemia.As a prerequisite for studies of the acute inflammatory responses to H. pylori strains and antigens the expression of different putative virulence factors of H. pylori was studied by sensitive inhibition ELISA assays using specific monoclonal antibodies. The expression of three conserved antigens varied considerably between the different strains and culture conditions tested. A model of cultured human stomach explants was modified to allow studies of cytokine responses in culture media, as measured by ELISA, to acute experimental H. pylori infection and after stimulation with different antigens. Infection as well as antigen stimulation of the explants induced strong chemokine and cytokine responses. The different H. pylori LPS preparations tested induced cytokine production of comparable levels as after inoculation with whole bacteria. Furthermore, some H. pylori strains and antigens induced particularly strong chemokine responses indicating the presence of proinflammatory H. pylori strains or antigens