Mucosal B cell responses in the stomach and duodenum of Helicobacter pylori infected and non-infected subjects

Abstract

Infection with Helicobacter pylori is the main cause of duodenal ulcers and is also closely associated with the development of dyspepsia, gastric ulcers and gastric cancer. The bacteria are non-invasive and colonise only the human stomach and regions with gastric metaplasia in the duodenum. The aims of this thesis were to study the ability of the non-infected and H. pylori infected stomach, respectively, to produce immunoglobulins (Ig) as well as to evaluate whether antigen-specific antibody responses can be induced in the stomach by natural H. pylori infection or by oral vaccination. By determining Ig levels in gastric aspirates as well as frequencies of Ig-secreting cells in gastric biopsies collected from H. pylori-negative subjects, it was demonstrated that the non-infected stomach produces Igs which are transported into the gastric lumen. Furthermore, in the fasting state the release of IgA into the lumen varied cyclically in association with the migrating motor complex (MMC) both in the stomach and in the duodenum. When studying antibody responses in gastric aspirates and gastric tissue from H. pylori infected patients with duodenal ulcers (DU) and asymptomatic H. pylori carriers it was shown that H. pylori infection induces dramatically increased frequencies of IgA-secreting cells in the gastric mucosa as well as local H. pylori specific antibody responses. These antibodies were primarily directed against H. pylori whole membrane proteins, flagellin and urease. However, no differences in antibody responses could be detected between the DU patients and the asymptomatic H. pylori carriers. Despite the strong antibody responses against H. pylori locally in the stomach, spontaneous clearance of infection is rare. However, animal studies have demonstrated the possibility of inducing protective immunity against H. pylori infection by oral immunisation. Thus, there is hope of developing a human vaccine against H. pylori which preferably should elicit a specific immune response locally in the stomach and duodenum. To evaluate if it is possible to induce B cell responses in the gastric mucosa by oral vaccination, both H. pylori infected and non-infected subjects were immunised with an oral cholera vaccine. While both the H. pylori infected and the non-infected subjects responded to the vaccination with increased antibody responses in the duodenum, only the H. pylori infected subjects developed specific antibody responses in the stomach. In conclusion, this thesis shows that particularly the inflamed stomach produces large amounts of Igs, predominantly IgA, and that antigen-specific antibody responses can be induced locally in the stomach both by natural infection with H. pylori and by oral vaccination.