The mucosal immune response against Helicobacter pylori infection

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Laboratory Medicine

Sammanfattning: H. pylori infection affects more than half of the world’s population. The clinical consequences range from asymptomatic gastritis to peptic ulceration and gastric malignancy. H. pylori infection triggers strong humoral and cellular immune responses, both systemically and locally in the gastric mucosa. These responses, however, do not result in eradication of the bacteria. The aims of our studies were to identify genes associated with H. pylori-induced inflammation in the human and mouse gastric mucosa and to investigate the mechanism underlying vaccination-induced protection. We have studied the gene expression profiles in gastric tissue in 12 H. pylori-infected patients and 9 H. pylori-negative controls using cDNA arrays. We found a remarkably consistent pattern of genes differentially expressed in normal and H. pylori-infected gastric mucosa and identified a "Helicobacter-infection signature", which includes a set of genes encoding Toll-like receptors, adhesion molecules, metalloproteinases, chemokines and interleukins. We subsequently studied the role of one of the genes identified in the first study, matrix metalloproteinase-9 (MMP-9), in H. pylori-induced gastritis. We demonstrated a large, on average 19-fold, increase of MMP-9 expression in the antrum of H. pylori infected patients, as compared to controls. In contrast, there was no difference in the levels of tissue inhibitors of metalloproteinases (TIMP)-1 or -2 between the groups. The increase in MMP-9 activity in the gastric mucosa, was probably caused by tissue-resident macrophages. The net increase in gastric MMP activity is likely to contribute to tissue damage in H. pylori-associated gastritis. The inflammatory gene expression profiles in three groups of patients infected with triple-negative strains (lacking CagA, BabA2 and VacAs1, but expressing VacAs2), doublepositive strains (type I strains, expressing CagA and VacAs1) and triple-positive strains (expressing CagA, VacAs1 and BabA2) were subsequently investigated. The gene expression pattern in the antrum mucosa from patients infected with different H. pylori strains was similar and no differentially expressed genes could be identified by pair-wise comparisons, suggesting a lack of correlation between the host inflammatory responses in the gastric mucosa and expression of the BabA2, CagA and VacAs1 genes. We have also explored the potential mechanism underlying the BabA-induced protection by gene expression profiling in antrum gastric mucosa in a set of naïve, unimmunized/challenged and immunized/challenged mice. The protection was neither associated with an altered Th1/Th2 cytokine expression pattern, nor with an up-regulation of expression of adipocyte-specific cytokines. Severe gastric inflammation was not associated with protection. Furthermore, we could not identify any gene that was specifically induced by the immunization procedure, as the putative “immunization signature” identified was part of the“H. pylori-infection signature”. Thus, the specific immune response elicited is most likely underlying the protective mechanism.

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