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Background: Clarithromycin (CAM) may have certain indirect effects on Helicobacter pylori (H. pylori ) other than its inhibitory activity on bacterial growth, as indicated in other infections with Gram-negative micro-organisms. In the present study, we examined the effects of lower concentrations of CAM on the release of heat shock protein B (HspB), one of the major antigenic proteins from H. pylori cells, as well as the changes in humoral immune response and histological degree of antral gastritis in patients who received eradication therapy with CAM. Methods: The H. pylori strain 26695 and three CAM-resistant clinical isolates were cultured in broth with and without CAM (2–500 ng/mL). Expression of H. pylori proteins was examined by two-dimensional (2D)-electrophoresis followed by N-terminal amino acid sequencing. Changes in host immune response and histological degree of antral gastritis were monitored in patients with peptic ulcer disease who received H. pylori eradication therapy. Results: 2D electrophoresis showed 26 spots in extracellularly released proteins with different profiles from those in cytoplasmic proteins. The release of HspB increased after incubation with CAM (30–500 ng/mL) in all three H. pylori clinical isolates tested. Patients with failed H. pylori eradication after triple therapy with CAM, but not those with failed eradication after dual therapy without CAM, showed an increase in serum IgG1 and IgG2 antibodies against HspB along with a decrease in the degree of neutrophil and H. pylori colonization density in tissue sections. Conclusions: CAM may induce a humoral immune response against H. pylori and a decrease in gastric mucosal inflammation through up-regulation of the release of HspB from the bacteria in infected patients. [ABSTRACT FROM AUTHOR]