H+K+-ATPase-specific Th1-type immune response in gastric mucosa of patients with autoimmune gastritis

MM D'Elios, MD ^a, A Amedei, MSc ^a, MP Bergman, MSc ^b, A Azzurri, MD ^a, M Benagiano, MSc ^a, BJ Appelmelk, PhD ^b, G Del Prete, MD ^a

H. pylori infects half of the world's population and has been implicated in the pathogenesis of gastric cancer, especially in those patients with extensive corpus gastritis, hypochlorydria and gastric atrophy frequently associated with anti-canalicular autoantibodies. The pathophysiological features of these patients are similar to those suffering of autoimmune gastritis (AIG). The proton pump H+K+-ATPase of parietal cells is the major autoantigen recognized by autoantibodies. AIM To define the antigen repertoire and the functional properties of gastric T cells derived from autoimmune gastritis patients. METHODS In vivo activated T cells from the infiltrates of the gastric mucosa of patients with AIG were isolated and cloned. The ability of gastric T cell clones to proliferate and to produce cytokines in response to H+K+-ATPase, as well as their Fas-Fas ligand mediated apoptosis in target cells and perforin-mediated cytotoxicity were assessed. RESULTS A proportion (about 25%) of CD4+ clones from the gastric corpus of AIG patients proliferated in response to H+K+-ATPase. The epitope analysis of the T cells is currently under investigation. Most of these clones (88%) showed a T helper type-1 profile, whereas a few secreted both Th1 and Th2 cytokines. Virtually all the H+K+-ATPase-specific clones induced Fas-Fas ligand-mediated apoptosis in target cells and expressed perforin-mediated cytotoxicity. CONCLUSIONS Activation of Th1 proapoptotic/cytotoxic T cells in the gastric mucosa can represent an effector mechanism for the target cell destruction. Severe corpus inflammation driven by proton-pump autoantigen may represent one important host factor involved in the destruction of gastric glands and consequent gastric atrophy.

KEY WORDS: gastric cancer, cytokines, host response, gastric preneoplastic lesions, T cell, gastric inflammation.

For more information, contact delios@cesit1.unifi.it

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Autoimmunity.

http://www.cancerprev.org/Journal/Issues/26/101/1292/4263