H+,K+-ATPase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis

Background & Aims: The proton pump H+,K+-adenosine triphosphatase (H+,K+-ATPase) of parietal cells is the major humoral autoantigen in both human and experimental autoimmune gastritis (AIG) characterized by an inflammatory infiltrate in the gastric mucosa and loss of parietal cells. The aim of this study was to detect H+,K+-ATPase-specific T cells in the gastric mucosa of patients with AIG and to define their functional properties. Methods: In vivo-activated T cells from the infiltrates of the gastric mucosa of 5 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 expression of B-cell help, perforin-mediated cytotoxicity, and Fas-Fas ligand-mediated apoptosis in target cells, were assessed. Results: A proportion (25%) of the CD4(+) clones from the gastric corpus of AIG patients proliferated in response to porcine H+,K+-ATPase. Most of these clones (88%) showed a Th1 profile, whereas a few secreted both Th1 and Th2 cytokines. Virtually all of the H+,K+-ATPase-specific clones produced tumor necrosis factor alpha and provided substantial help for B-cell immunoglobulin production, and most of them expressed perforin-mediated cytotoxicity against antigen-presenting cells and induced Fas-Fas ligand-mediated apoptosis in target cells. Conclusions: Activation of proton pump-specific Th1 cytotoxic/proapoptotic T cells in the gastric mucosa can represent an effector mechanism for the target cell destruction in AIG.