Gastroenterology

Gastroenterology

Volume 120, Issue 2, February 2001, Pages 377-386
Gastroenterology

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

https://doi.org/10.1053/gast.2001.21187Get rights and content

Abstract

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 α 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.

GASTROENTEROLOGY 2001;120:377-386

Section snippets

Patients

Five women (mean age, 48; range, 33–56 years) from Tuscany with type A chronic AIG and 5 women (mean age, 51; range, 40–59 years) with Helicobacter pylori–induced uncomplicated type B chronic gastritis without atrophy (Hp-CG) provided their informed consent for this study, which was performed after the approval by the local Ethical Committee. All AIG patients had serum gastric PCA, as assessed by indirect immunofluorescence. These autoantibodies proved to be specific for gastric H+,K+-ATPase,

Reactivity to H+,K+-ATPase and cytokine profile of gastric T-cell clones

In vivo–activated T cells present in the lymphocytic infiltrates of the gastric antrum and corpus of 5 PCA-positive patients with chronic AIG without evidence of previous or actual infection with H. pylori were isolated and cloned. Likewise, control T-cell clones were generated from in vivo–activated T cells isolated from the gastric antrum and corpus of 5 PCA-negative, age- and sex-matched patients with uncomplicated Hp-CG. A total number of 175 CD4+ and 55 CD8+ clones were obtained from the

Discussion

We have investigated the pathogenic mechanisms of human AIG in this study. Data showed for the first time that T cells specific for H+,K+-ATPase of parietal cells are present in the gastric mucosa of patients with AIG. These autoreactive T cells were found to be Th1 effector cells with cytolytic potential through both perforins and Fas–Fas ligand interaction, and we propose that parietal cell loss in AIG proceeds through an autoimmune T-cell attack. In vivo–activated T cells present in the

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    ☆☆

    Supported in part by grants from the University of Florence, the Italian Ministry of University and Scientific Research (MURST), and the Associazione Italiana per la Ricerca sul Cancro; and by grants of the Federation of European Microbiological Societies (FEMS) and The Netherlands Organisation for Scientific Research (NWO) (to M.P.B.).

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