Molecular Specificity and Functional Properties of Autoreactive T-Cell Response in Human Gastric Autoimmunity

Abstract

Human autoimmune gastritis (AIG) is a chronic inflammatory disorder of the gastric corpus. We have defined the antigen repertoire and the functional properties of in vivo activated CD4⁺ T cells derived from the gastric mucosa of patients with AIG. A remarkable proportion of the CD4⁺ T cell clones proliferated in response to H⁺,K⁺-ATPase. Six epitopes identified in the α chain, and 5 in the β chain, of gastric K⁺,K⁺-ATPase were recognized by autoreactive gastric T cell clones. The majority of the autoreactive T cell clones secreted IFN-γ and showed a T helper 1 (Th1) profile. All clones produced TNF-α,provided help for B cell immunoglobulin production, expressed perforin-mediated cytotoxicity, and most induced Fas-Fas ligand-mediated apoptosis. Data suggest that activation of gastric H⁺,K⁺-ATPase-specific Th1 T cells is crucial in the pathogenesis of human gastric autoimmunity and atrophy.

Key Words:

• autoimmunity
• mucosal immunity
• proton pump
• T cell epitopes
• Th1 cells
• interferon-γ
• cytokines
• apoptosis
• Helicobacter pylori

Notes

This work was supported in part by MIUR and by the Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.). M. P. Bergman was partially supported by grants of the Federation of European Microbiological Societies (FEMS) and the Netherlands Organisation for Scientific Research (NWO).