Prevention of gastric autoimmunity by transgenic expression of a proton pump subunit in the thymus

Abstract

Autoimmune gastritis is an excellent example of the organ-specific autoimmune diseases. The gastric lesion, characterized by loss of parietal and chief cells from the mucosa and submucosal lymphocytic infiltration, is the underlying basis for pernicious anaemia, the most common cause of vitamin B12 deficiency in whites of northern European origin (Gleeson and Toh, 1991; Toh et al, 1992). The gastric parietal cell appears to be the principal cell targeted since autoantibodies to parietal cells and to intrinsic factor (a parietal cell secretory product) are found in most patients with pernicious anaemia and parietal cell autoantibody titres correlate with severity of gastritis. These parietal cell autoantibodies are directed against the catalytic α and the glycoprotein β-subunit of the gastric H⁺/K⁺-ATPase (proton pump), the enzyme responsible for gastric acid secretion (Karlsson et al, 1988; Goldkorn et al, 1989; Toh et al, 1990). To investigate the immunopathogeriesis of autoimmune gastritis, we have adopted an experimental model of autoimmune gastritis induced by neonatal thymectomy carried out 2–4 days after birth in BALB/c mice. The murine disease is an ideal model since it displays the major features of the human disease with loss of parietal and chief cells accompanied by submucosal immunocytic infiltration and circulating parietal cell autoantibodies (Fukuma et al, 1989). These parietal cell autoantibodies also target the α and β-subunits of the proton pump (Jones et al, 1991). The murine disease appears to be cell-mediated, since the disease can be transferred by CD4⁺ T cells but not by autoantibodies (Sakaguchi et al, 1985).