I. R. Van Driel

Immunization with gastric H+/K+‐ATPase induces a reversible autoimmune gastritis

The gastric H+/K+‐ATPase has been implicated as a major autoantigen in pernicious anaemia in humans and in thymectomy‐induced autoimmune gastritis in mice. Here we have shown that autoimmune gastritis can be generated by direct immunization of non‐thymectomized BALB/c mice with mouse gastric H+/K+‐ATPase in complete Freund’s adjuvant. The gastritis was characterized by infiltration of the gastric submucosa and mucosa with macrophages, CD4+ and CD8+ T cells, and B cells and by circulating autoantibodies to the H+/K+‐ATPase. The mononuclear infiltrate within the gastric mucosa was accompanied by loss of parietal and zymogenic cells and accumulation of small immature epithelial cells. Splenocytes from gastritic mice adoptively transferred gastritis to naive recipients. Cessation of immunization resulted in decrease in autoantibody titre and regeneration of parietal and zymogenic cells. The results directly confirm that the gastric H+/K+‐ATPase is the causative autoantigen in the genesis of autoimmune gastritis. Recovery of the lesion following cessation of immunization suggests that homeostatic mechanisms can reverse a destructive autoimmune process.

Identification of a gastritogenic epitope of the H/K ATPase beta-subunit.

We have previously shown that autoimmune gastritis can be elicited in mice by immunization with the gastric parietal cell H/K ATPase αβ heterodimer and that tolerance specifically induced to the H/K ATPase β‐subunit protects mice from the development of gastritis. Here we have identified the immunodominant gastritogenic epitope of the H/K ATPase β‐subunit (H/Kβ). Epitope mapping was carried out with a panel of 21 overlapping peptides that spanned the entire sequence of the gastric H/K ATPase β‐subunit. T cells from gastric H/K ATPase‐immunized mice responded to only one of the overlapping peptides, namely H/Kβ253–277. Furthermore, a single subcutaneous immunization of 6‐week‐old BALB/c mice with the ATPase β‐subunit peptides resulted in a T‐cell response to only H/Kβ253–277. Multiple immunization with the overlapping H/K ATPase peptides demonstrated that H/Kβ253–277 was capable of inducing a mononuclear infiltrate specifically within the gastric mucosa. We conclude that H/Kβ253–277 is the dominant gastritogenic epitope of the gastric H/K ATPase.