Spontaneous autoimmune gastritis in C3H/He mice: a new mouse model for gastric autoimmunity

Abstract

Autoimmune gastritis is the underlying pathological lesion of pernicious anemia in humans. The lesion is characterized by a chronic inflammatory infiltrate in the gastric mucosa with loss of parietal and zymogenic cells. It is associated with circulating autoantibodies to the gastric H/K-ATPase, the enzyme responsible for acidification of gastric juice. Experimental models of autoimmune gastritis have previously been produced in mice after a variety of manipulations, including thymectomy. Here we report for the first time a spontaneous mouse model of autoimmune gastritis in C3H/He mice. The spontaneous gastritis is also accompanied by circulating autoantibodies to the gastric H/K-ATPase. The spontaneous mouse model should be useful for studies directed toward the immunopathogenesis and treatment of autoimmune gastritis.

Figure 1.

Indirect immunofluorescence staining on paraffin embedded-normal mouse stomach sections. Parietal cell reactivity in sera from a C3H/He mouse (A), a neonatally thymectomized BALB/cCrSlc mouse (B), a patient with pernicious anemia (C), and a C3H/He mouse without parietal cell reactivity (D). Magnification, objective ×20.

Figure 2.

H&E-stained sections of paraffin-embedded mouse stomachs showing gastritis in C3H/He (A) and neonatally thymectomized BALB/c mice (B). Areas of mononuclear cell infiltration are indicated by arrows. (C) Stained section of a nongastritic C3H/He mouse stomach. Magnification, objective ×25.

Figure 3.

Modified Maxwell’s staining of paraffin-embedded mouse stomachs from nongastritic (A) and gastritic (B) C3H/He mice. Parietal cells stain blue-green, zymogenic (chief) cells stain red-purple, and mucus-secreting cells stain yellow. Note the change in cellular composition in C3H/He mice with gastritis. Magnification, objective ×25.

Figure 4.

Breeding program used to generate C3H/He mouse line with higher incidence of autoimmune gastritis. Mice with parietal cell autoantibodies from each generation were selected for breeding. Sequential generations of mice are labeled A through E. ○, females without parietal cell reactivity; •, females with parietal cell reactivity; □, males without parietal cell reactivity; ▪, males with parietal cell reactivity.

Figure 5.

Incidence of gastritis in C3H/He mice with parietal cell- and H/K-ATPase-reactive autoantibodies. Anti-H/K-ATPase reactivity was detected by ELISA (filled bars). Parietal cell autoantibodies were detected by indirect immunofluorescence (IIF) on paraffin-embedded stomach sections. Anti-parietal cell reactivity was scored as follows: −, negative; +, weakly positive; ++, positive; and +++, strongly positive. Gastritis was assessed by histology and indicated by a filled square. Mice without gastritis are indicated by an open square.

Figure 6.

A: Development of anti-H/K-ATPase antibodies in C3H/He mice. Sera were collected from four C3H/He mice at 4, 6, 8, and 10 weeks of age and assayed for gastric H/K ATPase reactivity by ELISA. Each symbol represents the antibody reactivity with gastric H/K ATPase for an individual mouse over the course of the study. B: Serum titer of antibodies to the gastric H/K-ATPase in C3H/He mice and neonatally thymectomized (NTx) BALB/cCrSlc mice. Serum antibody titers were determined by ELISA on gastric H/K-ATPase-coated plates and taken as the highest dilution that produced an optical density reading above baseline.