Role of Peyer's patches in the induction of Helicobacter pylori-induced gastritis

Abstract

Helicobacter pylori is a Gram-negative spiral bacterium that causes gastritis and peptic ulcer and has been implicated in the pathogenesis of gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. Although Th1 immunity is involved in gastritis and the accumulation of H. pylori-specific CD4(+) T cells in the H. pylori-infected gastric mucosa in human patients, how T cells are primed with H. pylori antigens is unknown because no apparent lymphoid tissues are present in the stomach. We demonstrate here that Peyer's patches (PPs) in the small intestine play critical roles in H. pylori-induced gastritis; no gastritis is induced in H. pylori-infected mice lacking PPs. We also observed that the coccoid form of H. pylori is phagocytosed by dendritic cells in PPs. We propose that H. pylori converts to the coccoid form in the anaerobic small intestine and stimulates the host immune system through PPs.

Fig. 1.

Naive CD4⁺ T cells did not induce gastritis in H. pylori-infected γ_c-Rag double knockout (DKO) mice. (a–c) Wild-type (a) or Rag2^−/− (b and c) mice were infected with H. pylori. Two months after the infection, gastric specimens were prepared. (d–h) Rag2^−/− (d), β-Rag DKO (e and f), and γ_c-Rag DKO (g and h) mice were infected with H. pylori. Two months after the infection, naive (d–g) or primed (h) splenic CD4⁺ T cells were transferred. Two months after the cell transfer, gastric specimens were prepared. Specimens were stained with H&E (a, b, d, e, g, and h), anti-H. pylori antisera (brown) (c), or chloroacetate esterase (red) for infiltrated neutrophils and mast cells (f). (Scale bars: 200 μm.)

Fig. 2.

PPs are critical for the priming of CD4⁺ T cells in H. pylori infection. (a–e) Small intestines from wild-type (WT) (a) and PP-null (e) mice were stained with anti-B220 mAb, and small intestines from Rag2^−/− (b), β-Rag DKO (c), and γ_c-Rag DKO (d) mice were stained with anti-CD45 mAb. (f and g) Schemes of the generation of PP-null WT (f) or PP-null-Rag2^−/− (g) mice. (h and i) PP-null WT mice were infected with H. pylori. Two months after the infection, gastric specimens were prepared. (j and k) PP-null-Rag2^−/− mice were infected with H. pylori. Two months after the infection, naive (j) or primed (k) splenic CD4⁺ T cells were transferred. Two months after the cell transfer, gastric specimens were prepared. Specimens were stained with H&E (h, j, and k) or anti-H. pylori antisera (brown) (i). (Scale bars: 200 μm.)

Fig. 3.

The coccoid form of H. pylori is captured by DCs in PPs. The coccoid or helical form of H. pylori was inoculated into the ligated small intestines of wild-type mice. (a) After the indicated incubation times, PPs were stained with anti-H. pylori antibody. (b) Twenty hours after inoculation of the coccoid form, PPs were stained with anti-CD11c mAb (green) and anti-H. pylori antibody (red). (Scale bars: 0 h,100 μm; 20 h, 20 μm.)

Fig. 4.

Gastritis is induced by CD4⁺ T cells primed by the coccoid form of H. pylori. Two months after infection of γ_c-Rag DKO mice with the helical form of H. pylori, splenic CD4⁺ T cells from wild-type (WT) mice orally infected by the coccoid form of H. pylori were transferred to the infected γ_c-Rag DKO mice (a). Two months after the cell transfer, gastric specimens were prepared. Specimens were stained with H&E (b) or chloroacetate esterase (red) for infiltrated neutrophils and mast cells (c). (Scale bars: 200 μm.)