Molecular mimicry between Helicobacter pylori antigens and H+, K+ --adenosine triphosphatase in human gastric autoimmunity

Abstract

Autoimmune gastritis and Helicobacter pylori-associated gastric atrophy develop through similar mechanisms involving the proton pump H+,K+-adenosine triphosphatase as autoantigen. Here, we report that H. pylori-infected patients with gastric autoimmunity harbor in vivo-activated gastric CD4+ T cells that recognize both H+, K+-adenosine triphosphatase and H. pylori antigens. We characterized the submolecular specificity of such gastric T cells and identified cross-reactive epitopes from nine H. pylori proteins. Cross-reactive H. pylori peptides induced T cell proliferation and expression of T helper type 1 functions. We suggest that in genetically susceptible individuals, H. pylori infection can activate cross-reactive gastric T cells leading to gastric autoimmunity via molecular mimicry.

Figure 1.

Proliferation to H⁺,K⁺-ATPase and H. pylori of gastric T cell clones. T cell blasts from 13 CD4⁺ clones derived from the gastric mucosa of H. pylori–infected patients with chronic autoimmune gastritis (four from patient 1, two from patient 2, one from patient 3, and six from patient 4) were cocultured with autologous irradiated APCs in the presence of optimal concentrations of H⁺,K⁺-ATPase, H. pylori lysate, or porcine albumin as control antigen. Results represent mean values (±SD) of MIs measured in five consecutive experiments.

Figure 2.

TCR Vβ chain repertoire of cross-reactive gastric T cell clones. The clonality of T cell clones reactive to both H⁺,K⁺-ATPase and H. pylori lysate was analyzed by a panel of 22 monoclonal antibodies specific for human TCR Vβ chain families, as detailed in Materials and Methods. T cell blasts from each clone were divided in aliquots and stained with each of the monoclonal antibody and the appropriate isotype controls.

Figure 3.

Dose–response effect of graded concentrations of the self (closed symbols) and the corresponding bacterial peptides (open symbols) on the proliferative response of gastric T cell clones reactive to both H⁺,K⁺-ATPase and H. pylori lysate. Results represent mean values ± SD of 6 representative out of 10 T cell clones tested.

Figure 4.

IFN-γ production by cross-reactive gastric T cell clones. Cytokine production was assessed in response to H. pylori lysate, H⁺,K⁺-ATPase, the H⁺,K⁺-ATPase epitope and the cross-reactive H. pylori epitope that induced T cell clone proliferation. For each clone, controls included medium alone, a couple of H⁺,K⁺-ATPase peptides flanking the stimulatory epitope and the series of candidate H. pylori epitopes that failed to induce T cell clone proliferation. Numbers in parentheses indicate the location of cross-reactive epitopes within the indicated H. pylori proteins. Results represent mean values ± SD of 4 representative out of 10 T cell clones tested.