A High-Incidence Model for Autoimmune Gastritis Figure 7. Autoimmune gastritis does not develop in the absence of gastric H/Ka or H/Kb. Gastric pathology in (A) H/Ka2/2 mice received either H/Ka2/2 CD4+ T cells or no inoculum (2) (B) H/ Kb2/2 mice received either H/Ka2/2 CD4+ T cells or no inoculum (2) (C) WT mice received H/Ka2/2 CD4+ T cells. Images representative of results of at least 9 mice in each group are shown. (D) Serum samples were collected from H/Ka2/2, H/Kb2/2 or WT mice that received CD4+ T cells from H/Ka2/2 mice. H+/K+ ATPase-specific autoantibodies in serum were detected by ELISA using serial 2-fold dilutions of mouse sera, with a starting dilution factor of 50. Data pooled from four independent experiments. Error bars, standard error. doi:10.1371/journal.pone.0027153.g007 autoimmune gastritis since it has been firmly established by many studies that CD4+ T cells and not other cell types are able to initiate autoimmune gastritis [7–17]. It is clear that T and B cell populations reactive to the H+/K+ ATPase are present in the repertoire of normal mice [5,14–16,21,24,28–33]. Therefore, we suggest that the H+/K+ ATPase-specific T and B cells from the recipient are then recruited to the lesion and the recipient-derived B cells are responsible for the production of autoantibodies. It has been previously documented that CD4+ T cells from H/ Kb2/2 mice induce autoimmune gastritis in athymic BALB/c mice but not in irradiated wildtype mice [24]. CD4+ T cells from H/Ka2/2 mice caused gastritis in irradiated wildtype mice suggesting that this population is more pathogenic than CD4+ T cells from H/Kb2/2 mice. These data support a more dominant role for immune response against H/Ka in the pathogenesis of autoimmune gastritis, consistent with findings in TCR transgenic mice [7,8]. Unlike other disease models that utilised Treg cell-depleted polyclonal T cells from wildtype mice to induce autoimmunity [15], it was not necessary to remove Treg cells from H/Ka2/2 CD4+ T cell population for the induction of severe autoimmune gastritis. Furthermore, the development of autoimmune gastritis in the recipient mice was not caused by a reduced level of Treg cells from the donor population since gastritic mice contained similar proportion of Treg cells in the paragastric lymph node compared to non-gastritic controls. We have previously demonstrated that Treg cells from H/Ka2/2 mice were as effective as Tregs cells from wildtype mice in suppressing H/Ka-specific autoreactive T cells [34]. Therefore, our findings here support previous work indicating that T cell repertoires that had not undergone peripheral T cell deletion are unable to be suppressed by the normal Treg cell population [24,35]. Although a normal level of Treg cells was detected in the paragastric lymph node of gastritic mice, and a significantly higher percentage of Treg cells was found in the stomach of gastritic mice compared to normal mice, Treg cells were not able to prevent or suppress disease. This is consistent with the finding that although Treg cells accumulated in the CNS when experimental allergic encephalomyelitis was triggered [36], they were not able to prevent the expansion and function of myelin oligodendrocyte glycoprotein-specific T cells, since the local inflammatory cytokine milieu rendered pathogenic T cells resistant to Treg suppression. Depletion of parietal cells is a hallmark of autoimmune gastritis and the main reason that pernicious anemia is a life-threatening disease because parietal cells produce intrinsic factor, the lack of which is fatal. We found that depletion of parietal cells in this disease model was dependent upon the presence of both H+/K+ ATPase subunits as CD4+ T cells from H/Ka2/2 mice only induced parietal cell depletion in wildtype mice but not in H/ Ka2/2 and H/Kb2/2 mice. Parietal cell depletion was not caused by T cell response towards H/Kb since H/Ka2/2 CD4+ T cells did not induce parietal cell depletion in H/Ka2/2 PLoS ONE | www.plosone.org 6 November 2011 | Volume 6 | Issue 11 | e27153