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Background and Aim Autoimmune gastritis ( AIG), an organ-specific autoimmune disease, is accompanied by achlorhydria, pernicious anemia, gastric carcinoid tumors, and gastric cancer. Patients with AIG initially respond to corticosteroids but have a great potential to relapse after treatment is withdrawn. This study examines the roles of cytokines in order to identify potential therapeutic options for AIG patients. Methods Using a mouse model of AIG, we monitored disease progression and administered antibodies in vivo to block cytokines. Results We developed a mouse model of AIG with early onset and rapid progression in which neonatal thymectomy ( NTx) was performed on programmed cell death 1-deficient ( PD-1−/−) mice on the BALB/c background. Using NTx- PD-1−/− mice, we found that in AIG lesions, interferon-γ, and tumor necrosis factor ( TNF)-α together with interleukin-21 ( IL-21) were highly expressed in the inflamed gastric mucosa. In addition, as with the injection of dexamethasone, in vivo administration of either anti- TNF-α or anti- IL-21 suppressed the development of AIG in NTx- PD-1−/− mice. Conclusions These data reveal the essential role of IL-21 in the development of AIG and suggest that in addition to corticosteroids, anti- TNF-α as well as anti- IL-21 have the potential to induce the remission of AIG, offering additional therapeutic options for AIG patients. [ABSTRACT FROM AUTHOR]

Interferon (IFN)-γ acts as a critical proinflammatory mediator in autoimmune processes, whereas it exerts regulatory functions to limit tissue damage associated with inflammation. However, a detailed understanding of the complex roles of IFN-γ in the development of organ-specific autoimmunity is still lacking. Recently, we found that programmed cell death 1-deficient mice thymectomized 3 days after birth (NTx-PD-1− / −  mice) concurrently developed autoimmune hepatitis (AIH) and autoimmune gastritis (AIG). In this study, we investigated the roles of IFN-γ in the development of AIH and AIG in this mouse model. In NTx-PD-1− / −  mice, serum levels of IFN-γ were markedly elevated. Neutralization of IFN-γ prevented the development of AIG. However, the same treatment exacerbated hepatic T-cell infiltration in AIH. Because of the loss of anti-proliferative effects by IFN-γ, neutralization of IFN-γ increased T-cell proliferation in the spleen and liver, resulting in exacerbated T-cell infiltration in the liver. On the other hand, in the development of AIG, CD4++ T-cell migration into the gastric mucosa is essential for induction. CCL20 expression was up-regulated in the gastric mucosa, and anti-CCL20 suppressed CD4++ T-cell infiltration into the gastric mucosa. Importantly, anti-IFN-γ suppressed CCL20 expression and infiltration of CD4++ T cells in the gastric mucosa, whereas in vivo injection of recombinant IFN-γ up-regulated CCL20 expression in the stomach, suggesting that IFN-γ is critically involved in CD4++ T-cell accumulation in AIG by up-regulating local CCL20 expression. In conclusion, IFN-γ is involved differently in the development of AIH and of AIG. IFN-γ negatively regulates T-cell proliferation in fatal AIH, whereas it initiates development of AIG. These findings imply that increased production of IFN-γ induced by an organ-specific autoimmunity may trigger the concurrent development of another organ-specific autoimmune disease. [ABSTRACT FROM AUTHOR]

Background & Aims: To clarify mechanisms involved in the development of autoimmune hepatitis (AIH), we recently developed a mouse model of spontaneous AIH by inducing a concurrent loss of Foxp3+ regulatory T cells and programmed cell death 1 (PD-1)–mediated signaling. Fatal AIH in these mice was characterized by severe T-cell infiltration and huge production of antinuclear antibodies (Abs). This study aims to identify induction sites, responsible T-cell subsets, and key molecules for induction of AIH. Methods: To develop the mouse model of AIH, neonatal thymectomy (NTx) was performed on PD-1–deficient (PD-1−/−) mice. We then conducted neonatal splenectomy or in vivo administration of Abs to cytokines, chemokines, or cell-surface molecules. Results: In NTx-PD-1−/− mice, either neonatal splenectomy or in vivo CD4+ T-cell depletion suppressed CD4+ and CD8+ T-cell infiltration in the liver. In the induction phase of AIH, splenic CD4+ T cells were localized in B-cell follicles with huge germinal centers and showed the Bcl6+ inducible costimulator (ICOS)+ interleukin (IL)-21+ IL-21 receptor (IL-21R)+ follicular helper T (TFH) cell phenotype. Blocking Abs to ICOS or IL-21 suppressed TFH-cell generation and induction of AIH. In addition, IL-21 produced by TFH cells drove CD8+ T-cell activation. Splenic TFH cells and CD8+ T cells expressed CCR6, and CCL20 expression was elevated in the liver. Administration of anti-CCL20 suppressed migration of these T cells to the liver and induction of AIH. Conclusions: Dysregulated TFH cells in the spleen are responsible for the induction of fatal AIH, and CCR6-CCL20 axis-dependent migration of splenic T cells is crucial to induce AIH in NTx-PD-1 −/− mice. [ABSTRACT FROM AUTHOR]

Abstract: It is unclear what roles TNF-α has in the development of autoimmune hepatitis (AIH) and whether AIH is responsive to anti-TNF-α. We recently developed a mouse model of fatal AIH that develops in PD-1-deficient mice thymectomized three days after birth, finding that CCR6-CCL20 axis-dependent migration of dysregulated splenic T cells is crucial to induce AIH. In this study, we show the indispensable role of TNF-α in the development of AIH. Administering anti-TNF-α prevented the induction, but treatment by anti-TNF-α after the induction did not suppress progression. Administering anti-TNF-α did not prevent splenic T-cell activation, but did suppress hepatic CCL20 expression. In contrast, administering anti-CCL20 suppressed AIH but not elevated serum TNF-α levels. TNF-α stimulation enhanced CCL20 expression in hepatocytes. These findings suggest that TNF-α is essential in the induction of AIH through upregulation of hepatic CCL20 expression, which allows migration of dysregulated splenic T cells. [Copyright &y& Elsevier]

Abstract: Cytotoxin-associated gene A (CagA) acts directly on gastric epithelial cells. However, the roles of CagA in host adaptive immunity against Helicobacter pylori (H. pylori) infection are not fully understood. In this study, to investigate the roles of CagA in the development of H. pylori-induced chronic gastritis, we used an adoptive-transfer model in which spleen cells from C57BL/6 mice with or without H. pylori infection were transferred into RAG2−/− mice, with gastric colonization of either CagA+ H. pylori or CagA− H. pylori. Colonization of CagA+ H. pylori but not CagA− H. pylori in the host gastric mucosa induced severe chronic gastritis in RAG2−/− mice transferred with spleen cells from H. pylori-uninfected mice. In addition, when CagA+ H. pylori-primed spleen cells were transferred into RAG2−/− mice, CD4+ T cell infiltration in the host gastric mucosa were observed only in RAG2−/− mice infected with CagA+ H. pylori but not CagA− H. pylori, suggesting that colonization of CagA+ H. pylori in the host gastric mucosa is essential for the migration of H. pylori-primed CD4+ T cells. On the other hand, transfer of CagA− H. pylori-primed spleen cells into CagA+ H. pylori-infected RAG2−/− mice induced more severe chronic gastritis with less Foxp3+ regulatory T-cell infiltration as compared to transfer of CagA+ H. pylori-primed spleen cells. In conclusion, CagA in the stomach plays an important role in the migration of H. pylori-primed CD4+ T cells in the gastric mucosa, whereas CagA-dependent T-cell priming induces regulatory T-cell differentiation, suggesting dual roles for CagA in the pathophysiology of H. pylori-induced chronic gastritis. [Copyright &y& Elsevier]