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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]

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]