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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 Patients with AIG initially respond to corticosteroids but have a great potential to relapse after treatment is withdrawn.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., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Thymic stromal lymphopoietin (TSLP), mainly produced by epithelial cells, activates a variety of cell types, including dendritic cells, mast cells, T cells, and B cells. It is involved in the pathogenesis of allergic inflammation in the lung, skin, and gastrointestinal tract. In addition, TSLP promotes Th2-type intestinal immunity against helminth infection and regulates Th1-type inflammation in a mouse model of colitis, suggesting that it plays crucial roles in intestinal immune homeostasis. Although autoimmune gastritis (AIG), mediated by inflammatory Th1 responses, develops in the gastric mucosa, it is not clear whether TSLP is involved in regulating these responses in AIG. The aim of this study was to examine the roles of TSLP in the development of AIG. Because BALB/c mice thymectomized 3 d after birth (NTx mice) develop AIG, we used this model to test the role of TSLP in the development of AIG. We found that in AIG-bearing mice, TSLP was expressed in the inflamed stomach and that the serum anti-parietal cell Ab levels in neonatal thymectomized TSLPR-deficient mice (NTx-TSLPR(-/-) mice) were significantly elevated over those in NTx-TSLPR(+/+) mice. In addition, NTx-TSLPR(-/-) mice exhibited an earlier onset of AIG than that observed in NTx-TSLPR(+/+) mice. The rapid development of AIG in NTx-TSLPR(-/-) mice resulted in more aggressive CD4(+) T cell infiltration and more severe loss of parietal and chief cells in the progression phase of AIG, accompanied by enhanced production of IL-12/23p40 and IFN-γ. Taken together, these data suggested that TSLP negatively regulates the development of AIG.

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]