{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T22:19:13Z","timestamp":1784067553992,"version":"3.55.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":427,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"name":"Grants-in-aid for Scientific Research from Japan Society for the Promotion of Science (JSPS)","award":["23590973"],"award-info":[{"award-number":["23590973"]}]},{"name":"Grants-in-aid for Scientific Research from Japan Society for the Promotion of Science (JSPS)","award":["21229009"],"award-info":[{"award-number":["21229009"]}]}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,7]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Clinical manifestations of autoimmune hepatitis (AIH) range from mild chronic to acute, sometimes fulminant hepatitis. However, it is unknown how the progression to fatal hepatitis occurs. We developed a mouse model of fatal AIH by inducing a concurrent loss of forkhead box P3+ regulatory T cells and programmed cell death-1 (PD-1)-mediated signaling. In this model, dysregulated follicular helper T cells in the spleen are responsible for the induction, and the C-C chemokine receptor 6\/C-C chemokine ligand 20 axis is crucial for the migration of these T cells into the liver. Using this fatal AIH model, we aimed to clarify key molecules triggering fatal AIH progression. During progression, T-bet together with interferon (IFN)-\u03b3 and C-X-C chemokine receptor (CXCR)3 were highly expressed in the inflamed liver, suggesting helper T (Th)1-type inflammation. T cells that dominantly expanded in the spleen and the inflamed liver were CXCR3-expressing CD8+ T cells; depletion of these CD8+ T cells suppressed AIH progression. Expression of one CXCR3 ligand, chemokine (C-X-C motif) ligand (CXCL)9, was elevated in the liver. CXCL9-expressing macrophages\/Kupffer cells were colocalized with infiltrating T cells, and<\/jats:bold>\n                                 <jats:bold>\n                                    in vivo\n                                 <\/jats:bold>\n                                 <jats:bold>administration of anti-CXCL9 suppressed AIH progression. In addition, serum levels of interleukin (IL)-18, but not IL-1\u03b2, were elevated during progression, and dendritic cells in the spleen and liver highly produced IL-18.<\/jats:bold>\n                                 <jats:bold>\n                                    In vivo\n                                 <\/jats:bold>\n                                 <jats:bold>administration of anti-IL-18R suppressed the increase of splenic CXCR3+ T cells and the progression to fatal AIH. Moreover, tumor necrosis factor alpha, but not IFN-\u03b3, was involved in up-regulating CXCL9 in the liver and for increased serum levels of IL-18.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion :<\/jats:title>\n            <jats:p>\n                                 <jats:bold>These data suggest that, in our mouse model, fatal progression of AIH is mediated by IL-18-dependent differentiation of T cells into Th1 cells and effector T cells, respectively, and that CXCR3-CXCL9 axis-dependent migration of those T cells is crucial for fatal progression. (Hepatology 2014;60:224\u2013236)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.27087","type":"journal-article","created":{"date-parts":[[2014,2,24]],"date-time":"2014-02-24T17:58:06Z","timestamp":1393264686000},"page":"224-236","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":68,"title":["Progression of Autoimmune Hepatitis is Mediated by IL-18-Producing Dendritic Cells and Hepatic CXCL9 Expression in 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