{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T22:24:11Z","timestamp":1761863051350,"version":"3.40.3"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2012,1,1]],"date-time":"2012-01-01T00:00:00Z","timestamp":1325376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The proapoptotic Bcl-2 homolog Bim was shown to control the apoptosis of both T cells and hepatocytes. This dual role of Bim might be particularly relevant for the development of viral hepatitis, in which both the sensitivity of hepatocytes to apoptosis stimuli and the persistence of cytotoxic T cells are essential factors for the outcome of the disease. The relevance of Bim in regulating survival of cytotoxic T cells or induction of hepatocyte death has only been investigated in separate systems, and their relative contributions to the pathogenesis of T cell-mediated hepatitis remain unclear. Using the highly dynamic model system of lymphocytic choriomeningitis virus-mediated hepatitis and bone marrow chimeras, we found that Bim has a dual role in the development of lymphocytic choriomeningitis virus-induced, T cell-mediated hepatitis. Although the absence of Bim in parenchymal cells led to markedly attenuated liver damage, loss of Bim in the lymphoid compartment moderately enhanced hepatitis. However, when both effects were combined in Bim\u2212\/\u2212 mice, the effect of Bim deficiency in the lymphoid compartment was overcompensated for by the reduced sensitivity of Bim\u2212\/\u2212 hepatocytes to T cell-induced apoptosis, resulting in the protection of Bim\u2212\/\u2212 mice from hepatitis.<\/jats:p>","DOI":"10.4049\/jimmunol.1101864","type":"journal-article","created":{"date-parts":[[2011,12,8]],"date-time":"2011-12-08T03:03:05Z","timestamp":1323313385000},"page":"916-922","source":"Crossref","is-referenced-by-count":10,"title":["The Proapoptotic Bcl-2 Family Member Bim Plays a Central Role during the Development of Virus-Induced Hepatitis"],"prefix":"10.1093","volume":"188","author":[{"given":"Christoph","family":"Lauer","sequence":"first","affiliation":[{"name":"Division of Experimental Pathology, Institute of Pathology, University of Bern , CH-3010 Bern ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Brunner","sequence":"additional","affiliation":[{"name":"Division of Biochemical Pharmacology, Department of Biology, University of Konstanz , 78457 Konstanz ,","place":["Germany"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia","family":"Corazza","sequence":"additional","affiliation":[{"name":"Division of Experimental Pathology, Institute of Pathology, University of Bern , CH-3010 Bern ,","place":["Switzerland"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2012,1,15]]},"reference":[{"key":"2025032409463102800_r1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1146\/annurev.pathol.1.110304.100230","article-title":"Immunobiology and pathogenesis of viral hepatitis","volume":"1","author":"Guidotti","year":"2006","journal-title":"Annu. 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Med."},{"key":"2025032409463102800_r7","doi-asserted-by":"crossref","first-page":"8781","DOI":"10.1128\/JVI.75.18.8781-8791.2001","article-title":"Concerted action of the FasL\/Fas and perforin\/granzyme A and B pathways is mandatory for the development of early viral hepatitis but not for recovery from viral infection","volume":"75","author":"Balkow","year":"2001","journal-title":"J. Virol."},{"key":"2025032409463102800_r8","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1099\/vir.0.82428-0","article-title":"Contributions of the lymphocytic choriomeningitis virus glycoprotein and polymerase to strain-specific differences in murine liver pathogenicity","volume":"88","author":"Bergthaler","year":"2007","journal-title":"J. Gen. 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