{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:05:42Z","timestamp":1791273942632,"version":"4.1.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2018,3,25]],"date-time":"2018-03-25T00:00:00Z","timestamp":1521936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2018,3,25]],"date-time":"2018-03-25T00:00:00Z","timestamp":1521936000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,5]]},"abstract":"\n Hepatocellular carcinoma (HCC) is a frequent neoplasia and a leading cause of inflammation\u2010related cancer mortality. Despite that most HCCs arise from persistent inflammatory conditions, pathways linking chronic inflammation to cancer development are still incompletely elucidated. We dissected the role of adaptive immunity in the Mdr2 knockout (\n Mdr2<\/jats:italic>\n \u2013\/\u2013<\/jats:sup>\n ) mouse, a model of inflammation\u2010associated cancer, in which ablation of adaptive immunity has been induced genetically (\n Rag2<\/jats:italic>\n \u2013\/\u2013<\/jats:sup>\n Mdr2<\/jats:italic>\n \u2013\/\u2013<\/jats:sup>\n and\n \u03bcMt\u2010Mdr2\u2013\/\u2013<\/jats:italic>\n mice) or with\n in vivo<\/jats:italic>\n treatments using lymphocyte\u2010specific depleting antibodies (anti\u2010CD20 or anti\u2010CD4\/CD8). We found that activated B and T lymphocytes, secreting fibrogenic tumor necrosis factor alpha (TNF\u03b1) and other proinflammatory cytokines, infiltrated liver of the\n Mdr2<\/jats:italic>\n \u2013\/\u2013<\/jats:sup>\n mice during chronic fibrosing cholangitis. Lymphocyte ablation, in the\n Rag2<\/jats:italic>\n \u2013\/\u2013<\/jats:sup>\n Mdr2<\/jats:italic>\n \u2013\/\u2013<\/jats:sup>\n and\n \u03bcMt\u2010Mdr2\u2013\/\u2013<\/jats:italic>\n mice, strongly suppressed hepatic stellate cell (HSC) activation and extracellular matrix deposition, enhancing HSC transition to cellular senescence. Moreover, lack of lymphocytes changed the intrahepatic metabolic\/oxidative state, resulting in skewed macrophage polarization toward an anti\u2010inflammatory M2 phenotype. Remarkably, hepatocarcinogenesis was significantly suppressed in the\n Rag2<\/jats:italic>\n \u2013\/\u2013<\/jats:sup>\n Mdr2<\/jats:italic>\n \u2013\/\u2013<\/jats:sup>\n mice, correlating with reduced TNF\u03b1\/NF\u2010\u03baB (nuclear factor kappa B) pathway activation. Ablation of CD20\n +<\/jats:sup>\n B cells, but not of CD4\n +<\/jats:sup>\n \/CD8\n +<\/jats:sup>\n T cells, in\n Mdr2<\/jats:italic>\n \u2013\/\u2013<\/jats:sup>\n mice, promoted senescence\u2010mediated fibrosis resolution and inhibited the protumorigenic TNF\u03b1\/NF\u2010\u03baB pathway. Interestingly, presence of infiltrating B cells correlated with increased tumor aggressiveness and reduced disease\u2010free survival in human HCC.\n Conclusion:<\/jats:italic>\n Adaptive immunity sustains liver fibrosis (LF) and favors HCC growth in chronic injury, by modulating innate components of inflammation and limiting the extent of HSC senescence. Therapies designed for B\u2010cell targeting may be an effective strategy in LF. (H\n epatology<\/jats:sc>\n 2018;67:1970\u20101985).\n <\/jats:p>","DOI":"10.1002\/hep.29636","type":"journal-article","created":{"date-parts":[[2017,11,3]],"date-time":"2017-11-03T12:36:03Z","timestamp":1509712563000},"page":"1970-1985","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":81,"title":["B lymphocytes limit senescence\u2010driven fibrosis resolution and favor hepatocarcinogenesis in mouse liver injury"],"prefix":"10.1097","volume":"67","author":[{"given":"Francesca","family":"Faggioli","sequence":"first","affiliation":[{"name":"Milan Unit, Istituto di Ricerca Genetica e Biomedica,National Research Council,Milan,Italy"},{"name":"Humanitas Clinical and Research Center,Rozzano,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Palagano","sequence":"additional","affiliation":[{"name":"Humanitas Clinical and Research Center,Rozzano,Italy"},{"name":"Department of Medical Biotechnologies and Translational Medicine,University of Milan,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Di Tommaso","sequence":"additional","affiliation":[{"name":"Pathology Unit,Humanitas Clinical and Research Center,Rozzano,Italy"},{"name":"Department of Biomedical Sciences,Humanitas University,Rozzano,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Donadon","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and General Surgery,Humanitas Clinical and Research Center,Rozzano,Italy"},{"name":"Department of Biomedical Sciences,Humanitas University,Rozzano,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Marrella","sequence":"additional","affiliation":[{"name":"Milan Unit, Istituto di Ricerca Genetica e Biomedica,National Research Council,Milan,Italy"},{"name":"Humanitas Clinical and Research Center,Rozzano,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Recordati","sequence":"additional","affiliation":[{"name":"Mouse and Animal Pathology Laboratory,Fondazione Filarete,Milano,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Mantero","sequence":"additional","affiliation":[{"name":"Milan Unit, Istituto di Ricerca Genetica e Biomedica,National Research Council,Milan,Italy"},{"name":"Humanitas Clinical and Research Center,Rozzano,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Villa","sequence":"additional","affiliation":[{"name":"Milan Unit, Istituto di Ricerca Genetica e Biomedica,National Research Council,Milan,Italy"},{"name":"Humanitas Clinical and Research Center,Rozzano,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Vezzoni","sequence":"additional","affiliation":[{"name":"Milan Unit, Istituto di Ricerca 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