{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T15:59:43Z","timestamp":1793289583634,"version":"4.5.0"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":549,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,3]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>Previous studies have shown that human nonalcoholic steatohepatitis (NASH) is often associated with the presence of circulating antibodies against protein adducted by lipid peroxidation products. Here we used the methionine-choline deficient (MCD) model of NASH to characterize the possible involvement of adaptive immunity in NASH. In mice fed up to 8 weeks with the MCD diet the extension of liver injury and lobular inflammation paralleled the development of immunoglobulin G (IgG) against malonyldialdehyde (MDA) and 4-hydroxynonenal (4-HNE)-derived antigens as well as with the hepatic recruitment of CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T-lymphocytes responsive to the same antigens. Moreover, in these animals the individual IgG reactivity against MDA-adducts positively correlated with transaminase release and hepatic tumor necrosis factor alpha (TNF-\u03b1) expression. To substantiate the role of immune responses triggered by oxidative stress in the progression of NASH, mice were immunized with MDA-adducted bovine serum albumin (MDA-BSA) before feeding the MCD diet. MDA-BSA immunization did not affect control mice livers, but further stimulated transaminase release, lobular inflammation, and the hepatic expression of proinflammatory cytokine in MCD-fed mice. The increased severity of NASH in immunized MCD-fed mice involved liver recruitment and the T helper (Th)-1 activation of CD4<jats:sup>+<\/jats:sup> T cells that, in turn, further stimulated macrophage M1 responses. Moreover, hepatic fibrosis was also evident in these animals in relation with an IL-15-mediated increase of natural killer T-cells (NKT) and the up-regulation in liver production of osteopontin by NKT cells and hepatic macrophages. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: These results indicate that oxidative stress can contribute to the progression of NASH by stimulating both humoral and cellular immune responses, pointing to the possible role of adaptive immunity in the pathogenesis of the disease. (HEPATOLOGY 2014;59:886\u2013897)<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.26749","type":"journal-article","created":{"date-parts":[[2013,10,12]],"date-time":"2013-10-12T01:48:04Z","timestamp":1381542484000},"page":"886-897","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":251,"title":["Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH"],"prefix":"10.1097","volume":"59","author":[{"given":"Salvatore","family":"Sutti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aastha","family":"Jindal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Locatelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Vacchiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Gigliotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Bozzola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Albano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-20-20250207","doi-asserted-by":"crossref","first-page":"339350","DOI":"10.1055\/s-0028-1091978","article-title":"The epidemiology of nonalcoholic fatty liver disease: a global perspective.","volume":"28","author":"Lazo","year":"2008","journal-title":"Semin Liver Dis"},{"key":"R2-20-20250207","doi-asserted-by":"crossref","first-page":"7281","DOI":"10.1016\/j.molmed.2007.12.003","article-title":"Molecular basis and mechanisms of progression of nonalcoholic steatohepatitis.","volume":"14","author":"Marra","year":"2008","journal-title":"Trends Mol Med"},{"key":"R3-20-20250207","doi-asserted-by":"crossref","first-page":"18361846","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"R4-20-20250207","doi-asserted-by":"crossref","first-page":"13251365","DOI":"10.1089\/ars.2009.3058","article-title":"Redox balance in the pathogenesis of nonalcoholic fatty liver disease: mechanisms and therapeutic opportunities.","volume":"15","author":"Gambino","year":"2011","journal-title":"Antioxid Redox Signal"},{"key":"R5-20-20250207","doi-asserted-by":"crossref","first-page":"5662","DOI":"10.1016\/S0168-8278(02)00073-9","article-title":"In situ detection of lipid peroxidation and oxidative DNA damage in nonalcoholic fatty liver disease.","volume":"37","author":"Seki","year":"2002","journal-title":"J Hepatol"},{"key":"R6-20-20250207","doi-asserted-by":"crossref","first-page":"149714502","DOI":"10.1111\/j.1572-0241.2004.30159.x","article-title":"Systemic lipid peroxidation and its metabolic and dietary correlates in patients with nonalcoholic steatohepatitis.","volume":"99","author":"Chalasani","year":"2004","journal-title":"Am J Gastroenterol"},{"key":"R7-20-20250207","doi-asserted-by":"crossref","first-page":"235248","DOI":"10.1161\/CIRCRESAHA.110.223875","article-title":"Oxidationspecific epitopes are dangerassociated molecular patterns recognized by pattern recognition receptors of innate immunity.","volume":"108","author":"Miller","year":"2011","journal-title":"Circ Res"},{"key":"R8-20-20250207","first-page":"24652475","article-title":"The innate immune response to products of phospholipid peroxidation.","volume":"1818","author":"Weismann","year":"2012","journal-title":"Biochim Biophys Acta"},{"key":"R9-20-20250207","doi-asserted-by":"crossref","first-page":"171180","DOI":"10.1046\/j.1365-2796.2000.00656.x","article-title":"Immune response to oxidative neoepitopes on LDL and phospholipids modulate the development of atherosclerosis.","volume":"247","author":"Palinski","year":"2000","journal-title":"J Int Med"},{"key":"R10-20-20250207","doi-asserted-by":"crossref","first-page":"567573","DOI":"10.1016\/j.autrev.2008.04.019","article-title":"Autoimmunity and oxidatively modified antigens.","volume":"7","author":"Kurien","year":"2008","journal-title":"Autoimmun Rev"},{"key":"R11-20-20250207","doi-asserted-by":"crossref","first-page":"471476","DOI":"10.3892\/ijmm_00000487","article-title":"Oxidative stress parameters in paediatric nonalcoholic fatty liver disease.","volume":"26","author":"Nobili","year":"2010","journal-title":"Int J Molec Med"},{"key":"R12-20-20250207","doi-asserted-by":"crossref","first-page":"987993","DOI":"10.1136\/gut.2004.057968","article-title":"Immune response toward lipid peroxidation products as a predictor of the progression of nonalcoholic fatty liver disease (NAFLD) to advanced fibrosis.","volume":"54","author":"Albano","year":"2005","journal-title":"Gut"},{"key":"R13-20-20250207","doi-asserted-by":"crossref","first-page":"16351648","DOI":"10.1111\/j.1440-1746.2008.05543.x","article-title":"Animal model of NASH: getting both pathology and metabolic contest right.","volume":"23","author":"Larter","year":"2008","journal-title":"J Gastroenterol Hepatol"},{"key":"R14-20-20250207","doi-asserted-by":"crossref","first-page":"6369","DOI":"10.1111\/j.1365-2249.2007.03404.x","article-title":"Antibodies against oxidized phospholipids in laboratory tests exploring lupus anticoagulant activity.","volume":"149","author":"Rolla","year":"2007","journal-title":"Clin Exp Immunol"},{"key":"R15-20-20250207","doi-asserted-by":"crossref","first-page":"13131321","DOI":"10.1002\/hep.20701","article-title":"Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease.","volume":"41","author":"Kleiner","year":"2005","journal-title":"Hepatology"},{"key":"R16-20-20250207","doi-asserted-by":"crossref","first-page":"279287","DOI":"10.1042\/CS20120289","article-title":"NFkB1 deficiency stimulates the progression of nonalcoholic steatohepatitis (NASH) in mice by promoting NKTmediated responses.","volume":"124","author":"Locatelli","year":"2013","journal-title":"Clin Sci (Lond)"},{"key":"R17-20-20250207","doi-asserted-by":"crossref","first-page":"6068","DOI":"10.1002\/(SICI)1097-0320(20000501)40:1<60::AID-CYTO8>3.0.CO;2-J","article-title":"Optimization of whole blood antigen specific cytokine assay for CD4 T cells.","volume":"40","author":"Nomura","year":"2000","journal-title":"Cytometry"},{"key":"R18-20-20250207","doi-asserted-by":"crossref","first-page":"894903","DOI":"10.1002\/hep.25660","article-title":"Specific immunization strategies against oxidized lowdensity lipoprotein: a novel way to reduce nonalcoholic steatohepatitis in mice.","volume":"56","author":"Bieghs","year":"2012","journal-title":"Hepatology"},{"key":"R19-20-20250207","doi-asserted-by":"crossref","first-page":"257264","DOI":"10.1016\/j.smim.2009.05.011","article-title":"Macrophage CD40 signaling: a pivotal regulator of disease protection and pathogenesis.","volume":"21","author":"Suttles","year":"2009","journal-title":"Semin Immunol"},{"key":"R20-20-20250207","doi-asserted-by":"crossref","first-page":"880885","DOI":"10.1002\/hep.20826","article-title":"Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease.","volume":"42","author":"Li","year":"2005","journal-title":"Hepatology"},{"key":"R22-20-20250207","doi-asserted-by":"crossref","first-page":"17881796","DOI":"10.4049\/jimmunol.1202814","article-title":"Tim3galectin9 regulate the homeostasis of hepatic NKT cells in a murine model of nonalcoholic fatty liver disease.","volume":"190","author":"Tang","year":"2013","journal-title":"J Immunol"},{"key":"R23-20-20250207","doi-asserted-by":"crossref","first-page":"13231329","DOI":"10.1136\/gutjnl-2011-301857","article-title":"NKTassociated hedgehog and osteopontin drive fibrogenesis in nonalcoholic fatty liver disease.","volume":"61","author":"Syn","year":"2012","journal-title":"Gut"},{"key":"R24-20-20250207","doi-asserted-by":"crossref","first-page":"594608","DOI":"10.1002\/hep.24701","article-title":"Osteopontin, an oxidant stresssensitive cytokine, upregulates collagenI via integrin (V)(3) engagement and PI3KpAktNFB signaling.","volume":"55","author":"Urtasun","year":"2012","journal-title":"Hepatology"},{"key":"R25-20-20250207","doi-asserted-by":"crossref","first-page":"384390","DOI":"10.1016\/j.it.2010.08.001","article-title":"Adaptive immunity and adipose tissue biology.","volume":"31","author":"Kaminski","year":"2010","journal-title":"Trends Immunol"},{"key":"R26-20-20250207","first-page":"25832592","article-title":"Lymphocytes in obesityrelated adipose tissue inflammation.","volume":"55","author":"Chatzigeorgiou","year":"2012","journal-title":"Diabetology"},{"key":"R27-20-20250207","doi-asserted-by":"crossref","first-page":"195203","DOI":"10.1038\/nrgastro.2010.21","article-title":"Pathology of nonalcoholic fatty liver disease.","volume":"7","author":"Brunt","year":"2010","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"R28-20-20250207","doi-asserted-by":"crossref","first-page":"18721879","DOI":"10.1093\/jn\/138.10.1872","article-title":"Nacethylcysteine attenuates progression of liver pathology in a rat model of nonalcoholic steatohepatitis.","volume":"138","author":"Baumgardner","year":"2008","journal-title":"J Nutr"},{"key":"R29-20-20250207","doi-asserted-by":"crossref","first-page":"801810","DOI":"10.1016\/j.jhep.2012.11.014","article-title":"Nonalcoholic steatohepatitis: the role of oxidized lowdensity lipoproteins.","volume":"58","author":"Walenbergh","year":"2013","journal-title":"J Hepatol"},{"key":"R30-20-20250207","doi-asserted-by":"crossref","first-page":"508519","DOI":"10.1038\/nri1882","article-title":"The immune response in atherosclerosis: a doubleedged sword.","volume":"6","author":"Hansson","year":"2006","journal-title":"Nat Rev Immunol"},{"key":"R31-20-20250207","doi-asserted-by":"crossref","first-page":"22512260","DOI":"10.1161\/ATVBAHA.111.231357","article-title":"CD40L deficiency ameliorates adipose tissue inflammation and metabolic manifestations of obesity in mice.","volume":"31","author":"Poggi","year":"2011","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"R32-20-20250207","doi-asserted-by":"crossref","first-page":"11201130","DOI":"10.1007\/s10875-011-9571-1","article-title":"Altered phenotype and functionality of circulating immune cells characterize adult patients with nonalcoholic steatohepatitis.","volume":"31","author":"Inzaugarat","year":"2011","journal-title":"J Clin Immunol"},{"key":"R33-20-20250207","doi-asserted-by":"crossref","first-page":"611621","DOI":"10.1007\/s10875-011-9635-2","article-title":"The role of innate cells is coupled to a Th1polarized immune response in pediatric nonalcoholic steatohepatitis.","volume":"32","author":"Ferreyra Solari","year":"2012","journal-title":"J Clin Immunol"},{"key":"R34-20-20250207","doi-asserted-by":"crossref","first-page":"51335138","DOI":"10.1073\/pnas.1215840110","article-title":"B cells promote inflammation in obesity and type 2 diabetes through regulation of Tcell function and an inflammatory cytokine profile.","volume":"110","author":"DeFuria","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"R35-20-20250207","doi-asserted-by":"crossref","first-page":"30723082","DOI":"10.1172\/JCI24798","article-title":"Attenuated liver fibrosis in the absence of B cells.","volume":"115","author":"Novobrantseva","year":"2005","journal-title":"J Clin Invest"},{"key":"R36-20-20250207","doi-asserted-by":"crossref","first-page":"527535","DOI":"10.1002\/hep.24044","article-title":"B cell depletion therapy exacerbates murine primary biliary cirrhosis.","volume":"53","author":"Dhirapong","year":"2011","journal-title":"Hepatology"},{"key":"R37-20-20250207","first-page":"793800","article-title":"Role of NKT cells in autoimmune liver disease.","volume":"10","author":"SantodomingoGarzon","year":"2011","journal-title":"Autoimmun Rev"},{"key":"R39-20-20250207","first-page":"19982007","article-title":"Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease.","volume":"51","author":"Syn","year":"2010","journal-title":"Hepatology"},{"key":"R40-20-20250207","doi-asserted-by":"crossref","first-page":"673680","DOI":"10.1097\/MEG.0b013e32831bc3d6","article-title":"Role of liverinfiltrating CD3CD56 natural killer T cells in the pathogenesis of nonalcoholic fatty liver disease.","volume":"21","author":"Tajiri","year":"2009","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"R41-20-20250207","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1016\/j.cytogfr.2010.09.003","article-title":"Role of IL15 in immune and infectious diseases.","volume":"22","author":"Di Sabatino","year":"2011","journal-title":"Cytokine Growth Factor Rev"},{"key":"R42-20-20250207","doi-asserted-by":"crossref","first-page":"61496159","DOI":"10.4049\/jimmunol.0802470","article-title":"Hepatocytes and IL15: a favorable microenvironment for T cell survival and CD8 T cell differentiation.","volume":"182","author":"Correia","year":"2009","journal-title":"J Immunol"},{"key":"R43-20-20250207","doi-asserted-by":"crossref","first-page":"410418","DOI":"10.1016\/j.jhep.2006.04.008","article-title":"Interleukin15 increases hepatic regenerative activity.","volume":"45","author":"Suzuki","year":"2006","journal-title":"J Hepatol"},{"key":"R44-20-20250207","doi-asserted-by":"crossref","first-page":"265280","DOI":"10.1111\/j.1440-1827.2011.02649.x","article-title":"Osteopontin intrinsic tissue regulator of intractable inflammatory disease.","volume":"61","author":"Uede","year":"2011","journal-title":"Pathol Int"},{"key":"R45-20-20250207","doi-asserted-by":"crossref","first-page":"539550","DOI":"10.1016\/j.immuni.2004.08.012","article-title":"Osteopontin as a mediator of NKT cell function in T cellmediated liver diseases.","volume":"21","author":"Diao","year":"2004","journal-title":"Immunity"},{"key":"R46-20-20250207","doi-asserted-by":"crossref","first-page":"106115","DOI":"10.1002\/hep.23998","article-title":"Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis.","volume":"53","author":"Syn","year":"2011","journal-title":"Hepatology"},{"key":"R47-20-20250207","doi-asserted-by":"crossref","first-page":"G264G273","DOI":"10.1152\/ajpgi.00002.2004","article-title":"Upregulation of osteopontin expression is involved in the development of nonalcoholic steatohepatitis in a dietary murine model.","volume":"287","author":"Sahai","year":"2004","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"R48-20-20250207","doi-asserted-by":"crossref","first-page":"e15","DOI":"10.1017\/S1462399411001839","article-title":"Osteopontin in macrophage functions.","volume":"13","author":"Ritting","year":"2011","journal-title":"Exp Rev Mol Med"},{"key":"R49-20-20250207","doi-asserted-by":"crossref","first-page":"10001005","DOI":"10.1111\/j.1478-3231.2006.01314.x","article-title":"Quantitative trait loci analysis of mice administered the methioninecholine deficient dietary model of experimental steatohepatitis.","volume":"26","author":"Rangnekar","year":"2006","journal-title":"Liver Int"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep.26749","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/01515467-201403000-00020","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T17:01:14Z","timestamp":1738947674000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/01515467-201403000-00020"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,3]]},"references-count":47,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2014]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.26749","relation":{},"ISSN":["0270-9139"],"issn-type":[{"value":"0270-9139","type":"print"}],"subject":[],"published":{"date-parts":[[2014,3]]}}}