{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T10:04:44Z","timestamp":1776247484274,"version":"3.50.1"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2020,1,12]],"date-time":"2020-01-12T00:00:00Z","timestamp":1578787200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatol Commun"],"published-print":{"date-parts":[[2020,4]]},"abstract":"<jats:p>Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. The immune system in patients with AH is hyperactive and yet dysfunctional. Here, we investigated whether this immune\u2010dysregulated state is related to the alcoholic impact on immune checkpoints (ICPs). We used multiplex immunoassays and enzyme\u2010linked immunosorbent assay to quantify plasma levels of 18 soluble ICPs (sICPs) from 81 patients with AH, 65 heavy drinkers without liver diseases (HDCs), and 39 healthy controls (HCs) at baseline, 33 patients with AH and 32 HDCs at 6\u2010month follow\u2010up, and 18 patients with AH and 29 HDCs at 12\u2010month follow\u2010up. We demonstrated that baseline levels of 6 sICPs (soluble T\u2010cell immunoglobulin and mucin domain 3 [sTIM\u20103], soluble cluster of differentiation [sCD]27, sCD40, soluble Toll\u2010like receptor\u20102 [sTLR\u20102], soluble herpesvirus entry mediator [sHVEM], and soluble lymphotoxin\u2010like inducible protein that competes with glycoprotein D for herpes virus entry on T cells [sLIGHT])  were up\u2010regulated, while 11 sICPs (soluble B\u2010 and T\u2010lymphocyte attenuator [sBTLA], sCD160, soluble cytotoxic T\u2010lymphocyte\u2010associated protein 4 [sCTLA\u20104], soluble lymphocyte\u2010activation gene 3 [sLAG\u20103], soluble programmed death 1 [sPD\u20101], sPD ligand 1 [sPD\u2010L1], sCD28, soluble glucocorticoid\u2010induced tumor necrosis factor receptor\u2010related protein [sGITR], sGITR ligand [sGITRL], sCD80, and inducible T\u2010cell costimulator [sICOS]) were down\u2010regulated in patients with AH compared to HDCs. The up\u2010regulated sICPs except sLIGHT and down\u2010regulated sCD80, sCD160, sCTLA\u20104, and sLAG\u20103 correlated positively or negatively with AH disease severity, bacterial translocation, and inflammatory factors. At follow\u2010up, abstinent patients with AH still had higher levels of several sICPs compared to HDCs. We also compared expression of 10 membrane\u2010bound ICPs (mICPs) on peripheral blood mononuclear cells (PBMCs) from patients with AH and HCs by flow cytometry and found that several mICPs were dysregulated on blood cells from patients with AH. The function and regulation of sICPs and mICPs were studied using PBMCs from patients with AH and HCs. Recombinant sHVEM affected tumor necrosis factor (TNF)\u2010\u03b1 and interferon\u2010\u03b3 production by T cells from patients with AH and HCs. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Both sICPs and mICPs were dysregulated in patients with AH, and alcohol abstinence did not fully reverse these abnormalities. The HVEM axis plays a role in regulating T\u2010cell function in patients with AH.<\/jats:p>","DOI":"10.1002\/hep4.1475","type":"journal-article","created":{"date-parts":[[2020,1,13]],"date-time":"2020-01-13T05:41:21Z","timestamp":1578894081000},"page":"588-605","source":"Crossref","is-referenced-by-count":18,"title":["Immune Checkpoint Axes Are Dysregulated in\u00a0Patients With Alcoholic\u00a0Hepatitis"],"prefix":"10.1097","volume":"4","author":[{"given":"Wei","family":"Li","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology,Indiana University School of Medicine,Indianapolis,IN"},{"name":"Department of Clinical Laboratory,the Second Affiliated Hospital and Yuying Children\u2019s Hospital of Wenzhou Medical University,Wenzhou,Zhejiang,China"},{"name":"School of Laboratory Medicine,Wenzhou Medical University,Wenzhou,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology,Indiana University School of Medicine,Indianapolis,IN"},{"name":"School of Laboratory Medicine,Wenzhou Medical University,Wenzhou,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haitao","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoqing","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arun J.","family":"Sanyal","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Virginia Commonwealth University,Richmond,VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7620-573X","authenticated-orcid":false,"given":"Vijay H.","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Mayo Clinic,Rochester,MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yongliang","family":"Lou","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine,Wenzhou Medical University,Wenzhou,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoqun","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory,the Second Affiliated Hospital and Yuying Children\u2019s Hospital of Wenzhou Medical University,Wenzhou,Zhejiang,China"},{"name":"School of Laboratory Medicine,Wenzhou Medical University,Wenzhou,China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naga","family":"Chalasani","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Department of Medicine,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qigui","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology,Indiana University School of Medicine,Indianapolis,IN"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2020,1,12]]},"reference":[{"key":"hep41475-bib-0001-20240114","first-page":"185","article-title":"Impact of alcohol abuse on the adaptive immune system","volume":"37","year":"2015","journal-title":"Alcohol Res"},{"key":"hep41475-bib-0002-20240114","first-page":"237","article-title":"The role of innate immunity in alcoholic liver 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