{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T00:46:56Z","timestamp":1793234816254,"version":"4.5.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T00:00:00Z","timestamp":1612483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background and Aims<\/jats:title><jats:p>Patients with cirrhosis and acute-on-chronic liver failure (ACLF) have immunosuppression, indicated by an increase in circulating immune-deficient monocytes. The aim of this study was to investigate simultaneously the major blood-immune cell subsets in these patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and Methods<\/jats:title><jats:p>Blood taken from 67 patients with decompensated cirrhosis (including 35 critically ill with ACLF in the intensive care unit), and 12 healthy subjects, was assigned to either measurements of clinical blood counts and microarray (genomewide) analysis of RNA expression in whole-blood; microarray (genomewide) analysis of RNA expression in blood neutrophils; or assessment of neutrophil antimicrobial functions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Several features were found in patients with ACLF and not in those without ACLF. Indeed, clinical blood count measurements showed that patients with ACLF were characterized by leukocytosis, neutrophilia, and lymphopenia. Using the CIBERSORT method to deconvolute the whole-blood RNA-expression data, revealed that the hallmark of ACLF was the association of neutrophilia with increased proportions of macrophages M0-like monocytes and decreased proportions of memory lymphocytes (of B-cell, CD4 T-cell lineages), CD8 T cells and natural killer cells. Microarray analysis of neutrophil RNA expression revealed that neutrophils from patients with ACLF had a unique phenotype including induction of glycolysis and granule genes, and downregulation of cell-migration and cell-cycle genes. Moreover, neutrophils from these patients had defective production of the antimicrobial superoxide anion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Genomic analysis revealed that, among patients with decompensated cirrhosis, those with ACLF were characterized by dysregulation of blood immune cells, including increases in neutrophils (that had a unique phenotype) and macrophages M0-like monocytes, and depletion of several lymphocyte subsets (including memory lymphocytes). All these lymphocyte alterations, along with defective neutrophil superoxide anion production, may contribute to immunosuppression in ACLF, suggesting targets for future therapies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2020.619039","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T02:23:05Z","timestamp":1612750985000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":81,"title":["Characterization of Blood Immune Cells in Patients With Decompensated Cirrhosis Including ACLF"],"prefix":"10.3389","volume":"11","author":[{"given":"Emmanuel","family":"Weiss","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"de la Grange","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myl\u00e8ne","family":"Defaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Jos\u00e9","family":"Lozano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferr\u00e1n","family":"Aguilar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pushpa","family":"Hegde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariane","family":"Jolly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucile","family":"Moga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sukriti","family":"Sukriti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Banwari","family":"Agarwal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haqeeqat","family":"Gurm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Tanguy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanne","family":"Poisson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan","family":"Cl\u00e0ria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paer-Selim","family":"Abback","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axel","family":"P\u00e9rianin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gautam","family":"Mehta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv","family":"Jalan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Francoz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre-Emmanuel","family":"Rautou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Lotersztajn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente","family":"Arroyo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Durand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Moreau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1426","DOI":"10.1053\/j.gastro.2013.02.042","article-title":"Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis","volume":"144","author":"Moreau","year":"2013","journal-title":"Gastroenterology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1914900","article-title":"Acute-on-chronic liver failure","volume":"382","author":"Arroyo","year":"2020","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28740","article-title":"Systemic inflammation in decompensated cirrhosis. Characterization and role in acute-on-chronic liver failure","volume":"64","author":"Cl\u00e0ria","year":"2016","journal-title":"Hepatology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1053\/j.gastro.2014.11.045","article-title":"Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK","volume":"148","author":"Bernsmeier","year":"2015","journal-title":"Gastroenterology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.06.012","article-title":"Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure","volume":"61","author":"Jalan","year":"2014","journal-title":"J Hepatol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1016\/j.jhep.2019.11.009","article-title":"Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF","volume":"72","author":"Moreau","year":"2020","journal-title":"J Hepatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2003.12.010","article-title":"Tumour necrosis factor-alpha expression by activated monocytes and altered T-cell homeostasis in ascitic alcoholic cirrhosis: amelioration with norfloxacin","volume":"40","author":"Albillos","year":"2004","journal-title":"J Hepatol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3516","article-title":"Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2","volume":"20","author":"O\u2019Brien","year":"2014","journal-title":"Nat Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-314184","article-title":"CD14+CD15-HLA-DR-myeloid-derived suppressor cells impair antimicrobial responses in patients with acute-on-chronic liver failure","volume":"67","author":"Bernsmeier","year":"2018","journal-title":"Gut"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316888","article-title":"Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity","volume":"68","author":"Korf","year":"2019","journal-title":"Gut"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.02.017","article-title":"Epigenetic basis for monocyte dysfunction in patients with severe alcoholic hepatitis","volume":"73","author":"Weichselbaum","year":"2020","journal-title":"J Hepatol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-314240","article-title":"Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis","volume":"67","author":"Fern\u00e1ndez","year":"2018","journal-title":"Gut"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/ajg.2017.471","article-title":"Prediction of Fungal Infection Development and Their Impact on Survival Using the NACSELD Cohort","volume":"113","author":"Bajaj","year":"2018","journal-title":"Am J Gastroenterol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21737","article-title":"Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome","volume":"46","author":"Mookerjee","year":"2007","journal-title":"Hepatology"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-313443","article-title":"NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7\/8 activation","volume":"67","author":"Rolas","year":"2018","journal-title":"Gut"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.12.005","article-title":"Impaired intracellular signaling, myeloperoxidase release and bactericidal activity of neutrophils from patients with alcoholic cirrhosis","volume":"64","author":"Boussif","year":"2016","journal-title":"J Hepatol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2013.05.042","article-title":"Defective thymopoiesis and poor peripheral homeostatic replenishment of T-helper cells cause T-cell lymphopenia in cirrhosis","volume":"59","author":"Lario","year":"2013","journal-title":"J Hepatol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.12.025","article-title":"Gene- and exon-expression profiling reveals an extensive LPS-induced response in immune cells in patients with cirrhosis","volume":"58","author":"Gandoura","year":"2013","journal-title":"J Hepatol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2146","DOI":"10.1038\/s41467-018-04450-y","article-title":"Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver","volume":"9","author":"Hegde","year":"2018","journal-title":"Nat Commun"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.03.008","article-title":"Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients","volume":"165","author":"Banchereau","year":"2016","journal-title":"Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/ni.2789","article-title":"Molecular signatures of antibody responses derived from a systems biology study of five human vaccines","volume":"15","author":"Li","year":"2014","journal-title":"Nat Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3337","article-title":"Robust enumeration of cell subsets from tissue expression profiles","volume":"12","author":"Newman","year":"2015","journal-title":"Nat Methods"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2004114","article-title":"RNA identification of PRIME cells predicting rheumatoid arthritis flares","volume":"383","author":"Orange","year":"2020","journal-title":"N Engl J Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.06.013","article-title":"The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology","volume":"73","author":"Trebicka","year":"2020","journal-title":"J Hepatol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/imr.12440","article-title":"Granulopoiesis and granules of human neutrophils","volume":"273","author":"Cowland","year":"2016","journal-title":"Immunol Rev"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00346","article-title":"Neutrophil Heterogeneity as Therapeutic Opportunity in Immune-Mediated Disease","volume":"10","author":"Grieshaber-Bouyer","year":"2019","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032713-120236","article-title":"Metabolic Regulation of Immune Responses","volume":"32","author":"Ganeshan","year":"2014","journal-title":"Annu Rev Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.immuni.2018.02.002","article-title":"Developmental Analysis of Bone Marrow Neutrophils Reveals Populations Specialized in Expansion, Trafficking, and Effector Functions","volume":"48","author":"Evrard","year":"2018","journal-title":"Immunity"},{"key":"B29","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.jim.2017.01.013","article-title":"Characterization of human leukocyte-HUVEC adhesion: Effect of cell preparation methods","volume":"443","author":"Marino","year":"2017","journal-title":"J Immunol Methods"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01044","article-title":"Review of Defective NADPH Oxidase Activity and Myeloperoxidase Release in Neutrophils From Patients With Cirrhosis","volume":"10","author":"Moreau","year":"2019","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1053\/j.gastro.2014.11.041","article-title":"Blockade of PD1 and TIM3 Restores Innate and Adaptive Immunity in Patients With Acute Alcoholic Hepatitis","volume":"148","author":"Markwick","year":"2015","journal-title":"Gastroenterology"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.10.011","article-title":"CD8+ T cells from patients with cirrhosis display a phenotype that may contribute to cirrhosis-associated immune dysfunction","volume":"49","author":"Leboss\u00e9","year":"2019","journal-title":"EBioMedicine"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nri3660","article-title":"Emergency granulopoiesis","volume":"14","author":"Manz","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.11.001","article-title":"A Neutrophil Timer Coordinates Immune Defense and Vascular Protection","volume":"51","author":"Adrover","year":"2019","journal-title":"Immunity"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2016.08.011","article-title":"Identification of CD177 as the most dysregulated parameter in a microarray study of purified neutrophils from septic shock patients","volume":"178","author":"Demaret","year":"2016","journal-title":"Immunol Lett"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2016.08.011","article-title":"Activating Immunity to Fight a Foe \u2014 A New Path","volume":"382","author":"Hotchkiss","year":"2020","journal-title":"N Engl J Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2355-0","article-title":"Viral and host factors related to the clinical outcome of COVID-19","volume":"583","author":"Zhang","year":"2020","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nri3552","article-title":"Sepsis-induced Immunosuppression: From Cellular Dysfunctions to Immunotherapy","volume":"13","author":"Hotchkiss","year":"2013","journal-title":"Nat Rev Immunol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1016\/j.cell.2019.07.032","article-title":"Effector T(H)17 Cells Give Rise to Long-Lived T(RM) Cells that Are Essential for an Immediate Response against Bacterial Infection","volume":"178","author":"Amezcua Vesely","year":"2019","journal-title":"Cell"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1038\/s41467-017-01661-7","article-title":"Conventional CD4+ T cells present bacterial antigens to induce cytotoxic and memory CD8+ T cell responses","volume":"8","author":"Cruz-Adalia","year":"2017","journal-title":"Nat Commun"},{"key":"B41","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.coi.2019.04.013","article-title":"Granulysin: killer lymphocyte safeguard against microbes","volume":"60","author":"Dotiwala","year":"2019","journal-title":"Curr Opin Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1016\/j.cell.2018.12.034","article-title":"Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma","volume":"175","author":"Sade-Feldman","year":"2018","journal-title":"Cell"},{"key":"B43","doi-asserted-by":"publisher","first-page":"348","DOI":"10.1016\/j.cell.2018.11.045","article-title":"Gene Regulatory Programs Conferring Phenotypic Identities to Human NK Cells","volume":"176","author":"Collins","year":"2019","journal-title":"Cell"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.619039\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T02:23:09Z","timestamp":1612750989000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.619039\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,5]]},"references-count":43,"alternative-id":["10.3389\/fimmu.2020.619039"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2020.619039","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,5]]},"article-number":"619039"}}