{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T01:32:33Z","timestamp":1793323953367,"version":"4.5.0"},"reference-count":89,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Medical University of Warsaw","award":["1M24\/1\/M\/MBM\/N\/21\/21"],"award-info":[{"award-number":["1M24\/1\/M\/MBM\/N\/21\/21"]}]},{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["2024\/54\/E\/NZ6\/00334"],"award-info":[{"award-number":["2024\/54\/E\/NZ6\/00334"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Chronic hepatitis C (CHC), caused by the hepatitis C virus, commonly leads to liver fibrosis. CHC is also related to T-cell exhaustion, phenotypically manifesting as overexpression of inhibitory receptors (iRs), e.g., programmed death receptor-1 (PD-1), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and lymphocyte activation gene 3 (LAG-3), which have corresponding plasma-soluble analogs. Galectin-3 (Gal-3) is a pro-fibrotic and pro-inflammatory molecule, but its role in CHC is controversial. The study aimed to assess the relationship between plasma levels of soluble PD-1 (sPD-1), sTIM-3, sLAG-3 and Gal-3 and the degree of fibrosis in CHC and successful CHC treatment effect on these markers. The study comprised 98 CHC patients, qualified for treatment with direct-acting antivirals. Plasma samples were collected prior to and six months post-treatment. iRs were determined by ELISA. sPD-1 levels were significantly higher in more advanced fibrosis (F2\u2009+\u2009F3 vs. F0\/1). Regardless of the degree of fibrosis, sPD-1 and sLAG-3 levels significantly decreased after therapy. sTIM-3 levels also decreased, however, mostly in patients with no or mild (i.e., F0\/1) fibrosis. Furthermore, Gal-3 increased in patients with more advanced fibrosis (F2\u2009+\u2009F3). sPD-1 is associated with liver disease stage in CHC and effective treatment is related to the iRs levels reduction.<\/jats:p>","DOI":"10.1038\/s41598-025-99096-4","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T15:25:50Z","timestamp":1746199550000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Plasma levels of soluble PD-1, TIM-3, LAG-3 and galectin-3 and the degree of liver fibrosis in CHC and the impact of successful antiviral treatment on their levels"],"prefix":"10.1038","volume":"15","author":[{"given":"Sylwia","family":"Osuch","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Kumorek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawe\u0142","family":"Koz\u0142owski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Berak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Kochanowicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamila","family":"Cort\u00e9s-Fendorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"issue":"6","key":"99096_CR1","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1177\/2040622315603642","volume":"6","author":"JM Wilder","year":"2015","unstructured":"Wilder, J. M. & Muir, A. J. Strategies for treating chronic HCV infection in patients with cirrhosis: latest evidence and clinical outcomes. Ther. Adv. Chronic Dis. 6 (6), 314\u2013327 (2015).","journal-title":"Ther. Adv. Chronic Dis."},{"issue":"6","key":"99096_CR2","doi-asserted-by":"publisher","first-page":"1746","DOI":"10.1002\/hep.22534","volume":"48","author":"CK Aitken","year":"2008","unstructured":"Aitken, C. K. et al. High incidence of hepatitis C virus reinfection in a cohort of injecting drug users. Hepatology 48 (6), 1746\u20131752 (2008).","journal-title":"Hepatology"},{"issue":"1","key":"99096_CR3","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1186\/s12916-019-1411-9","volume":"17","author":"N Scott","year":"2019","unstructured":"Scott, N. et al. The case for a universal hepatitis C vaccine to achieve hepatitis C elimination. BMC Med. 17 (1), 175 (2019).","journal-title":"BMC Med."},{"issue":"8","key":"99096_CR4","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/nri1412","volume":"4","author":"TA Wynn","year":"2004","unstructured":"Wynn, T. A. Fibrotic disease and the T(H)1\/T(H)2 paradigm. Nat. Rev. Immunol. 4 (8), 583\u2013594 (2004).","journal-title":"Nat. Rev. Immunol."},{"issue":"32","key":"99096_CR5","doi-asserted-by":"publisher","first-page":"11033","DOI":"10.3748\/wjg.v20.i32.11033","volume":"20","author":"G Sebastiani","year":"2014","unstructured":"Sebastiani, G., Gkouvatsos, K. & Pantopoulos, K. Chronic hepatitis C and liver fibrosis. World J. Gastroenterol. 20 (32), 11033\u201311053 (2014).","journal-title":"World J. Gastroenterol."},{"issue":"2","key":"99096_CR6","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1172\/JCI24282","volume":"115","author":"R Bataller","year":"2005","unstructured":"Bataller, R. & Brenner, D. A. Liver fibrosis. J. Clin. Invest. 115 (2), 209\u2013218 (2005).","journal-title":"J. Clin. Invest."},{"issue":"2","key":"99096_CR7","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1136\/gut.2005.088690","volume":"56","author":"Y Inagaki","year":"2007","unstructured":"Inagaki, Y. & Okazaki, I. Emerging insights into transforming growth factor beta Smad signal in hepatic fibrogenesis. Gut 56 (2), 284\u2013292 (2007).","journal-title":"Gut"},{"issue":"12","key":"99096_CR8","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1038\/nrgastro.2010.168","volume":"7","author":"H Sahin","year":"2010","unstructured":"Sahin, H., Trautwein, C. & Wasmuth, H. E. Functional role of chemokines in liver disease models. Nat. Rev. Gastroenterol. Hepatol. 7 (12), 682\u2013690 (2010).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"99096_CR9","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1034\/j.1600-0528.2002.017408.x","volume":"174","author":"PA Knolle","year":"2000","unstructured":"Knolle, P. A. & Gerken, G. Local control of the immune response in the liver. Immunol. Rev. 174, 21\u201334 (2000).","journal-title":"Immunol. Rev."},{"issue":"3","key":"99096_CR10","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1055\/s-0030-1255354","volume":"30","author":"TA Wynn","year":"2010","unstructured":"Wynn, T. A. & Barron, L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis. 30 (3), 245\u2013257 (2010).","journal-title":"Semin Liver Dis."},{"issue":"4","key":"99096_CR11","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1055\/s-2007-991511","volume":"27","author":"G Szabo","year":"2007","unstructured":"Szabo, G., Mandrekar, P. & Dolganiuc, A. Innate immune response and hepatic inflammation. Semin Liver Dis. 27 (4), 339\u2013350 (2007).","journal-title":"Semin Liver Dis."},{"issue":"6","key":"99096_CR12","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1046\/j.1440-1746.2001.02445.x","volume":"16","author":"GA MacDonald","year":"2001","unstructured":"MacDonald, G. A. et al. Lipid peroxidation in hepatic steatosis in humans is associated with hepatic fibrosis and occurs predominately in acinar zone 3. J. Gastroenterol. Hepatol. 16 (6), 599\u2013606 (2001).","journal-title":"J. Gastroenterol. Hepatol."},{"issue":"4","key":"99096_CR13","doi-asserted-by":"publisher","first-page":"875","DOI":"10.3390\/cells9040875","volume":"9","author":"N Roehlen","year":"2020","unstructured":"Roehlen, N., Crouchet, E. & Baumert, T. F. Liver fibrosis: mechanistic concepts and therapeutic perspectives. Cells 9(4), 875 (2020).","journal-title":"Cells"},{"key":"99096_CR14","unstructured":"Raz, A., Pazerini, G. & Carmi, P. Identification of the metastasis-associated, galactoside-binding lectin as a chimeric gene product with homology to an IgE-binding protein. Cancer Res, 49(13): pp. 3489-93. (1989)."},{"issue":"8","key":"99096_CR15","first-page":"2173","volume":"51","author":"A Raz","year":"1991","unstructured":"Raz, A. et al. Molecular cloning and chromosomal mapping of a human galactoside-binding protein. Cancer Res. 51 (8), 2173\u20132178 (1991).","journal-title":"Cancer Res."},{"issue":"11","key":"99096_CR16","doi-asserted-by":"publisher","first-page":"5148","DOI":"10.1128\/IAI.02006-06","volume":"75","author":"L Breuilh","year":"2007","unstructured":"Breuilh, L. et al. Galectin-3 modulates immune and inflammatory responses during helminthic infection: impact of galectin-3 deficiency on the functions of dendritic cells. Infect. Immun. 75 (11), 5148\u20135157 (2007).","journal-title":"Infect. Immun."},{"issue":"3","key":"99096_CR17","doi-asserted-by":"publisher","first-page":"389","DOI":"10.3390\/biom10030389","volume":"10","author":"A Hara","year":"2020","unstructured":"Hara, A. et al. Galectin-3 as a Next-Generation biomarker for detecting early stage of various diseases. Biomolecules 10(3), 389 (2020).","journal-title":"Biomolecules"},{"key":"99096_CR18","first-page":"A57","volume":"74","author":"A Miah","year":"2019","unstructured":"Miah, A. & Tongue, S. P. S89 ex vivo studies of the gal-3-fibrosome hypothesis in IPF and non-fibrotic control lung tissue and myofibroblasts. Thorax 74, A57 (2019).","journal-title":"Thorax"},{"issue":"13","key":"99096_CR19","doi-asserted-by":"publisher","first-page":"5060","DOI":"10.1073\/pnas.0511167103","volume":"103","author":"NC Henderson","year":"2006","unstructured":"Henderson, N. C. et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc. Natl. Acad. Sci. U S A. 103 (13), 5060\u20135065 (2006).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"issue":"1","key":"99096_CR20","doi-asserted-by":"publisher","first-page":"453","DOI":"10.2119\/molmed.2014.00178","volume":"21","author":"I Jeftic","year":"2015","unstructured":"Jeftic, I. et al. Galectin-3 ablation enhances liver steatosis, but attenuates inflammation and IL-33-Dependent fibrosis in obesogenic mouse model of nonalcoholic steatohepatitis. Mol. Med. 21 (1), 453\u2013465 (2015).","journal-title":"Mol. Med."},{"key":"99096_CR21","doi-asserted-by":"publisher","first-page":"105881","DOI":"10.1016\/j.biocel.2020.105881","volume":"130","author":"RJ Slack","year":"2021","unstructured":"Slack, R. J., Mills, R. & Mackinnon, A. C. The therapeutic potential of galectin-3 Inhibition in fibrotic disease. Int. J. Biochem. Cell. Biol. 130, 105881 (2021).","journal-title":"Int. J. Biochem. Cell. Biol."},{"issue":"3","key":"99096_CR22","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1136\/gut.2005.069153","volume":"55","author":"J Foucher","year":"2006","unstructured":"Foucher, J. et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 55 (3), 403\u2013408 (2006).","journal-title":"Gut"},{"issue":"5","key":"99096_CR23","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1111\/j.1440-1746.2010.06612.x","volume":"26","author":"LA Adams","year":"2011","unstructured":"Adams, L. A. Biomarkers of liver fibrosis. J. Gastroenterol. Hepatol. 26 (5), 802\u2013809 (2011).","journal-title":"J. Gastroenterol. Hepatol."},{"issue":"41","key":"99096_CR24","doi-asserted-by":"publisher","first-page":"11567","DOI":"10.3748\/wjg.v21.i41.11567","volume":"21","author":"Y Lurie","year":"2015","unstructured":"Lurie, Y. et al. Non-invasive diagnosis of liver fibrosis and cirrhosis. World J. Gastroenterol. 21 (41), 11567\u201311583 (2015).","journal-title":"World J. Gastroenterol."},{"issue":"2","key":"99096_CR25","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1053\/jhep.2003.50346","volume":"38","author":"CT Wai","year":"2003","unstructured":"Wai, C. T. et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 38 (2), 518\u2013526 (2003).","journal-title":"Hepatology"},{"issue":"6","key":"99096_CR26","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1002\/hep.21178","volume":"43","author":"RK Sterling","year":"2006","unstructured":"Sterling, R. K. et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV\/HCV coinfection. Hepatology 43 (6), 1317\u20131325 (2006).","journal-title":"Hepatology"},{"issue":"8","key":"99096_CR27","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nri3862","volume":"15","author":"EJ Wherry","year":"2015","unstructured":"Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15 (8), 486\u2013499 (2015).","journal-title":"Nat. Rev. Immunol."},{"issue":"6","key":"99096_CR28","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/ni.2035","volume":"12","author":"EJ Wherry","year":"2011","unstructured":"Wherry, E. J. T cell exhaustion. Nat. Immunol. 12 (6), 492\u2013499 (2011).","journal-title":"Nat. Immunol."},{"issue":"4","key":"99096_CR29","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1111\/j.1365-2567.2010.03255.x","volume":"129","author":"JS Yi","year":"2010","unstructured":"Yi, J. S., Cox, M. A. & Zajac, A. J. T-cell exhaustion: characteristics, causes and conversion. Immunology 129 (4), 474\u2013481 (2010).","journal-title":"Immunology"},{"key":"99096_CR30","doi-asserted-by":"publisher","first-page":"760","DOI":"10.3389\/fimmu.2017.00760","volume":"8","author":"J Bi","year":"2017","unstructured":"Bi, J. & Tian, Z. NK Cell. Exhaustion Front. Immunol., 8: 760. (2017).","journal-title":"NK Cell. Exhaustion Front. Immunol."},{"issue":"5","key":"99096_CR31","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1097\/COH.0000000000000092","volume":"9","author":"S Moir","year":"2014","unstructured":"Moir, S. & Fauci, A. S. B-cell exhaustion in HIV infection: the role of immune activation. Curr. Opin. HIV AIDS. 9 (5), 472\u2013477 (2014).","journal-title":"Curr. Opin. HIV AIDS"},{"issue":"16","key":"99096_CR32","doi-asserted-by":"publisher","first-page":"5644","DOI":"10.3390\/ijms21165644","volume":"21","author":"J Kemming","year":"2020","unstructured":"Kemming, J., Thimme, R. & Neumann-Haefelin, C. Adaptive immune response against hepatitis C virus. Int. J. Mol. Sci. 21(16), 5644 (2020).","journal-title":"Int. J. Mol. Sci."},{"issue":"33","key":"99096_CR33","doi-asserted-by":"publisher","first-page":"14733","DOI":"10.1073\/pnas.1009731107","volume":"107","author":"HT Jin","year":"2010","unstructured":"Jin, H. T. et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl. Acad. Sci. U S A. 107 (33), 14733\u201314738 (2010).","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"issue":"2","key":"99096_CR34","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1056\/NEJMra1703481","volume":"378","author":"MA Postow","year":"2018","unstructured":"Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-Related adverse events associated with immune checkpoint Blockade. N Engl. J. Med. 378 (2), 158\u2013168 (2018).","journal-title":"N Engl. J. Med."},{"issue":"10","key":"99096_CR35","doi-asserted-by":"publisher","first-page":"3650","DOI":"10.3390\/ijms21103650","volume":"21","author":"F Schmitz","year":"2020","unstructured":"Schmitz, F., Wolf, D. & Holderried, T. A. W. The role of immune checkpoints after cellular therapy. Int. J. Mol. Sci. 21(10), 3650 (2020).","journal-title":"Int. J. Mol. Sci."},{"issue":"17","key":"99096_CR36","doi-asserted-by":"publisher","first-page":"3009","DOI":"10.2174\/0929867324666170804143706","volume":"26","author":"B Li","year":"2019","unstructured":"Li, B., Chan, H. L. & Chen, P. Immune checkpoint inhibitors: basics and challenges. Curr. Med. Chem. 26 (17), 3009\u20133025 (2019).","journal-title":"Curr. Med. Chem."},{"issue":"5","key":"99096_CR37","doi-asserted-by":"publisher","first-page":"1389","DOI":"10.3390\/ijms19051389","volume":"19","author":"T Shi","year":"2018","unstructured":"Shi, T. et al. Cancer immunotherapy: A focus on the regulation of immune checkpoints. Int. J. Mol. Sci., 19(5), 1389 (2018).","journal-title":"Int. J. Mol. Sci."},{"issue":"8","key":"99096_CR38","doi-asserted-by":"publisher","first-page":"799","DOI":"10.3390\/v12080799","volume":"12","author":"S Osuch","year":"2020","unstructured":"Osuch, S., Metzner, K. J. & Caraballo Cortes, K. Reversal of T cell exhaustion in chronic HCV infection. Viruses 12(8), 799 (2020).","journal-title":"Viruses"},{"key":"99096_CR39","doi-asserted-by":"publisher","first-page":"310","DOI":"10.3389\/fimmu.2015.00310","volume":"6","author":"SA Fuertes Marraco","year":"2015","unstructured":"Fuertes Marraco, S. A. et al. Inhibitory receptors beyond T cell exhaustion. Front. Immunol. 6, 310 (2015).","journal-title":"Front. Immunol."},{"issue":"4","key":"99096_CR40","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/nrc3239","volume":"12","author":"DM Pardoll","year":"2012","unstructured":"Pardoll, D. M. The Blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer. 12 (4), 252\u2013264 (2012).","journal-title":"Nat. Rev. Cancer"},{"issue":"7","key":"99096_CR41","doi-asserted-by":"publisher","first-page":"2957","DOI":"10.4049\/jimmunol.1100038","volume":"188","author":"PM Odorizzi","year":"2012","unstructured":"Odorizzi, P. M. & Wherry, E. J. Inhibitory receptors on lymphocytes: insights from infections. J. Immunol. 188 (7), 2957\u20132965 (2012).","journal-title":"J. Immunol."},{"issue":"1","key":"99096_CR42","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.immuni.2007.05.016","volume":"27","author":"MJ Butte","year":"2007","unstructured":"Butte, M. J. et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 27 (1), 111\u2013122 (2007).","journal-title":"Immunity"},{"issue":"10","key":"99096_CR43","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1038\/ni.2691","volume":"14","author":"CN Jenne","year":"2013","unstructured":"Jenne, C. N. & Kubes, P. Immune surveillance by the liver. Nat. Immunol. 14 (10), 996\u20131006 (2013).","journal-title":"Nat. Immunol."},{"issue":"10","key":"99096_CR44","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/s41575-023-00807-x","volume":"20","author":"L Hammerich","year":"2023","unstructured":"Hammerich, L. & Tacke, F. Hepatic inflammatory responses in liver fibrosis. Nat. Rev. Gastroenterol. Hepatol. 20 (10), 633\u2013646 (2023).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"99096_CR45","doi-asserted-by":"publisher","first-page":"1926","DOI":"10.3389\/fimmu.2019.01926","volume":"10","author":"A Vranjkovic","year":"2019","unstructured":"Vranjkovic, A. et al. Direct-Acting antiviral treatment of HCV infection does not resolve the dysfunction of Circulating CD8(+) T-Cells in advanced liver disease. Front. Immunol. 10, 1926 (2019).","journal-title":"Front. Immunol."},{"key":"99096_CR46","doi-asserted-by":"publisher","first-page":"205873842110610","DOI":"10.1177\/20587384211061051","volume":"35","author":"N Huang","year":"2021","unstructured":"Huang, N. et al. Splenic CD4(+) and CD8(+) T-cells highly expressed PD-1 and Tim-3 in cirrhotic patients with HCV infection and portal hypertension. Int. J. Immunopathol. Pharmacol. 35, 20587384211061051 (2021).","journal-title":"Int. J. Immunopathol. Pharmacol."},{"issue":"1","key":"99096_CR47","doi-asserted-by":"publisher","first-page":"16060","DOI":"10.1038\/s41598-020-73137-6","volume":"10","author":"S Osuch","year":"2020","unstructured":"Osuch, S. et al. Decrease of T-cells exhaustion markers programmed cell death-1 and T-cell Immunoglobulin and mucin domain-containing protein 3 and plasma IL-10 levels after successful treatment of chronic hepatitis C. Sci. Rep. 10 (1), 16060 (2020).","journal-title":"Sci. Rep."},{"issue":"7","key":"99096_CR48","doi-asserted-by":"publisher","first-page":"3723","DOI":"10.1128\/JVI.00006-15","volume":"89","author":"KL Clayton","year":"2015","unstructured":"Clayton, K. L. et al. Soluble T cell Immunoglobulin mucin domain 3 is shed from CD8\u2009+\u2009T cells by the Sheddase ADAM10, is increased in plasma during untreated HIV infection, and correlates with HIV disease progression. J. Virol. 89 (7), 3723\u20133736 (2015).","journal-title":"J. Virol."},{"issue":"7","key":"99096_CR49","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1097\/QAD.0000000000002165","volume":"33","author":"E Zilber","year":"2019","unstructured":"Zilber, E. et al. Soluble plasma programmed death 1 (PD-1) and Tim-3 in primary HIV infection. AIDS 33 (7), 1253\u20131256 (2019).","journal-title":"AIDS"},{"issue":"2","key":"99096_CR50","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.cellimm.2005.07.007","volume":"235","author":"C Nielsen","year":"2005","unstructured":"Nielsen, C. et al. Alternative splice variants of the human PD-1 gene. Cell. Immunol. 235 (2), 109\u2013116 (2005).","journal-title":"Cell. Immunol."},{"issue":"12","key":"99096_CR51","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/j.it.2003.10.001","volume":"24","author":"F Triebel","year":"2003","unstructured":"Triebel, F. LAG-3: a regulator of T-cell and DC responses and its use in therapeutic vaccination. Trends Immunol. 24 (12), 619\u2013622 (2003).","journal-title":"Trends Immunol."},{"issue":"5","key":"99096_CR52","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1080\/08820130902912332","volume":"38","author":"H Wu","year":"2009","unstructured":"Wu, H. et al. Soluble PD-1 is associated with aberrant regulation of T cells activation in aplastic anemia. Immunol. Invest. 38 (5), 408\u2013421 (2009).","journal-title":"Immunol. Invest."},{"issue":"12","key":"99096_CR53","doi-asserted-by":"publisher","first-page":"2699","DOI":"10.1084\/jem.20082429","volume":"205","author":"DA Hafler","year":"2008","unstructured":"Hafler, D. A. & Kuchroo, V. TIMs: central regulators of immune responses. J. Exp. Med. 205 (12), 2699\u20132701 (2008).","journal-title":"J. Exp. Med."},{"issue":"4","key":"99096_CR54","doi-asserted-by":"publisher","first-page":"331","DOI":"10.3343\/alm.2018.38.4.331","volume":"38","author":"HW Moon","year":"2018","unstructured":"Moon, H. W. et al. Usefulness of enhanced liver fibrosis, glycosylation isomer of Mac-2 binding protein, Galectin-3, and soluble suppression of tumorigenicity 2 for assessing liver fibrosis in chronic liver diseases. Ann. Lab. Med. 38 (4), 331\u2013337 (2018).","journal-title":"Ann. Lab. Med."},{"issue":"7","key":"99096_CR55","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1111\/jvh.13102","volume":"26","author":"WJ Jeng","year":"2019","unstructured":"Jeng, W. J. & Yang, H. I. Discrepant range of sPD-1 in different studies of chronic hepatitis B. A letter in response to soluble programmed death-1 is a useful indicator for inflammatory and fibrosis severity in chronic hepatitis B. J. Viral Hepat. 26 (7), 930 (2019).","journal-title":"J. Viral Hepat."},{"issue":"7","key":"99096_CR56","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1111\/jvh.13055","volume":"26","author":"L Zhou","year":"2019","unstructured":"Zhou, L. et al. Soluble programmed death-1 is a useful indicator for inflammatory and fibrosis severity in chronic hepatitis B. J. Viral Hepat. 26 (7), 795\u2013802 (2019).","journal-title":"J. Viral Hepat."},{"issue":"7","key":"99096_CR57","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1111\/jvh.13118","volume":"26","author":"L Zhou","year":"2019","unstructured":"Zhou, L. et al. Reply to the letter by Jeng et al. \u2018Discrepant range of sPD-1 in different studies of chronic hepatitis B\u2019. J. Viral Hepat. 26 (7), 931\u2013932 (2019).","journal-title":"J. Viral Hepat."},{"issue":"1","key":"99096_CR58","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1186\/s40425-018-0449-0","volume":"6","author":"D Gu","year":"2018","unstructured":"Gu, D. et al. Soluble immune checkpoints in cancer: production, function and biological significance. J. Immunother Cancer. 6 (1), 132 (2018).","journal-title":"J. Immunother Cancer"},{"issue":"1","key":"99096_CR59","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.cellimm.2014.05.006","volume":"290","author":"S Dai","year":"2014","unstructured":"Dai, S. et al. The PD-1\/PD-Ls pathway and autoimmune diseases. Cell. Immunol. 290 (1), 72\u201379 (2014).","journal-title":"Cell. Immunol."},{"issue":"4","key":"99096_CR60","doi-asserted-by":"publisher","first-page":"444","DOI":"10.5937\/jomb0-24692","volume":"39","author":"S Liu","year":"2020","unstructured":"Liu, S. et al. Soluble programmed death-1 (sPD-1) and programmed death ligand 1 (sPD-L1) as potential biomarkers for the diagnosis and prognosis of glioma patients. J. Med. Biochem. 39 (4), 444\u2013451 (2020).","journal-title":"J. Med. Biochem."},{"issue":"1","key":"99096_CR61","doi-asserted-by":"publisher","first-page":"251","DOI":"10.3892\/etm.2015.2876","volume":"11","author":"Y Li","year":"2016","unstructured":"Li, Y. et al. Role of soluble programmed death-1 (sPD-1) and sPD-ligand 1 in patients with cystic echinococcosis. Exp. Ther. Med. 11 (1), 251\u2013256 (2016).","journal-title":"Exp. Ther. Med."},{"issue":"4","key":"99096_CR62","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.3892\/mmr.2013.1326","volume":"7","author":"D Wang","year":"2013","unstructured":"Wang, D. et al. Aberrant production of soluble inducible T-cell co-stimulator (sICOS) and soluble programmed cell death protein 1 (sPD-1) in patients with chronic hepatitis C. Mol. Med. Rep. 7 (4), 1197\u20131202 (2013).","journal-title":"Mol. Med. Rep."},{"issue":"12","key":"99096_CR63","doi-asserted-by":"publisher","first-page":"e0238540","DOI":"10.1371\/journal.pone.0238540","volume":"15","author":"K Migita","year":"2020","unstructured":"Migita, K. et al. Association of soluble T cell Immunoglobulin domain and mucin-3 (sTIM-3) and mac-2 binding protein glycosylation isomer (M2BPGi) in patients with autoimmune hepatitis. PLoS One. 15 (12), e0238540 (2020).","journal-title":"PLoS One"},{"key":"99096_CR64","doi-asserted-by":"publisher","first-page":"754961","DOI":"10.3389\/fimmu.2021.754961","volume":"12","author":"M Guo","year":"2021","unstructured":"Guo, M. et al. Serum LAG-3 predicts outcome and treatment response in hepatocellular carcinoma patients with transarterial chemoembolization. Front. Immunol. 12, 754961 (2021).","journal-title":"Front. Immunol."},{"issue":"12","key":"99096_CR65","doi-asserted-by":"publisher","first-page":"1788","DOI":"10.1111\/jgh.13017","volume":"30","author":"N Chen","year":"2015","unstructured":"Chen, N. et al. Lymphocyte activation gene 3 negatively regulates the function of intrahepatic hepatitis C virus-specific CD8\u2009+\u2009T cells. J. Gastroenterol. Hepatol. 30 (12), 1788\u20131795 (2015).","journal-title":"J. Gastroenterol. Hepatol."},{"issue":"9","key":"99096_CR66","doi-asserted-by":"publisher","first-page":"101513","DOI":"10.1016\/j.isci.2020.101513","volume":"23","author":"CIA Okwor","year":"2020","unstructured":"Okwor, C. I. A. et al. Expression of inhibitory receptors on T and NK cells defines immunological phenotypes of HCV patients with advanced liver fibrosis. iScience 23 (9), 101513 (2020).","journal-title":"iScience"},{"key":"99096_CR67","doi-asserted-by":"publisher","first-page":"p6275987","DOI":"10.1155\/2017\/6275987","volume":"2017","author":"R Lukic","year":"2017","unstructured":"Lukic, R. et al. Potential hepatoprotective role of Galectin-3 during HCV infection in End-Stage renal disease patients. Dis. Markers. 2017, p6275987 (2017).","journal-title":"Dis. Markers"},{"key":"99096_CR68","doi-asserted-by":"publisher","first-page":"744518","DOI":"10.3389\/fmed.2021.744518","volume":"8","author":"Y An","year":"2021","unstructured":"An, Y. et al. Role of galectins in the liver diseases: A systematic review and Meta-Analysis. Front. Med. (Lausanne). 8, 744518 (2021).","journal-title":"Front. Med. (Lausanne)"},{"issue":"4","key":"99096_CR69","doi-asserted-by":"publisher","first-page":"444","DOI":"10.15403\/jgld-4341","volume":"31","author":"K Weigand","year":"2022","unstructured":"Weigand, K. et al. Serum Galectin-3 in hepatitis C virus infection declines after successful virus eradication by Direct-Acting antiviral therapy. J. Gastrointestin Liver Dis. 31 (4), 444\u2013452 (2022).","journal-title":"J. Gastrointestin Liver Dis."},{"issue":"1","key":"99096_CR70","doi-asserted-by":"publisher","first-page":"47","DOI":"10.4103\/1319-3767.151228","volume":"21","author":"M Ulu","year":"2015","unstructured":"Ulu, M. et al. Prognostic significance of serum galectin-3 levels in patients with hepatocellular cancer and chronic viral hepatitis. Saudi J. Gastroenterol. 21 (1), 47\u201350 (2015).","journal-title":"Saudi J. Gastroenterol."},{"issue":"24","key":"99096_CR71","first-page":"9467","volume":"26","author":"C Mermutluoglu","year":"2022","unstructured":"Mermutluoglu, C. et al. Evulation of prolidase enzyme, and galectin levels as a marker for fibrosis in patients with chronic hepatitis B. Eur. Rev. Med. Pharmacol. Sci. 26 (24), 9467\u20139472 (2022).","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"issue":"2","key":"99096_CR72","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1007\/s13337-021-00697-0","volume":"32","author":"C Bhattacharjee","year":"2021","unstructured":"Bhattacharjee, C. et al. Current therapeutics against HCV. Virusdisease 32 (2), 228\u2013243 (2021).","journal-title":"Virusdisease"},{"issue":"3","key":"99096_CR73","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1016\/j.jhep.2014.05.043","volume":"61","author":"B Martin","year":"2014","unstructured":"Martin, B. et al. Restoration of HCV-specific CD8\u2009+\u2009T cell function by interferon-free therapy. J. Hepatol. 61 (3), 538\u2013543 (2014).","journal-title":"J. Hepatol."},{"issue":"11","key":"99096_CR74","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1111\/apt.15732","volume":"51","author":"J Xia","year":"2020","unstructured":"Xia, J. et al. Profiles of serum soluble programmed death-1 and programmed death-ligand 1 levels in chronic hepatitis B virus-infected patients with different disease phases and after anti-viral treatment. Aliment. Pharmacol. Ther. 51 (11), 1180\u20131187 (2020).","journal-title":"Aliment. Pharmacol. Ther."},{"issue":"1","key":"99096_CR75","doi-asserted-by":"publisher","first-page":"39","DOI":"10.20411\/pai.v4i1.267","volume":"4","author":"MTM Shata","year":"2019","unstructured":"Shata, M. T. M. et al. HBV and HIV\/HBV infected patients have distinct immune exhaustion and apoptotic serum biomarker profiles. Pathog Immun. 4 (1), 39\u201365 (2019).","journal-title":"Pathog Immun."},{"key":"99096_CR76","doi-asserted-by":"publisher","first-page":"1123342","DOI":"10.3389\/fimmu.2023.1123342","volume":"14","author":"CY Chiu","year":"2023","unstructured":"Chiu, C. Y. et al. Soluble immune checkpoints as correlates for HIV persistence and T cell function in people with HIV on antiretroviral therapy. Front. Immunol. 14, 1123342 (2023).","journal-title":"Front. Immunol."},{"issue":"2","key":"99096_CR77","doi-asserted-by":"publisher","first-page":"ofaa033","DOI":"10.1093\/ofid\/ofaa033","volume":"7","author":"H Hoel","year":"2020","unstructured":"Hoel, H. et al. Soluble T-Cell Immunoglobulin mucin Domain-3 is associated with hepatitis C virus coinfection and Low-Grade inflammation during chronic human immunodeficiency virus infection. Open. Forum Infect. Dis. 7 (2), ofaa033 (2020).","journal-title":"Open. Forum Infect. Dis."},{"issue":"4","key":"99096_CR78","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1053\/j.gastro.2017.06.012","volume":"153","author":"F Kanwal","year":"2017","unstructured":"Kanwal, F. et al. Risk of hepatocellular Cancer in HCV patients treated with Direct-Acting antiviral agents. Gastroenterology 153 (4), 996\u20131005e1 (2017).","journal-title":"Gastroenterology"},{"issue":"7","key":"99096_CR79","doi-asserted-by":"publisher","first-page":"e0254243","DOI":"10.1371\/journal.pone.0254243","volume":"16","author":"M Llorens-Revull","year":"2021","unstructured":"Llorens-Revull, M. et al. Partial restoration of immune response in hepatitis C patients after viral clearance by direct-acting antiviral therapy. PLoS One. 16 (7), e0254243 (2021).","journal-title":"PLoS One"},{"issue":"4","key":"99096_CR80","doi-asserted-by":"publisher","first-page":"1486","DOI":"10.3892\/ijo.2012.1551","volume":"41","author":"D Bellarosa","year":"2012","unstructured":"Bellarosa, D. et al. SAHA\/Vorinostat induces the expression of the CD137 receptor\/ligand system and enhances apoptosis mediated by soluble CD137 receptor in a human breast cancer cell line. Int. J. Oncol. 41 (4), 1486\u20131494 (2012).","journal-title":"Int. J. Oncol."},{"key":"99096_CR81","doi-asserted-by":"publisher","first-page":"21","DOI":"10.3389\/fimmu.2016.00021","volume":"7","author":"M Krishna","year":"2016","unstructured":"Krishna, M. & Nadler, S. G. Immunogenicity to Biotherapeutics - The role of Anti-drug immune complexes. Front. Immunol. 7, 21 (2016).","journal-title":"Front. Immunol."},{"issue":"1","key":"99096_CR82","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1186\/s12967-016-1071-x","volume":"14","author":"SF Monaghan","year":"2016","unstructured":"Monaghan, S. F. et al. Soluble programmed cell death receptor-1 (sPD-1): a potential biomarker with anti-inflammatory properties in human and experimental acute respiratory distress syndrome (ARDS). J. Transl Med. 14 (1), 312 (2016).","journal-title":"J. Transl Med."},{"issue":"2","key":"99096_CR83","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1016\/j.alit.2016.08.008","volume":"66","author":"R Nasiri Kalmarzi","year":"2017","unstructured":"Nasiri Kalmarzi, R. et al. Inverse correlation of soluble programmed cell death-1 ligand-1 (sPD-L1) with eosinophil count and clinical severity in allergic rhinitis patients. Allergol. Int. 66 (2), 326\u2013331 (2017).","journal-title":"Allergol. Int."},{"key":"99096_CR84","doi-asserted-by":"publisher","first-page":"587460","DOI":"10.3389\/fimmu.2020.587460","volume":"11","author":"M Khan","year":"2020","unstructured":"Khan, M. et al. Soluble PD-1: predictive, prognostic, and therapeutic value for Cancer immunotherapy. Front. Immunol. 11, 587460 (2020).","journal-title":"Front. Immunol."},{"issue":"11","key":"99096_CR85","doi-asserted-by":"publisher","first-page":"e95870","DOI":"10.1371\/journal.pone.0095870","volume":"9","author":"HY Cheng","year":"2014","unstructured":"Cheng, H. Y. et al. Circulating programmed death-1 as a marker for sustained high hepatitis B viral load and risk of hepatocellular carcinoma. PLoS One. 9 (11), e95870 (2014).","journal-title":"PLoS One"},{"issue":"28","key":"99096_CR86","doi-asserted-by":"publisher","first-page":"46020","DOI":"10.18632\/oncotarget.17546","volume":"8","author":"N Li","year":"2017","unstructured":"Li, N. et al. Circulating soluble programmed death-1 levels May differentiate immune-tolerant phase from other phases and hepatocellular carcinoma from other clinical diseases in chronic hepatitis B virus infection. Oncotarget 8 (28), 46020\u201346033 (2017).","journal-title":"Oncotarget"},{"key":"99096_CR87","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/bs.apha.2021.01.002","volume":"91","author":"JB Jacob","year":"2021","unstructured":"Jacob, J. B., Jacob, M. K. & Parajuli, P. Review of immune checkpoint inhibitors in immuno-oncology. Adv. Pharmacol. 91, 111\u2013139 (2021).","journal-title":"Adv. Pharmacol."},{"issue":"4","key":"99096_CR88","doi-asserted-by":"publisher","first-page":"144","DOI":"10.5114\/ceh.2016.63871","volume":"2","author":"R Flisiak","year":"2016","unstructured":"Flisiak, R. et al. Prevalence of HCV genotypes in Poland - the epiter study. Clin. Exp. Hepatol. 2 (4), 144\u2013148 (2016).","journal-title":"Clin. Exp. Hepatol."},{"issue":"1","key":"99096_CR89","doi-asserted-by":"publisher","first-page":"2","DOI":"10.5114\/ceh.2016.58849","volume":"2","author":"P Urbanek","year":"2016","unstructured":"Urbanek, P. et al. Epidemiology of HCV infection in the central European region. Clin. Exp. Hepatol. 2 (1), 2\u20136 (2016).","journal-title":"Clin. Exp. Hepatol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-99096-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-99096-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-99096-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T16:02:46Z","timestamp":1746201766000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-99096-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,2]]},"references-count":89,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["99096"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-99096-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,2]]},"assertion":[{"value":"16 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15436"}}