{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T01:45:54Z","timestamp":1766367954040,"version":"3.48.0"},"reference-count":66,"publisher":"Walter de Gruyter GmbH","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Non-alcoholic fatty liver disease (NAFLD) is a globally widespread disease. Recent investigations have highlighted a close association between immunity and NAFLD, but the causality between them has not been thoroughly examined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A total of 731 immunological traits and NAFLD cohorts were derived from genome-wide association study summary data, and single nucleotide polymorphisms significantly associated with immune traits were identified as instrumental variables. Moreover, 731 phenotypes include absolute cell counts, median fluorescence intensity (MFI), morphological parameters, and relative cell counts. The bidirectional two-sample Mendelian randomization (MR) was performed primarily using the inverse-variance weighted methods, and sensitivity analysis was carried out simultaneously.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Four immunophenotypes were identified to exert a protective effect against NAFLD, including HLA-DR\n                      <jats:sup>+<\/jats:sup>\n                      CD4\n                      <jats:sup>+<\/jats:sup>\n                      %lymphocytes, SSC-A on CD4\n                      <jats:sup>+<\/jats:sup>\n                      , CD24 MFI on IgD\n                      <jats:sup>\u2212<\/jats:sup>\n                      CD38\n                      <jats:sup>\u2212<\/jats:sup>\n                      , and CD8 MFI on CD28\n                      <jats:sup>\u2212<\/jats:sup>\n                      CD8\n                      <jats:sup>br<\/jats:sup>\n                      . Seven immunophenotypes were identified to be hazardous, including CD28\n                      <jats:sup>+<\/jats:sup>\n                      CD45RA\n                      <jats:sup>+<\/jats:sup>\n                      CD8\n                      <jats:sup>dim<\/jats:sup>\n                      %CD8\n                      <jats:sup>dim<\/jats:sup>\n                      , CD127 MFI on CD28\n                      <jats:sup>+<\/jats:sup>\n                      DN (CD4\n                      <jats:sup>\u2212<\/jats:sup>\n                      CD8\n                      <jats:sup>\u2212<\/jats:sup>\n                      ), CD20 MFI on IgD\n                      <jats:sup>+<\/jats:sup>\n                      CD38\n                      <jats:sup>br<\/jats:sup>\n                      , CD20 MFI on transitional, IgD MFI on transitional, CD3 MFI on central memory CD8\n                      <jats:sup>br<\/jats:sup>\n                      , and CD45 MFI on CD33\n                      <jats:sup>br<\/jats:sup>\n                      HLA-DR\n                      <jats:sup>+<\/jats:sup>\n                      CD14\n                      <jats:sup>\u2212<\/jats:sup>\n                      . However, reverse MR showed NAFLD had no causal effect on immunophenotypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The study demonstrated a potential causal link between several immunophenotypes and NAFLD, which contributes to advancing research and treatment of NAFLD based on immune-mediated mechanisms.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1515\/med-2025-1154","type":"journal-article","created":{"date-parts":[[2025,2,19]],"date-time":"2025-02-19T14:58:31Z","timestamp":1739977111000},"source":"Crossref","is-referenced-by-count":0,"title":["Examination of the causal role of immune cells in non-alcoholic fatty liver disease by a bidirectional Mendelian randomization study"],"prefix":"10.1515","volume":"20","author":[{"given":"Yu","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University , Nanning , 530021, Guangxi , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaodan","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Clinical Experimental Medicine, The First Affiliated Hospital of Guangxi Medical University , Nanning , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianing","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University , Nanning , 530021, Guangxi , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiquan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University , Nanning , 530021, Guangxi , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangfu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University , Nanning , 530021, Guangxi , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhixi","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University , Nanning , 530021, Guangxi , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University , Nanning , 530021, Guangxi , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lichun","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University , Nanning , 530021, Guangxi , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingling","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Clinical Experimental Medicine, The First Affiliated Hospital of Guangxi Medical University , Nanning , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoping","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Guangxi Medical University , Nanning , 530021, Guangxi , China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"374","published-online":{"date-parts":[[2025,2,19]]},"reference":[{"key":"2025122201305442214_j_med-2025-1154_ref_001","doi-asserted-by":"crossref","unstructured":"Hepatology TL. Redefining non-alcoholic fatty liver disease: what\u2019s in a name? Lancet Gastroenterol Hepatol. 2020;5(5):419. 10.1016\/s2468-1253(20)30091-1.","DOI":"10.1016\/S2468-1253(20)30091-1"},{"key":"2025122201305442214_j_med-2025-1154_ref_002","doi-asserted-by":"crossref","unstructured":"Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328\u201357. 10.1002\/hep.29367.","DOI":"10.1002\/hep.29367"},{"key":"2025122201305442214_j_med-2025-1154_ref_003","doi-asserted-by":"crossref","unstructured":"Han X, Luo Z, Wang W, Zheng P, Li T, Mei Z, et al. Efficacy and safety of rifaximin versus placebo or other active drugs in critical ill patients with hepatic encephalopathy. Front Pharmacol. 2021;12:696065. 10.3389\/fphar.2021.696065.","DOI":"10.3389\/fphar.2021.696065"},{"key":"2025122201305442214_j_med-2025-1154_ref_004","doi-asserted-by":"crossref","unstructured":"Liang Z, Li T, Jiang S, Xu J, Di W, Yang Z, et al. AMPK: a novel target for treating hepatic fibrosis. Oncotarget. 2017;8(37):62780\u201392. 10.18632\/oncotarget.19376.","DOI":"10.18632\/oncotarget.19376"},{"key":"2025122201305442214_j_med-2025-1154_ref_005","doi-asserted-by":"crossref","unstructured":"Manikat R, Ahmed A, Kim D. Up-to-date global epidemiology of nonalcoholic fatty liver disease. Hepatobiliary Surg Nutr. 2023;12(6):956\u20139. 10.21037\/hbsn-23-548.","DOI":"10.21037\/hbsn-23-548"},{"key":"2025122201305442214_j_med-2025-1154_ref_006","doi-asserted-by":"crossref","unstructured":"McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73(Suppl 1):4\u201313. 10.1002\/hep.31288.","DOI":"10.1002\/hep.31288"},{"key":"2025122201305442214_j_med-2025-1154_ref_007","doi-asserted-by":"crossref","unstructured":"Tilg H, Adolph TE, Dudek M, Knolle P. Non-alcoholic fatty liver disease: the interplay between metabolism, microbes and immunity. Nat Metab. 2021;3(12):1596\u2013607. 10.1038\/s42255-021-00501-9.","DOI":"10.1038\/s42255-021-00501-9"},{"key":"2025122201305442214_j_med-2025-1154_ref_008","doi-asserted-by":"crossref","unstructured":"Ortiz-L\u00f3pez N, Fuenzalida C, Dufeu MS, Pinto-Le\u00f3n A, Escobar A, Poniachik J, et al. The immune response as a therapeutic target in non-alcoholic fatty liver disease. Front Immunol. 2022;13:954869. 10.3389\/fimmu.2022.954869.","DOI":"10.3389\/fimmu.2022.954869"},{"key":"2025122201305442214_j_med-2025-1154_ref_009","doi-asserted-by":"crossref","unstructured":"Yang Y, Zhang S, Fan C, Yi W, Jiang S, Di S, et al. Protective role of silent information regulator 1 against hepatic ischemia: effects on oxidative stress injury, inflammatory response, and MAPKs. Expert Opin Ther Targets. 2016;20(5):519\u201331. 10.1517\/14728222.2016.1153067.","DOI":"10.1517\/14728222.2016.1153067"},{"key":"2025122201305442214_j_med-2025-1154_ref_010","doi-asserted-by":"crossref","unstructured":"Brenner C, Galluzzi L, Kepp O, Kroemer G. Decoding cell death signals in liver inflammation. J Hepatol. 2013;59(3):583\u201394. 10.1016\/j.jhep.2013.03.033.","DOI":"10.1016\/j.jhep.2013.03.033"},{"key":"2025122201305442214_j_med-2025-1154_ref_011","doi-asserted-by":"crossref","unstructured":"Ma DW, Ha J, Yoon KS, Kang I, Choi TG, Kim SS. Innate immune system in the pathogenesis of non-alcoholic fatty liver disease. Nutrients. 2023;15(9):2068. 10.3390\/nu15092068.","DOI":"10.3390\/nu15092068"},{"key":"2025122201305442214_j_med-2025-1154_ref_012","doi-asserted-by":"crossref","unstructured":"Sutti S, Jindal A, Locatelli I, Vacchiano M, Gigliotti L, Bozzola C, et al. Adaptive immune responses triggered by oxidative stress contribute to hepatic inflammation in NASH. Hepatology. 2014;59(3):886\u201397. 10.1002\/hep.26749.","DOI":"10.1002\/hep.26749"},{"key":"2025122201305442214_j_med-2025-1154_ref_013","doi-asserted-by":"crossref","unstructured":"Sanderson E, Glymour MM, Holmes MV, Kang H, Morrison J, Munaf\u00f2 MR, et al. Mendelian randomization. Nat Rev Methods Primers. 2022;2(1):6. 10.1038\/s43586-021-00092-5.","DOI":"10.1038\/s43586-021-00092-5"},{"key":"2025122201305442214_j_med-2025-1154_ref_014","doi-asserted-by":"crossref","unstructured":"Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531(7593):253\u20137. 10.1038\/nature16969.","DOI":"10.1038\/nature16969"},{"key":"2025122201305442214_j_med-2025-1154_ref_015","doi-asserted-by":"crossref","unstructured":"Dywicki J, Buitrago-Molina LE, Noyan F, Davalos-Misslitz AC, Hupa-Breier KL, Lieber M, et al. The detrimental role of regulatory T cells in nonalcoholic steatohepatitis. Hepatol Commun. 2022;6(2):320\u201333. 10.1002\/hep4.1807.","DOI":"10.1002\/hep4.1807"},{"key":"2025122201305442214_j_med-2025-1154_ref_016","doi-asserted-by":"crossref","unstructured":"Lalazar G, Mizrahi M, Turgeman I, Adar T, Ben Ya\u2019acov A, Shabat Y, et al. Oral administration of OKT3 MAb to patients with NASH, promotes regulatory T-cell induction, and alleviates insulin resistance: results of a phase IIa blinded placebo-controlled trial. J Clin Immunol. 2015;35(4):399\u2013407. 10.1007\/s10875-015-0160-6.","DOI":"10.1007\/s10875-015-0160-6"},{"key":"2025122201305442214_j_med-2025-1154_ref_017","doi-asserted-by":"crossref","unstructured":"Diedrich T, Kummer S, Galante A, Drolz A, Schlicker V, Lohse AW, et al. Characterization of the immune cell landscape of patients with NAFLD. PLoS ONE. 2020;15(3):e0230307. 10.1371\/journal.pone.0230307.","DOI":"10.1371\/journal.pone.0230307"},{"key":"2025122201305442214_j_med-2025-1154_ref_018","doi-asserted-by":"crossref","unstructured":"Ebrahim S, Davey Smith G. Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology? Hum Genet. 2008;123(1):15\u201333. 10.1007\/s00439-007-0448-6.","DOI":"10.1007\/s00439-007-0448-6"},{"key":"2025122201305442214_j_med-2025-1154_ref_019","doi-asserted-by":"crossref","unstructured":"Xu G, Xu Y, Zheng T, Liu T. Type 2 diabetes and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study. Sci Rep. 2024;14(1):5149. 10.1038\/s41598-024-55869-x.","DOI":"10.1038\/s41598-024-55869-x"},{"key":"2025122201305442214_j_med-2025-1154_ref_020","doi-asserted-by":"crossref","unstructured":"Orr\u00f9 V, Steri M, Sidore C, Marongiu M, Serra V, Olla S, et al. Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet. 2020;52(10):1036\u201345. 10.1038\/s41588-020-0684-4.","DOI":"10.1038\/s41588-020-0684-4"},{"key":"2025122201305442214_j_med-2025-1154_ref_021","doi-asserted-by":"crossref","unstructured":"Sidore C, Busonero F, Maschio A, Porcu E, Naitza S, Zoledziewska M, et al. Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers. Nat Genet. 2015;47(11):1272\u201381. 10.1038\/ng.3368.","DOI":"10.1038\/ng.3368"},{"key":"2025122201305442214_j_med-2025-1154_ref_022","doi-asserted-by":"crossref","unstructured":"Ghodsian N, Abner E, Emdin CA, Gobeil \u00c9, Taba N, Haas ME, et al. Electronic health record-based genome-wide meta-analysis provides insights on the genetic architecture of non-alcoholic fatty liver disease. Cell Rep Med. 2021;2(11):100437. 10.1016\/j.xcrm.2021.100437.","DOI":"10.1016\/j.xcrm.2021.100437"},{"key":"2025122201305442214_j_med-2025-1154_ref_023","doi-asserted-by":"crossref","unstructured":"Shi X, Wang T, Teng D, Hou S, Lin N. A mendelian randomization study investigates the causal relationship between immune cell phenotypes and cerebral aneurysm. Front Genet. 2024;15:1333855. 10.3389\/fgene.2024.1333855.","DOI":"10.3389\/fgene.2024.1333855"},{"key":"2025122201305442214_j_med-2025-1154_ref_024","doi-asserted-by":"crossref","unstructured":"Kamat MA, Blackshaw JA, Young R, Surendran P, Burgess S, Danesh J, et al. PhenoScanner V2: an expanded tool for searching human genotype-phenotype associations. Bioinformatics. 2019;35(22):4851\u20133. 10.1093\/bioinformatics\/btz469.","DOI":"10.1093\/bioinformatics\/btz469"},{"key":"2025122201305442214_j_med-2025-1154_ref_025","doi-asserted-by":"crossref","unstructured":"Palmer TM, Sterne JA, Harbord RM, Lawlor DA, Sheehan NA, Meng S, et al. Instrumental variable estimation of causal risk ratios and causal odds ratios in Mendelian randomization analyses. Am J Epidemiol. 2011;173(12):1392\u2013403. 10.1093\/aje\/kwr026.","DOI":"10.1093\/aje\/kwr026"},{"key":"2025122201305442214_j_med-2025-1154_ref_026","doi-asserted-by":"crossref","unstructured":"Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304\u201314. 10.1002\/gepi.21965.","DOI":"10.1002\/gepi.21965"},{"key":"2025122201305442214_j_med-2025-1154_ref_027","doi-asserted-by":"crossref","unstructured":"Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017;46(6):1985\u201398. 10.1093\/ije\/dyx102.","DOI":"10.1093\/ije\/dyx102"},{"key":"2025122201305442214_j_med-2025-1154_ref_028","doi-asserted-by":"crossref","unstructured":"Cho Y, Haycock PC, Sanderson E, Gaunt TR, Zheng J, Morris AP, et al. Exploiting horizontal pleiotropy to search for causal pathways within a Mendelian randomization framework. Nat Commun. 2020;11(1):1010. 10.1038\/s41467-020-14452-4.","DOI":"10.1038\/s41467-020-14452-4"},{"key":"2025122201305442214_j_med-2025-1154_ref_029","doi-asserted-by":"crossref","unstructured":"Burgess S, Thompson SG. Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol. 2017;32(5):377\u201389. 10.1007\/s10654-017-0255-x.","DOI":"10.1007\/s10654-017-0255-x"},{"key":"2025122201305442214_j_med-2025-1154_ref_030","doi-asserted-by":"crossref","unstructured":"Sookoian S, Pirola CJ. Genetics in non-alcoholic fatty liver disease: The role of risk alleles through the lens of immune response. Clin Mol Hepatol. 2023;29(Suppl):S184\u201395. 10.3350\/cmh.2022.0318.","DOI":"10.3350\/cmh.2022.0318"},{"key":"2025122201305442214_j_med-2025-1154_ref_031","doi-asserted-by":"crossref","unstructured":"Kado A, Tsutsumi T, Yotsuyanagi H, Ikeuchi K, Okushin K, Moriya K, et al. Differential peripheral memory T cell subsets sensitively indicate the severity of nonalcoholic fatty liver disease. Hepatol Res. 2024;54(6):525\u201339. 10.1111\/hepr.14009.","DOI":"10.1111\/hepr.14009"},{"key":"2025122201305442214_j_med-2025-1154_ref_032","doi-asserted-by":"crossref","unstructured":"Hu Y, Zhang H, Li J, Cong X, Chen Y, He G, et al. Gut-derived lymphocyte recruitment to liver and induce liver injury in non-alcoholic fatty liver disease mouse model. J Gastroenterol Hepatol. 2016;31(3):676\u201384. 10.1111\/jgh.13183.","DOI":"10.1111\/jgh.13183"},{"key":"2025122201305442214_j_med-2025-1154_ref_033","doi-asserted-by":"crossref","unstructured":"Weston CJ, Shepherd EL, Claridge LC, Rantakari P, Curbishley SM, Tomlinson JW, et al. Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. J Clin Invest. 2015;125(2):501\u201320. 10.1172\/jci73722.","DOI":"10.1172\/JCI73722"},{"key":"2025122201305442214_j_med-2025-1154_ref_034","doi-asserted-by":"crossref","unstructured":"Inzaugarat ME, Ferreyra Solari NE, Billordo LA, Abecasis R, Gadano AC, Cher\u00f1avsky AC. Altered phenotype and functionality of circulating immune cells characterize adult patients with nonalcoholic steatohepatitis. J Clin Immunol. 2011;31(6):1120\u201330. 10.1007\/s10875-011-9571-1.","DOI":"10.1007\/s10875-011-9571-1"},{"key":"2025122201305442214_j_med-2025-1154_ref_035","doi-asserted-by":"crossref","unstructured":"Her Z, Tan JHL, Lim YS, Tan SY, Chan XY, Tan WWS, et al. CD4(+) T cells mediate the development of liver fibrosis in high fat diet-induced NAFLD in humanized mice. Front Immunol. 2020;11:580968. 10.3389\/fimmu.2020.580968.","DOI":"10.3389\/fimmu.2020.580968"},{"key":"2025122201305442214_j_med-2025-1154_ref_036","doi-asserted-by":"crossref","unstructured":"Brockmann L, Soukou S, Steglich B, Czarnewski P, Zhao L, Wende S, et al. Molecular and functional heterogeneity of IL-10-producing CD4(+) T cells. Nat Commun. 2018;9(1):5457. 10.1038\/s41467-018-07581-4.","DOI":"10.1038\/s41467-018-07581-4"},{"key":"2025122201305442214_j_med-2025-1154_ref_037","doi-asserted-by":"crossref","unstructured":"Neumann K, Rudolph C, Neumann C, Janke M, Amsen D, Scheffold A. Liver sinusoidal endothelial cells induce immunosuppressive IL-10-producing Th1 cells via the Notch pathway. Eur J Immunol. 2015;45(7):2008\u201316. 10.1002\/eji.201445346.","DOI":"10.1002\/eji.201445346"},{"key":"2025122201305442214_j_med-2025-1154_ref_038","doi-asserted-by":"crossref","unstructured":"Chang J, Kunkel SL, Chang CH. Negative regulation of MyD88-dependent signaling by IL-10 in dendritic cells. Proc Natl Acad Sci U S A. 2009;106(43):18327\u201332. 10.1073\/pnas.0905815106.","DOI":"10.1073\/pnas.0905815106"},{"key":"2025122201305442214_j_med-2025-1154_ref_039","doi-asserted-by":"crossref","unstructured":"Jiang Q, Yang G, Xiao F, Xie J, Wang S, Lu L, et al. Role of Th22 cells in the pathogenesis of autoimmune diseases. Front Immunol. 2021;12:688066. 10.3389\/fimmu.2021.688066.","DOI":"10.3389\/fimmu.2021.688066"},{"key":"2025122201305442214_j_med-2025-1154_ref_040","doi-asserted-by":"crossref","unstructured":"Rolla S, Alchera E, Imarisio C, Bardina V, Valente G, Cappello P, et al. The balance between IL-17 and IL-22 produced by liver-infiltrating T-helper cells critically controls NASH development in mice. Clin Sci (Lond). 2016;130(3):193\u2013203. 10.1042\/cs20150405.","DOI":"10.1042\/CS20150405"},{"key":"2025122201305442214_j_med-2025-1154_ref_041","doi-asserted-by":"crossref","unstructured":"Strioga M, Pasukoniene V, Characiejus D. CD8+ CD28- and CD8+ CD57+ T cells and their role in health and disease. Immunology. 2011;134(1):17\u201332. 10.1111\/j.1365-2567.2011.03470.x.","DOI":"10.1111\/j.1365-2567.2011.03470.x"},{"key":"2025122201305442214_j_med-2025-1154_ref_042","doi-asserted-by":"crossref","unstructured":"Tulunay A, Yavuz S, Direskeneli H, Eksioglu-Demiralp E. CD8+ CD28-, suppressive T cells in systemic lupus erythematosus. Lupus. 2008;17(7):630\u20137. 10.1177\/0961203308089400.","DOI":"10.1177\/0961203308089400"},{"key":"2025122201305442214_j_med-2025-1154_ref_043","doi-asserted-by":"crossref","unstructured":"Lin YX, Wang LL, Yan LN, Cai P, Li B, Wen TF, et al. Analysis of CD8+ CD28- T-suppressor cells in living donor liver transplant recipients. Hepatobiliary Pancreat Dis Int. 2009;8(3):241\u20136.","DOI":"10.1016\/j.transproceed.2009.09.072"},{"key":"2025122201305442214_j_med-2025-1154_ref_044","doi-asserted-by":"crossref","unstructured":"Chang CC, Ciubotariu R, Manavalan JS, Yuan J, Colovai AI, Piazza F, et al. Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol. 2002;3(3):237\u201343. 10.1038\/ni760.","DOI":"10.1038\/ni760"},{"key":"2025122201305442214_j_med-2025-1154_ref_045","doi-asserted-by":"crossref","unstructured":"Yang N, Li Z, Jiao Z, Gu P, Zhou Y, Lu L, et al. A Trichosanthin-derived peptide suppresses type 1 immune responses by TLR2-dependent activation of CD8(+)CD28(\u2212) Tregs. Clin Immunol. 2014;153(2):277\u201387. 10.1016\/j.clim.2014.05.005.","DOI":"10.1016\/j.clim.2014.05.005"},{"key":"2025122201305442214_j_med-2025-1154_ref_046","doi-asserted-by":"crossref","unstructured":"Crompton T, Outram SV, Buckland J, Owen MJ. A transgenic T cell receptor restores thymocyte differentiation in interleukin-7 receptor alpha chain-deficient mice. Eur J Immunol. 1997;27(1):100\u20134. 10.1002\/eji.1830270115.","DOI":"10.1002\/eji.1830270115"},{"key":"2025122201305442214_j_med-2025-1154_ref_047","doi-asserted-by":"crossref","unstructured":"Han C, Pei H, Sheng Y, Wang J, Zhou X, Li W, et al. Double-negative T cells regulate the progression of liver fibrosis through Th9 cells differentiation. Liver Int. 2023;43(7):1604\u201313. 10.1111\/liv.15612.","DOI":"10.1111\/liv.15612"},{"key":"2025122201305442214_j_med-2025-1154_ref_048","doi-asserted-by":"crossref","unstructured":"Richards SJ, Jones RA, Roberts BE, Patel D, Scott CS. Relationships between 2H4 (CD45RA) and UCHL1 (CD45RO) expression by normal blood CD4 + CD8-, CD4-CD8 +, CD4-CD8dim +, CD3 + CD4-CD8- and CD3-CD4-CD8- lymphocytes. Clin Exp Immunol. 1990;81(1):149\u201355. 10.1111\/j.1365-2249.1990.tb05306.x.","DOI":"10.1111\/j.1365-2249.1990.tb05306.x"},{"key":"2025122201305442214_j_med-2025-1154_ref_049","doi-asserted-by":"crossref","unstructured":"Berman JS, Mahoney K, Saukkonen JJ, Masuyama J. Migration of distinct subsets of CD8 + blood T cells through endothelial cell monolayers in vitro. J Leukoc Biol. 1995;58(3):317\u201324. 10.1002\/jlb.58.3.317.","DOI":"10.1002\/jlb.58.3.317"},{"key":"2025122201305442214_j_med-2025-1154_ref_050","doi-asserted-by":"crossref","unstructured":"Camperio C, Muscolini M, Volpe E, Di Mitri D, Mechelli R, Buscarinu MC, et al. CD28 ligation in the absence of TCR stimulation up-regulates IL-17A and pro-inflammatory cytokines in relapsing-remitting multiple sclerosis T lymphocytes. Immunol Lett. 2014;158(1\u20132):134\u201342. 10.1016\/j.imlet.2013.12.020.","DOI":"10.1016\/j.imlet.2013.12.020"},{"key":"2025122201305442214_j_med-2025-1154_ref_051","doi-asserted-by":"crossref","unstructured":"Barrow F, Revelo XS. The B side of B cells in NAFLD. Hepatology. 2022;76(4):914\u20136. 10.1002\/hep.32481.","DOI":"10.1002\/hep.32481"},{"key":"2025122201305442214_j_med-2025-1154_ref_052","doi-asserted-by":"crossref","unstructured":"Kay R, Rosten PM, Humphries RK. CD24, a signal transducer modulating B cell activation responses, is a very short peptide with a glycosyl phosphatidylinositol membrane anchor. J Immunol. 1991;147(4):1412\u20136.","DOI":"10.4049\/jimmunol.147.4.1412"},{"key":"2025122201305442214_j_med-2025-1154_ref_053","doi-asserted-by":"crossref","unstructured":"Di Caro V, Phillips B, Engman C, Harnaha J, Trucco M, Giannoukakis N. Retinoic acid-producing, ex-vivo-generated human tolerogenic dendritic cells induce the proliferation of immunosuppressive B lymphocytes. Clin Exp Immunol. 2013;174(2):302\u201317. 10.1111\/cei.12177.","DOI":"10.1111\/cei.12177"},{"key":"2025122201305442214_j_med-2025-1154_ref_054","doi-asserted-by":"crossref","unstructured":"Lal G, Kulkarni N, Nakayama Y, Singh AK, Sethi A, Burrell BE, et al. IL-10 from marginal zone precursor B cells controls the differentiation of Th17, Tfh and Tfr cells in transplantation tolerance. Immunol Lett. 2016;170:52\u201363. 10.1016\/j.imlet.2016.01.002.","DOI":"10.1016\/j.imlet.2016.01.002"},{"key":"2025122201305442214_j_med-2025-1154_ref_055","doi-asserted-by":"crossref","unstructured":"Mensah FFK, Armstrong CW, Reddy V, Bansal AS, Berkovitz S, Leandro MJ, et al. CD24 expression and B cell maturation shows a novel link with energy metabolism: potential implications for patients with myalgic encephalomyelitis\/chronic fatigue syndrome. Front Immunol. 2018;9:2421. 10.3389\/fimmu.2018.02421.","DOI":"10.3389\/fimmu.2018.02421"},{"key":"2025122201305442214_j_med-2025-1154_ref_056","doi-asserted-by":"crossref","unstructured":"Barrow F, Khan S, Fredrickson G, Wang H, Dietsche K, Parthiban P, et al. Microbiota-driven activation of intrahepatic B cells aggravates NASH through innate and adaptive signaling. Hepatology. 2021;74(2):704\u201322. 10.1002\/hep.31755.","DOI":"10.1002\/hep.31755"},{"key":"2025122201305442214_j_med-2025-1154_ref_057","doi-asserted-by":"crossref","unstructured":"Shirani A, Stuve O, Cross AH. Role of B cells in relapsing-remitting and progressive multiple sclerosis and long-term effects of B cell depletion. Neurol Clin. 2024;42(1):137\u201353. 10.1016\/j.ncl.2023.06.001.","DOI":"10.1016\/j.ncl.2023.06.001"},{"key":"2025122201305442214_j_med-2025-1154_ref_058","doi-asserted-by":"crossref","unstructured":"He J, Li J, Lin Q, Ni H, Huang S, Cheng H, et al. Anti-CD20 treatment attenuates Th2 cell responses: implications for the role of lung follicular mature B cells in the asthmatic mice. Inflamm Res. 2024;73(3):433\u201346. 10.1007\/s00011-023-01847-4.","DOI":"10.1007\/s00011-023-01847-4"},{"key":"2025122201305442214_j_med-2025-1154_ref_059","doi-asserted-by":"crossref","unstructured":"Tesfagiorgis Y, Kemal EA, Craig HC, Parham KA, Kerfoot SM. Systemic administration of anti-CD20 indirectly reduces B cells in the inflamed meninges in a chronic model of central nervous system autoimmunity. J Neuroimmunol. 2024;387:578267. 10.1016\/j.jneuroim.2023.578267.","DOI":"10.1016\/j.jneuroim.2023.578267"},{"key":"2025122201305442214_j_med-2025-1154_ref_060","doi-asserted-by":"crossref","unstructured":"Weiskopf K, Schnorr PJ, Pang WW, Chao MP, Chhabra A, Seita J, et al. Myeloid cell origins, differentiation, and clinical implications. Microbiol Spectr. 2016;4(5):10.1128. 10.1128\/microbiolspec.MCHD-0031-2016.","DOI":"10.1128\/microbiolspec.MCHD-0031-2016"},{"key":"2025122201305442214_j_med-2025-1154_ref_061","doi-asserted-by":"crossref","unstructured":"Deczkowska A, David E, Ramadori P, Pfister D, Safran M, Li B, et al. XCR1( +) type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis. Nat Med. 2021;27(6):1043\u201354. 10.1038\/s41591-021-01344-3.","DOI":"10.1038\/s41591-021-01344-3"},{"key":"2025122201305442214_j_med-2025-1154_ref_062","doi-asserted-by":"crossref","unstructured":"Heier EC, Meier A, Julich-Haertel H, Djudjaj S, Rau M, Tschernig T, et al. Murine CD103(+) dendritic cells protect against steatosis progression towards steatohepatitis. J Hepatol. 2017;66(6):1241\u201350. 10.1016\/j.jhep.2017.01.008.","DOI":"10.1016\/j.jhep.2017.01.008"},{"key":"2025122201305442214_j_med-2025-1154_ref_063","doi-asserted-by":"crossref","unstructured":"Yin X, Yu H, Jin X, Li J, Guo H, Shi Q, et al. Human blood CD1c+ dendritic cells encompass CD5high and CD5low subsets that differ significantly in phenotype, gene expression, and functions. J Immunol. 2017;198(4):1553\u201364. 10.4049\/jimmunol.1600193.","DOI":"10.4049\/jimmunol.1600193"},{"key":"2025122201305442214_j_med-2025-1154_ref_064","doi-asserted-by":"crossref","unstructured":"Zeng F, Zhang Y, Han X, Zeng M, Gao Y, Weng J. Predicting non-alcoholic fatty liver disease progression and immune deregulations by specific gene expression patterns. Front Immunol. 2020;11:609900. 10.3389\/fimmu.2020.609900.","DOI":"10.3389\/fimmu.2020.609900"},{"key":"2025122201305442214_j_med-2025-1154_ref_065","doi-asserted-by":"crossref","unstructured":"Fujiwara N, Nakagawa H. Clinico-histological and molecular features of hepatocellular carcinoma from nonalcoholic fatty liver disease. Cancer Sci. 2023;114(10):3825\u201333. 10.1111\/cas.15925.","DOI":"10.1111\/cas.15925"},{"key":"2025122201305442214_j_med-2025-1154_ref_066","doi-asserted-by":"crossref","unstructured":"Waller KJ, Saihi H, Li W, Brindley JH, De Jong A, Syn WK, et al. Single-cell phenotypes of peripheral blood immune cells in early and late stages of non-alcoholic fatty liver disease. Clin Mol Hepatol. 2023;29(2):417\u201332. 10.3350\/cmh.2022.0205.","DOI":"10.3350\/cmh.2022.0205"}],"container-title":["Open Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/med-2025-1154\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/med-2025-1154\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T01:41:00Z","timestamp":1766367660000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/med-2025-1154\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,1]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,6,9]]},"published-print":{"date-parts":[[2025,6,9]]}},"alternative-id":["10.1515\/med-2025-1154"],"URL":"https:\/\/doi.org\/10.1515\/med-2025-1154","relation":{},"ISSN":["2391-5463"],"issn-type":[{"type":"electronic","value":"2391-5463"}],"subject":[],"published":{"date-parts":[[2025,1,1]]},"article-number":"20251154"}}