{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T15:12:51Z","timestamp":1791213171818,"version":"4.1.0"},"reference-count":106,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T00:00:00Z","timestamp":1642464000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["Investigator Grant no. 20441 to VR"],"award-info":[{"award-number":["Investigator Grant no. 20441 to VR"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The liver is a very tolerogenic organ. It is continually exposed to a multitude of antigens and is able to promote an effective immune response against pathogens and simultaneously immune tolerance against self-antigens. In spite of strong peripheral and central tolerogenic mechanisms, loss of tolerance can occur in autoimmune liver diseases, such as autoimmune hepatitis (AIH) through a combination of genetic predisposition, environmental factors, and an imbalance in immunological regulatory mechanisms. The liver hosts several types of conventional resident antigen presenting cells (APCs) such as dendritic cells, B cells and macrophages (Kupffer cells), and unconventional APCs including liver sinusoidal endothelial cells, hepatic stellate cells and hepatocytes. By standard (direct presentation and cross-presentation) and alternative mechanisms (cross-dressing and MHC class II-dressing), liver APCs presents self-antigen to naive T cells in the presence of costimulation leading to an altered immune response that results in liver injury and inflammation. Additionally, the transport of antigens and antigen:MHC complexes by trogocytosis and extracellular vesicles between different cells in the liver contributes to enhance antigen presentation and amplify autoimmune response. Here, we focus on the impact of antigen presentation on the immune response in the liver and on the functional role of the immune cells in the induction of liver inflammation. A better understanding of these key pathogenic aspects could facilitate the establishment of novel therapeutic strategies in AIH.<\/jats:p>","DOI":"10.3389\/fimmu.2021.814155","type":"journal-article","created":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T05:33:57Z","timestamp":1642484037000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":37,"title":["Impact of Antigen Presentation Mechanisms on Immune Response in Autoimmune Hepatitis"],"prefix":"10.3389","volume":"12","author":[{"given":"Rossella","family":"Fasano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Malerba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcella","family":"Prete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio Giovanni","family":"Solimando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Buonavoglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Silvestris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrizia","family":"Leone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"Racanelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21060","article-title":"The Liver as an Immunological Organ","volume":"43","author":"Racanelli","year":"2006","journal-title":"Hepatology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/cmi.2015.112","article-title":"Modulation of Liver Tolerance by Conventional and Nonconventional Antigen-Presenting Cells and Regulatory Immune Cells","volume":"13","author":"Horst","year":"2016","journal-title":"Cell Mol Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"18017","DOI":"10.1038\/nrdp.2018.17","article-title":"Autoimmune Hepatitis","volume":"4","author":"Mieli-Vergani","year":"2018","journal-title":"Nat Rev Dis Primers"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22322","article-title":"Simplified Criteria for the Diagnosis of Autoimmune Hepatitis","volume":"48","author":"Hennes","year":"2008","journal-title":"Hepatology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpg.2011.09.009","article-title":"Pathogenesis of Autoimmune Hepatitis","volume":"25","author":"Liberal","year":"2011","journal-title":"Best Pract Res Clin Gastroenterol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2015.08.012","article-title":"Autoimmune Hepatitis and Overlap Syndromes: Diagnosis and Management","volume":"13","author":"Vierling","year":"2015","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/apt.14324","article-title":"Review Article: Next-Generation Transformative Advances in the Pathogenesis and Management of Autoimmune Hepatitis","volume":"46","author":"Czaja","year":"2017","journal-title":"Aliment Pharmacol Ther"},{"key":"B8","article-title":"Autoimmune Hepatitis","volume-title":"StatPearls","author":"Linzay","year":"2021"},{"key":"B9","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/j.jhep.2015.06.030","article-title":"EASL Clinical Practice Guidelines: Autoimmune Hepatitis","volume":"63","year":"2015","journal-title":"J Hepatol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900124","article-title":"TNF-Producing Th1 Cells Are Selectively Expanded in Liver Infiltrates of Patients With Autoimmune Hepatitis","volume":"203","author":"Bovensiepen","year":"2019","journal-title":"J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2018.10.001","article-title":"Association of STAT4, TGFbeta1, SH2B3 and PTPN22 Polymorphisms With Autoimmune Hepatitis","volume":"105","author":"Chaouali","year":"2018","journal-title":"Exp Mol Pathol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/eci.12899","article-title":"Epigenetic Changes and Their Implications in Autoimmune Hepatitis","volume":"48","author":"Czaja","year":"2018","journal-title":"Eur J Clin Invest"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v25.i45.6579","article-title":"Examining Pathogenic Concepts of Autoimmune Hepatitis for Cues to Future Investigations and Interventions","volume":"25","author":"Czaja","year":"2019","journal-title":"World J Gastroenterol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1053\/j.gastro.2014.04.022","article-title":"Genome-Wide Association Study Identifies Variants Associated With Autoimmune Hepatitis Type 1","volume":"147","author":"de Boer","year":"2014","journal-title":"Gastroenterology"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2021.104214","article-title":"Genetic Aspects of Adult and Pediatric Autoimmune Hepatitis: A Concise Review","volume":"64","author":"Engel","year":"2021","journal-title":"Eur J Med Genet"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3109\/08820139.2014.1003651","article-title":"Meta-Analysis: The Relationship Between CTLA-4 +49 a\/G Polymorphism and Primary Biliary Cirrhosis and Type I Autoimmune Hepatitis","volume":"44","author":"Eskandari-Nasab","year":"2015","journal-title":"Immunol Invest"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.10.5199","article-title":"Cloning and Characterization of Human Lnk, an Adaptor Protein With Pleckstrin Homology and Src Homology 2 Domains That can Inhibit T Cell Activation","volume":"164","author":"Li","year":"2000","journal-title":"J Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/apt.15873","article-title":"Editorial: PNPLA3 Genotype and Liver Diseases-More Than Non-Alcoholic Fatty Liver Disease. Authors\u2019 Reply","volume":"52","author":"Mederacke","year":"2020","journal-title":"Aliment Pharmacol Ther"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddw341","article-title":"PNPLA3 Overexpression Results in Reduction of Proteins Predisposing to Fibrosis","volume":"25","author":"Pingitore","year":"2016","journal-title":"Hum Mol Genet"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2014.02.003","article-title":"The Association Between Cytotoxic T Lymphocyte Associated Antigen-4, Fas, Tumour Necrosis Factor-Alpha Gene Polymorphisms and Autoimmune Hepatitis: A Meta-Analysis","volume":"46","author":"Qin","year":"2014","journal-title":"Dig Liver Dis"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.2.703","article-title":"Impaired Lymphopoiesis and Altered B Cell Subpopulations in Mice Overexpressing Lnk Adaptor Protein","volume":"170","author":"Takaki","year":"2003","journal-title":"J Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-020117-043534","article-title":"Cellular and Molecular Mechanisms of Autoimmune Hepatitis","volume":"13","author":"Webb","year":"2018","journal-title":"Annu Rev Pathol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0676.2001.021004225.x","article-title":"Molecular Mimicry and Autoimmune Liver Disease: Virtuous Intentions, Malign Consequences","volume":"21","author":"Bogdanos","year":"2001","journal-title":"Liver"},{"key":"B24","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1111\/cei.13203","article-title":"Pathogens and Autoimmune Hepatitis","volume":"195","author":"Christen","year":"2019","journal-title":"Clin Exp Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.jaut.2012.11.001","article-title":"Molecular Mimicry Rather Than Identity Breaks T-Cell Tolerance in the CYP2D6 Mouse Model for Human Autoimmune Hepatitis","volume":"42","author":"Ehser","year":"2013","journal-title":"J Autoimmun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3791\/3644","article-title":"The CYP2D6 Animal Model: How to Induce Autoimmune Hepatitis in Mice","volume":"60","author":"Hintermann","year":"2012","journal-title":"J Vis Exp"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2003.02229.x","article-title":"Mimicry Between the Hepatitis C Virus Polyprotein and Antigenic Targets of Nuclear and Smooth Muscle Antibodies in Chronic Hepatitis C Virus Infection","volume":"133","author":"Gregorio","year":"2003","journal-title":"Clin Exp Immunol"},{"key":"B28","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.162.3.1802","article-title":"Mimicry Between the Hepatitis B Virus DNA Polymerase and the Antigenic Targets of Nuclear and Smooth Muscle Antibodies in Chronic Hepatitis B Virus Infection","volume":"162","author":"Gregorio","year":"1999","journal-title":"J Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.3.1481","article-title":"Cytochrome P4502D6(193-212): A New Immunodominant Epitope and Target of Virus\/Self Cross-Reactivity in Liver Kidney Microsomal Autoantibody Type 1-Positive Liver Disease","volume":"170","author":"Kerkar","year":"2003","journal-title":"J Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115443","article-title":"LKM-1 Autoantibodies Recognize a Short Linear Sequence in P450IID6, a Cytochrome P-450 Monooxygenase","volume":"88","author":"Manns","year":"1991","journal-title":"J Clin Invest"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djt184","article-title":"MHC Class I Antigen Processing and Presenting Machinery: Organization, Function, and Defects in Tumor Cells","volume":"105","author":"Leone","year":"2013","journal-title":"J Natl Cancer Inst"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/425351a","article-title":"Immunology: Professional Secrets","volume":"425","author":"Roy","year":"2003","journal-title":"Nature"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01643","article-title":"Current Concepts of Antigen Cross-Presentation","volume":"9","author":"Embgenbroich","year":"2018","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2015.11.002","article-title":"Cross-Dressing: An Alternative Mechanism for Antigen Presentation","volume":"168","author":"Campana","year":"2015","journal-title":"Immunol Lett"},{"key":"B35","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1038\/ni0903-815","article-title":"What is Trogocytosis and What Is Its Purpose","volume":"4","author":"Joly","year":"2003","journal-title":"Nat Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-018-0679-8","article-title":"Extracellular Vesicle-Mediated MHC Cross-Dressing in Immune Homeostasis, Transplantation, Infectious Diseases, and Cancer","volume":"40","author":"Zeng","year":"2018","journal-title":"Semin Immunopathol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.2AB0613-342RR","article-title":"Hepatocytes Induce Foxp3(+) Regulatory T Cells by Notch Signaling","volume":"96","author":"Burghardt","year":"2014","journal-title":"J Leukoc Biol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300826","article-title":"Hepatocytes Contribute to Immune Regulation in the Liver by Activation of the Notch Signaling Pathway in T Cells","volume":"191","author":"Burghardt","year":"2013","journal-title":"J Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.09.008","article-title":"Inhibition of Inflammatory CD4 T Cell Activity by Murine Liver Sinusoidal Endothelial Cells","volume":"58","author":"Carambia","year":"2013","journal-title":"J Hepatol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23191","article-title":"Priming of CD4+ T Cells by Liver Sinusoidal Endothelial Cells Induces CD25low Forkhead Box Protein 3- Regulatory T Cells Suppressing Autoimmune Hepatitis","volume":"50","author":"Kruse","year":"2009","journal-title":"Hepatology"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1172\/JCI21593","article-title":"The Site of Primary T Cell Activation Is a Determinant of the Balance Between Intrahepatic Tolerance and Immunity","volume":"114","author":"Bowen","year":"2004","journal-title":"J Clin Invest"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.23736\/S2724-5985.21.02853-1","article-title":"Breakdown in Hepatic Tolerance and Its Relation to Autoimmune Liver Diseases","volume":"67","author":"Bozward","year":"2021","journal-title":"Minerva Gastroenterol (Torino)"},{"key":"B43","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41423-020-00568-6","article-title":"Antigen Presentation, Autoantibody Production, and Therapeutic Targets in Autoimmune Liver Disease","volume":"18","author":"Horst","year":"2021","journal-title":"Cell Mol Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.746436","article-title":"Dysfunctional Immune Regulation in Autoimmune Hepatitis: From Pathogenesis to Novel Therapies","volume":"12","author":"Vuerich","year":"2021","journal-title":"Front Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/hep.28517","article-title":"Human Intrahepatic Regulatory T Cells Are Functional, Require IL-2 From Effector Cells for Survival, and Are Susceptible to Fas Ligand-Mediated Apoptosis","volume":"64","author":"Chen","year":"2016","journal-title":"Hepatology"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2021.102619","article-title":"Regulatory T Cells in Autoimmune Hepatitis: An Updated Overview","volume":"119","author":"Longhi","year":"2021","journal-title":"J Autoimmun"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/nature05479","article-title":"Regulatory T-Cell Functions Are Subverted and Converted Owing to Attenuated Foxp3 Expression","volume":"445","author":"Wan","year":"2007","journal-title":"Nature"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.11.6725","article-title":"Cutting Edge: Regulatory T Cells Induce CD4+CD25-Foxp3- T Cells or Are Self-Induced to Become Th17 Cells in the Absence of Exogenous TGF-Beta","volume":"178","author":"Xu","year":"2007","journal-title":"J Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00319","article-title":"The Other Function: Class II-Restricted Antigen Presentation by B Cells","volume":"8","author":"Adler","year":"2017","journal-title":"Front Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1007\/s12026-010-8189-3","article-title":"Tedder TF. B-Lymphocyte Effector Functions in Health and Disease","volume":"49","author":"DiLillo","year":"2011","journal-title":"Immunol Res"},{"key":"B51","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.immuni.2007.12.004","article-title":"Sites and Stages of Autoreactive B Cell Activation and Regulation","volume":"28","author":"Shlomchik","year":"2008","journal-title":"Immunity"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27991","article-title":"Depletion of B Cells Induces Remission of Autoimmune Hepatitis in Mice Through Reduced Antigen Presentation and Help to T Cells","volume":"62","author":"Beland","year":"2015","journal-title":"Hepatology"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1002\/hep.1840080302","article-title":"Expression of Class I and Class II Major Histocompatibility Complex Antigens on Human Hepatocytes","volume":"8","author":"Franco","year":"1988","journal-title":"Hepatology"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1053\/jhep.2003.50191","article-title":"MHC Class II-Expressing Hepatocytes Function as Antigen-Presenting Cells and Activate Specific CD4 T Lymphocyutes","volume":"37","author":"Herkel","year":"2003","journal-title":"Hepatology"},{"key":"B55","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.yexmp.2017.08.001","article-title":"Change in Nomenclature for the Immunologic Synapse From Troxis Necrosis to Trogocytosis","volume":"103","author":"French","year":"2017","journal-title":"Exp Mol Pathol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.6.3645","article-title":"Cutting Edge: CTLs Rapidly Capture Membrane Fragments From Target Cells in a TCR Signaling-Dependent Manner","volume":"166","author":"Hudrisier","year":"2001","journal-title":"J Immunol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2018.07.004","article-title":"Piecemeal Necrosis is Due to the Immunologic Synapse Formation and Internalization of Intact TCR-MHC II Complexes by CD4 T Cells","volume":"105","author":"French","year":"2018","journal-title":"Exp Mol Pathol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2017.71","article-title":"Extracellular Vesicles in Liver Disease and Potential as Biomarkers and Therapeutic Targets","volume":"14","author":"Szabo","year":"2017","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2015.01.004","article-title":"Ectosomes and Exosomes: Shedding the Confusion Between Extracellular Vesicles","volume":"25","author":"Cocucci","year":"2015","journal-title":"Trends Cell Biol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501112200","article-title":"Diacylglycerol Kinase Alpha Regulates the Secretion of Lethal Exosomes Bearing Fas Ligand During Activation-Induced Cell Death of T Lymphocytes","volume":"280","author":"Alonso","year":"2005","journal-title":"J Biol Chem"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601842","article-title":"T Cell-Induced Secretion of MHC Class II-Peptide Complexes on B Cell Exosomes","volume":"26","author":"Muntasell","year":"2007","journal-title":"EMBO J"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1080\/20013078.2019.1650458","article-title":"Endosomal Signalling via Exosome Surface TGFbeta-1","volume":"8","author":"Shelke","year":"2019","journal-title":"J Extracell Vesicles"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2014.04.028","article-title":"Transfer of MHC-Class-I Molecules Among Liver Sinusoidal Cells Facilitates Hepatic Immune Surveillance","volume":"61","author":"Scholzel","year":"2014","journal-title":"J Hepatol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.10.005","article-title":"Liver Antigen-Presenting Cells","volume":"54","author":"Crispe","year":"2011","journal-title":"J Hepatol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2004.03.008","article-title":"Impairment of CD4(+)CD25(+) Regulatory T-Cells in Autoimmune Liver Disease","volume":"41","author":"Longhi","year":"2004","journal-title":"J Hepatol"},{"key":"B66","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1002\/hep.23792","article-title":"A Multifaceted Imbalance of T Cells With Regulatory Function Characterizes Type 1 Autoimmune Hepatitis","volume":"52","author":"Ferri","year":"2010","journal-title":"Hepatology"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1002\/hep.27884","article-title":"In Autoimmune Hepatitis Type 1 or the Autoimmune Hepatitis-Sclerosing Cholangitis Variant Defective Regulatory T-Cell Responsiveness to IL-2 Results in Low IL-10 Production and Impaired Suppression","volume":"62","author":"Liberal","year":"2015","journal-title":"Hepatology"},{"key":"B68","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.jaut.2005.05.001","article-title":"Effect of CD4+ CD25+ Regulatory T-Cells on CD8 T-Cell Function in Patients With Autoimmune Hepatitis","volume":"25","author":"Longhi","year":"2005","journal-title":"J Autoimmun"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(07)70289-X","article-title":"T-Cell Regulation by CD4 Regulatory T Cells During Hepatitis B and C Virus Infections: Facts and Controversies","volume":"7","author":"Manigold","year":"2007","journal-title":"Lancet Infect Dis"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20062512","article-title":"Adenosine Generation Catalyzed by CD39 and CD73 Expressed on Regulatory T Cells Mediates Immune Suppression","volume":"204","author":"Deaglio","year":"2007","journal-title":"J Exp Med"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-6143.2010.03291.x","article-title":"Expression of CD39 by Human Peripheral Blood CD4+ CD25+ T Cells Denotes a Regulatory Memory Phenotype","volume":"10","author":"Dwyer","year":"2010","journal-title":"Am J Transplant"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.10.6780","article-title":"T Regulatory and Primed Uncommitted CD4 T Cells Express CD73, Which Suppresses Effector CD4 T Cells by Converting 5\u2019-Adenosine Monophosphate to Adenosine","volume":"177","author":"Kobie","year":"2006","journal-title":"J Immunol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26583","article-title":"Dysfunctional CD39(POS) Regulatory T Cells and Aberrant Control of T-Helper Type 17 Cells in Autoimmune Hepatitis","volume":"59","author":"Grant","year":"2014","journal-title":"Hepatology"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2005.01.005","article-title":"T Cell Immunity in Autoimmune Hepatitis","volume":"4","author":"Ichiki","year":"2005","journal-title":"Autoimmun Rev"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.44.2.107","article-title":"Class I and Class II Major Histocompatibility Complex Antigens on Hepatocytes: Importance of the Method of Detection and Expression in Histologically Normal and Diseased Livers","volume":"44","author":"Senaldi","year":"1991","journal-title":"J Clin Pathol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-04-1164","article-title":"Interferon-Gamma Switches Monocyte Differentiation From Dendritic Cells to Macrophages","volume":"101","author":"Delneste","year":"2003","journal-title":"Blood"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0603252","article-title":"Interferon-Gamma: An Overview of Signals, Mechanisms and Functions","volume":"75","author":"Schroder","year":"2004","journal-title":"J Leukoc Biol"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21658","article-title":"Cytochrome P450IID6-Specific CD8 T Cell Immune Responses Mirror Disease Activity in Autoimmune Hepatitis Type 2","volume":"46","author":"Longhi","year":"2007","journal-title":"Hepatology"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510240619","article-title":"Autoreactive CD4+ LKM-Specific and Anticlonotypic T-Cell Responses in LKM-1 Antibody-Positive Autoimmune Hepatitis","volume":"24","author":"Lohr","year":"1996","journal-title":"Hepatology"},{"key":"B80","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.jaut.2016.07.005","article-title":"Cutting Edge Issues in Autoimmune Hepatitis","volume":"75","author":"Liberal","year":"2016","journal-title":"J Autoimmun"},{"key":"B81","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41423-021-00768-8","article-title":"Autoimmmune Hepatitis","volume":"18","author":"Terziroli Beretta-Piccoli","year":"2021","journal-title":"Cell Mol Immunol"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1136\/gut.46.4.553","article-title":"Liver\/kidney Microsomal Antibody Type 1 Targets CYP2D6 on Hepatocyte Plasma Membrane","volume":"46","author":"Muratori","year":"2000","journal-title":"Gut"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1038\/nature04753","article-title":"Reciprocal Developmental Pathways for the Generation of Pathogenic Effector TH17 and Regulatory T Cells","volume":"441","author":"Bettelli","year":"2006","journal-title":"Nature"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0018909","article-title":"Interleukin-17 Contributes to the Pathogenesis of Autoimmune Hepatitis Through Inducing Hepatic Interleukin-6 Expression","volume":"6","author":"Zhao","year":"2011","journal-title":"PloS One"},{"key":"B85","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1038\/icb.2013.55","article-title":"Human T Follicular Helper (Tfh) Cells and Disease","volume":"92","author":"Ma","year":"2014","journal-title":"Immunol Cell Biol"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1038\/nature05969","article-title":"Essential Autocrine Regulation by IL-21 in the Generation of Inflammatory T Cells","volume":"448","author":"Nurieva","year":"2007","journal-title":"Nature"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.08.017","article-title":"Mtorc1 and Mtorc2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation","volume":"45","author":"Zeng","year":"2016","journal-title":"Immunity"},{"key":"B88","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1186\/s40064-016-2512-y","article-title":"Interleukin-21 Plays a Critical Role in the Pathogenesis and Severity of Type I Autoimmune Hepatitis","volume":"5","author":"Abe","year":"2016","journal-title":"Springerplus"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.5604\/16652681.1203152","article-title":"Elevated Circulating Levels of IL-21 and IL-22 Define a Cytokine Signature Profile in Type 2 Autoimmune Hepatitis Patients","volume":"15","author":"Thomas-Dupont","year":"2016","journal-title":"Ann Hepatol"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2425","article-title":"Foxp3+ Follicular Regulatory T Cells Control the Germinal Center Response","volume":"17","author":"Linterman","year":"2011","journal-title":"Nat Med"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.2174\/1566524013363672","article-title":"Pediatric Autoimmune Liver Diseases: The Molecular Basis of Humoral and Cellular Immunity","volume":"1","author":"Wen","year":"2001","journal-title":"Curr Mol Med"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1586\/17474124.1.1.113","article-title":"Autoimmune Hepatitis. Part A: Pathogenesis","volume":"1","author":"Czaja","year":"2007","journal-title":"Expert Rev Gastroenterol Hepatol"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1016\/j.dld.2021.05.033","article-title":"A Reasoned Approach to the Treatment of Autoimmune Hepatitis","volume":"53","author":"Vergani","year":"2021","journal-title":"Dig Liver Dis"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/512624","article-title":"Rituximab for the Treatment of Patients With Autoimmune Hepatitis Who Are Refractory or Intolerant to Standard Therapy","volume":"27","author":"Burak","year":"2013","journal-title":"Can J Gastroenterol"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2012.11.010","article-title":"Infliximab as a Rescue Treatment in Difficult-to-Treat Autoimmune Hepatitis","volume":"58","author":"Weiler-Normann","year":"2013","journal-title":"J Hepatol"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2020.100123","article-title":"Belimumab Is a Promising Third-Line Treatment Option for Refractory Autoimmune Hepatitis","volume":"2","author":"Arvaniti","year":"2020","journal-title":"JHEP Rep"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2018-214229","article-title":"Immunological and Clinical Effects of Low-Dose Interleukin-2 Across 11 Autoimmune Diseases in a Single, Open Clinical Trial","volume":"78","author":"Rosenzwajg","year":"2019","journal-title":"Ann Rheum Dis"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24039","article-title":"Autoantigen-Specific Regulatory T Cells, a Potential Tool for Immune-Tolerance Reconstitution in Type-2 Autoimmune Hepatitis","volume":"53","author":"Longhi","year":"2011","journal-title":"Hepatology"},{"key":"B99","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.coi.2021.03.019","article-title":"Manipulating Antigen Presentation for Antigen-Specific Immunotherapy of Autoimmune Diseases","volume":"70","author":"Streeter","year":"2021","journal-title":"Curr Opin Immunol"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01378","article-title":"Optimized Peptide-MHC Multimer Protocols for Detection and Isolation of Autoimmune T-Cells","volume":"9","author":"Dolton","year":"2018","journal-title":"Front Immunol"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1111\/tan.13789","article-title":"Peptide-MHC Class I and Class II Tetramers: From Flow to Mass Cytometry","volume":"95","author":"Christophersen","year":"2020","journal-title":"HLA"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1002\/hep.26380","article-title":"Genetic Predisposition and Environmental Danger Signals Initiate Chronic Autoimmune Hepatitis Driven by CD4+ T Cells","volume":"58","author":"Hardtke-Wolenski","year":"2013","journal-title":"Hepatology"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1038\/nature16962","article-title":"Expanding Antigen-Specific Regulatory Networks to Treat Autoimmunity","volume":"530","author":"Clemente-Casares","year":"2016","journal-title":"Nature"},{"key":"B104","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1038\/s41467-019-09893-5","article-title":"Suppression of a Broad Spectrum of Liver Autoimmune Pathologies by Single Peptide-MHC-Based Nanomedicines","volume":"10","author":"Umeshappa","year":"2019","journal-title":"Nat Commun"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2015.01.006","article-title":"Nanoparticle-Based Autoantigen Delivery to Treg-Inducing Liver Sinusoidal Endothelial Cells Enables Control of Autoimmunity in Mice","volume":"62","author":"Carambia","year":"2015","journal-title":"J Hepatol"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1111\/sji.12881","article-title":"Approaches to Inducing Antigen-Specific Immune Tolerance in Allergy and Autoimmunity: Focus on Antigen-Presenting Cells and Extracellular Vesicles","volume":"91","author":"Nazimek","year":"2020","journal-title":"Scand J Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.814155\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T09:47:36Z","timestamp":1674467256000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.814155\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,18]]},"references-count":106,"alternative-id":["10.3389\/fimmu.2021.814155"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.814155","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,18]]},"article-number":"814155"}}