{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T04:27:51Z","timestamp":1792124871620,"version":"4.4.0"},"reference-count":87,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Graves\u2019 disease (GD) is a thyroid-specific autoimmune disease with a high prevalence worldwide. The disease is primarily mediated by B cells, which produce autoantibodies against the thyroid-stimulating hormone receptor (TSHR), chronically stimulating it and leading to high levels of thyroid hormones in the body. Interest in characterizing the immune response in GD has motivated many phenotyping studies. The immunophenotype of the cells involved and the interplay between them and their secreted factors are crucial to understanding disease progression and future treatment options. T cell populations are markedly distinct, including increased levels of Th17 and follicular helper T cells (Tfh), while Treg cells appear to be impaired. Some B cells subsets are autoreactive, and anti-TSHR antibodies are the key disease-causing outcome of this interplay. Though some consensus across phenotyping studies will be discussed here, there are also complexities that are yet to be resolved. A better understanding of the immunophenotype of Graves\u2019 disease can lead to improved treatment strategies and novel drug targets.<\/jats:p>","DOI":"10.3390\/ijms24076835","type":"journal-article","created":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T05:21:23Z","timestamp":1680758483000},"page":"6835","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Characterizing the Interplay of Lymphocytes in Graves\u2019 Disease"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-9990-7194","authenticated-orcid":false,"given":"Mackenzie","family":"Hansen","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3541-1507","authenticated-orcid":false,"given":"Abigail","family":"Cheever","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3688-2191","authenticated-orcid":false,"given":"K.","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8747-6217","authenticated-orcid":false,"given":"Kim","family":"O\u2019Neill","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1056\/NEJMra1510030","article-title":"Graves\u2019 Disease","volume":"375","author":"Smith","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1089\/thy.2016.0229","article-title":"2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis","volume":"26","author":"Ross","year":"2016","journal-title":"Thyroid"},{"key":"ref_3","unstructured":"Feingold, K.R., Anawalt, B., Blackman, M.R., Boyce, A., Chrousos, G., Corpas, E., de Herder, W.W., Dhatariya, K., and Hofland, J. (2000). Endotext, MDText.com, Inc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1080\/17446651.2022.2052044","article-title":"Management of Graves\u2019 hyperthyroidism: Present and future","volume":"17","author":"Bartalena","year":"2022","journal-title":"Expert Rev. Endocrinol. Metab."},{"key":"ref_5","first-page":"177","article-title":"Current Diagnosis and Management of Graves\u2019 Disease","volume":"50","author":"Subekti","year":"2018","journal-title":"Acta Med. Indones"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1159\/000490384","article-title":"2018 European Thyroid Association Guideline for the Management of Graves\u2019 Hyperthyroidism","volume":"7","author":"Kahaly","year":"2018","journal-title":"Eur. Thyroid J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"794912","DOI":"10.3389\/fcell.2021.794912","article-title":"Genetics, Epigenetics, Cellular Immunology, and Gut Microbiota: Emerging Links With Graves\u2019 Disease","volume":"9","author":"Zhou","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1038\/ng.898","article-title":"A genome-wide association study identifies two new risk loci for Graves\u2019 disease","volume":"43","author":"Chu","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"788535","DOI":"10.3389\/fendo.2021.788535","article-title":"Emerging Insights Into the Role of Epigenetics and Gut Microbiome in the Pathogenesis of Graves\u2019 Ophthalmopathy","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sawicka-Gutaj, N., Gruszczy\u0144ski, D., Zawalna, N., Nijakowski, K., Muller, I., Karpi\u0144ski, T., Salvi, M., and Rucha\u0142a, M. (2022). Microbiota Alterations in Patients with Autoimmune Thyroid Diseases: A Systematic Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232113450"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Biscarini, F., Masetti, G., Muller, I., Verhasselt, H.L., Covelli, D., Colucci, G., Zhang, L., Draman, M.S., Okosieme, O., and Taylor, P. (2023). Gut microbiome associated with Graves\u2019 disease and Graves\u2019 orbitopathy: The INDIGO* multi-centre European study. J. Clin. Endocrinol. Metab.","DOI":"10.1210\/clinem\/dgad030"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3526","DOI":"10.1210\/clinem\/dgaa511","article-title":"Gut Dysbiosis Contributes to the Imbalance of Treg and Th17 Cells in Graves\u2019 Disease Patients by Propionic Acid","volume":"105","author":"Su","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41577-022-00727-y","article-title":"The impact of the gut microbiome on extra-intestinal autoimmune diseases","volume":"23","author":"Miyauchi","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"739707","DOI":"10.3389\/fcimb.2021.739707","article-title":"The Role of the Microbiota in Graves\u2019 Disease and Graves\u2019 Orbitopathy","volume":"11","author":"Hou","year":"2021","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1055\/s-0035-1559648","article-title":"Mechanisms of Action of TSHR Autoantibodies","volume":"47","author":"Furmaniak","year":"2015","journal-title":"Horm. Metab. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.autrev.2009.03.012","article-title":"TSH receptor autoantibodies","volume":"9","author":"Michalek","year":"2009","journal-title":"Autoimmun. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3992","DOI":"10.1096\/fj.10-161745","article-title":"Persistent cAMP signaling by thyrotropin (TSH) receptors is not dependent on internalization","volume":"24","author":"Neumann","year":"2010","journal-title":"FASEB J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1055\/s-0035-1559633","article-title":"Graves\u2019 Disease Mechanisms: The Role of Stimulating, Blocking, and Cleavage Region TSH Receptor Antibodies","volume":"47","author":"Morshed","year":"2015","journal-title":"Horm. Metab. Res."},{"key":"ref_19","first-page":"1024","article-title":"Anti-thyrotropin (TSH) receptor antibody binding epitopes of TSH receptor: Site-directed mutagenesis approach","volume":"52","author":"Akamizu","year":"1994","journal-title":"Nihon. Rinsho."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1089\/thy.1995.5.259","article-title":"Establishment and characterization of an antihuman thyrotropin (TSH) receptor-specific CD4+ T cell line from a patient with Graves\u2019 disease: Evidence for multiple T cell epitopes on the TSH receptor including the transmembrane domain","volume":"5","author":"Akamizu","year":"1995","journal-title":"Thyroid"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"120","DOI":"10.3389\/fendo.2016.00120","article-title":"Thyrotropin Receptor Epitope and Human Leukocyte Antigen in Graves\u2019 Disease","volume":"7","author":"Inaba","year":"2016","journal-title":"Front. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Latif, R., Teixeira, A., Michalek, K., Ali, M.R., Schlesinger, M., Baliram, R., Morshed, S.A., and Davies, T.F. (2012). Antibody protection reveals extended epitopes on the human TSH receptor. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044669"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"572","DOI":"10.5603\/EP.a2021.0076","article-title":"CD4+ cells in autoimmune thyroid disease","volume":"72","author":"Janyga","year":"2021","journal-title":"Endokrynol. Pol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/bs.ircmb.2018.05.007","article-title":"The Single-Cell Phenotypic Identity of Human CD8(+) and CD4(+) T Cells","volume":"341","author":"Brummelman","year":"2018","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1093\/intimm\/dxp021","article-title":"Th17 cells: From precursors to players in inflammation and infection","volume":"21","author":"Awasthi","year":"2009","journal-title":"Int. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s00281-019-00733-8","article-title":"The pathogenicity of Th17 cells in autoimmune diseases","volume":"41","author":"Yasuda","year":"2019","journal-title":"Semin. Immunopathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S56","DOI":"10.1007\/s10875-014-0040-5","article-title":"Unexpected targets and triggers of autoimmunity","volume":"34","author":"Lee","year":"2014","journal-title":"J. Clin. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8431838","DOI":"10.1155\/2017\/8431838","article-title":"Increased Circulating Th17 but Decreased CD4(+)Foxp3(+) Treg and CD19(+)CD1d(hi)CD5(+) Breg Subsets in New-Onset Graves\u2019 Disease","volume":"2017","author":"Qin","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1159\/000452541","article-title":"Imbalance of Th17\/Treg in Different Subtypes of Autoimmune Thyroid Diseases","volume":"40","author":"Li","year":"2016","journal-title":"Cell Physiol. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Peng, D., Xu, B., Wang, Y., Guo, H., and Jiang, Y. (2013). A high frequency of circulating th22 and th17 cells in patients with new onset graves\u2019 disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068446"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1089\/thy.2008.0423","article-title":"Increases of the Th1\/Th2 cell ratio in severe Hashimoto\u2019s disease and in the proportion of Th17 cells in intractable Graves\u2019 disease","volume":"19","author":"Nanba","year":"2009","journal-title":"Thyroid"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"16880","DOI":"10.1038\/s41598-022-19556-z","article-title":"Comprehensive immunophenotypic analysis reveals the pathological involvement of Th17 cells in Graves\u2019 disease","volume":"12","author":"Torimoto","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3109\/08916934.2013.879862","article-title":"Th17 and Treg cells in adolescents with Graves\u2019 disease. Impact of treatment with methimazole on these cell subsets","volume":"47","author":"Klatka","year":"2014","journal-title":"Autoimmunity"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1080\/08916934.2016.1183654","article-title":"Decreased proportions of CD4\u2009+\u2009IL17+\/CD4\u2009+\u2009CD25\u2009+\u2009CD127- and CD4\u2009+\u2009IL17+\/CD4\u2009+\u2009CD25\u2009+\u2009CD127\u2009-\u2009FoxP3+ T cells in children with autoimmune thyroid diseases","volume":"49","author":"Bossowski","year":"2016","journal-title":"Autoimmunity"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.molimm.2022.02.004","article-title":"Absolute reduction in peripheral regulatory T cells in patients with Graves\u2019 disease and post-treatment recovery","volume":"144","author":"Liu","year":"2022","journal-title":"Mol. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1590\/S0100-879X2012007500168","article-title":"The increased but non-predominant expression of Th17- and Th1-specific cytokines in Hashimoto\u2019s thyroiditis but not in Graves\u2019 disease","volume":"45","author":"Qin","year":"2012","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s12020-015-0759-7","article-title":"T regulatory (Treg) and T helper 17 (Th17) lymphocytes in thyroid autoimmunity","volume":"52","author":"Marazuela","year":"2016","journal-title":"Endocrine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1146\/annurev.immunol.021908.132710","article-title":"IL-17 and Th17 Cells","volume":"27","author":"Korn","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.immuni.2006.06.002","article-title":"Th17: An effector CD4 T cell lineage with regulatory T cell ties","volume":"24","author":"Weaver","year":"2006","journal-title":"Immunity"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/nri1806","article-title":"Regulatory T cells, tumour immunity and immunotherapy","volume":"6","author":"Zou","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"222","DOI":"10.3109\/08916934.2012.751981","article-title":"Lower proportions of CD4+CD25(high) and CD4+FoxP3, but not CD4+CD25+CD127(low) FoxP3+ T cell levels in children with autoimmune thyroid diseases","volume":"46","author":"Bossowski","year":"2013","journal-title":"Autoimmunity"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4734","DOI":"10.4049\/jimmunol.0904135","article-title":"Impairment of regulatory capacity of CD4+CD25+ regulatory T cells mediated by dendritic cell polarization and hyperthyroidism in Graves\u2019 disease","volume":"186","author":"Mao","year":"2011","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1080\/08916934.2019.1698553","article-title":"Low frequency of IL-10-producing B cells and high density of ILC2s contribute to the pathological process in Graves\u2019 disease, which may be related to elevated-TRAb levels","volume":"53","author":"Ji","year":"2020","journal-title":"Autoimmunity"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1111\/j.1365-2265.2009.03544.x","article-title":"Regulatory T cells in Graves\u2019 disease","volume":"71","author":"Pan","year":"2009","journal-title":"Clin. Endocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s11596-006-0515-6","article-title":"Changes of regulatory T cells in Graves\u2019 disease","volume":"26","author":"Wang","year":"2006","journal-title":"J. Huazhong Univ. Sci. Technol. Med. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1089\/thy.2012.0514","article-title":"Impairment of regulatory T-cell function in autoimmune thyroid disease","volume":"23","author":"Glick","year":"2013","journal-title":"Thyroid"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1089\/thy.2006.0231","article-title":"Apoptosis-induced decrease of intrathyroidal CD4(+)CD25(+) regulatory T cells in autoimmune thyroid diseases","volume":"17","author":"Nakano","year":"2007","journal-title":"Thyroid"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2204","DOI":"10.1002\/jcp.27180","article-title":"The pathogenesis of thyroid autoimmune diseases: New T lymphocytes\u2014Cytokines circuits beyond the Th1\u2212Th2 paradigm","volume":"234","author":"Li","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"R094","DOI":"10.1007\/s004240000019","article-title":"Changes in Th1\/Th2 cytokine balance in Graves\u2019 desease","volume":"440","author":"Kocjan","year":"2000","journal-title":"Pfl\u00fcgers Archiv. Eur. J. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1111\/imr.12860","article-title":"T follicular helper cells in germinal center B cell selection and lymphomagenesis","volume":"296","author":"Mintz","year":"2020","journal-title":"Immunol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1126\/science.aac4919","article-title":"T cell help controls the speed of the cell cycle in germinal center B cells","volume":"349","author":"Gitlin","year":"2015","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1210\/jc.2011-2003","article-title":"Increased frequency of follicular helper T cells in patients with autoimmune thyroid disease","volume":"97","author":"Zhu","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s12026-015-8647-z","article-title":"Elevated follicular helper T cells and expression of IL-21 in thyroid tissues are involved in the pathogenesis of Graves\u2019 disease","volume":"62","author":"Zhang","year":"2015","journal-title":"Immunol. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.it.2014.06.002","article-title":"Phenotype and functions of memory Tfh cells in human blood","volume":"35","author":"Schmitt","year":"2014","journal-title":"Trends Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"8972572","DOI":"10.1155\/2018\/8972572","article-title":"Constitutive Changes in Circulating Follicular Helper T Cells and Their Subsets in Patients with Graves\u2019 Disease","volume":"2018","author":"Liu","year":"2018","journal-title":"J. Immunol. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1007\/s12020-015-0546-5","article-title":"MiR-346 regulates CD4\u207aCXCR5\u207a T cells in the pathogenesis of Graves\u2019 disease","volume":"49","author":"Chen","year":"2015","journal-title":"Endocrine"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4075522","DOI":"10.1155\/2022\/4075522","article-title":"The Frequency of Intrathyroidal Follicular Helper T Cells Varies with the Progression of Graves\u2019 Disease and Hashimoto\u2019s Thyroiditis","volume":"2022","author":"Cai","year":"2022","journal-title":"J. Immunol. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1530\/eje.0.1500225","article-title":"The role of CXCR5 and its ligand CXCL13 in the compartmentalization of lymphocytes in thyroids affected by autoimmune thyroid diseases","volume":"150","author":"Aust","year":"2004","journal-title":"Eur. J. Endocrinol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s12020-013-0105-x","article-title":"Interleukin-21 is associated with disease activity in patients with Graves\u2019 disease","volume":"46","author":"Zhang","year":"2014","journal-title":"Endocrine"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nri3158","article-title":"Standardizing immunophenotyping for the Human Immunology Project","volume":"12","author":"Maecker","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.humimm.2021.12.001","article-title":"Aberrant expression of inhibitory receptors on B cells in patients with Graves\u2019 disease","volume":"83","author":"Liu","year":"2022","journal-title":"Hum. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1111\/cei.13615","article-title":"Double-negative (DN) B cells: An under-recognized effector memory B cell subset in autoimmunity","volume":"205","author":"Li","year":"2021","journal-title":"Clin. Exp. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.4049\/jimmunol.181.2.1375","article-title":"CD11c expression identifies a population of extrafollicular antigen-specific splenic plasmablasts responsible for CD4 T-independent antibody responses during intracellular bacterial infection","volume":"181","author":"Racine","year":"2008","journal-title":"J. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"635615","DOI":"10.3389\/fimmu.2021.635615","article-title":"Deep Phenotyping of CD11c(+) B Cells in Systemic Autoimmunity and Controls","volume":"12","author":"Wiedemann","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"836347","DOI":"10.3389\/fimmu.2022.836347","article-title":"CD11c+ B Cells Participate in the Pathogenesis of Graves\u2019 Disease by Secreting Thyroid Autoantibodies and Cytokines","volume":"13","author":"Cao","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1515\/JPEM.2003.16.1.63","article-title":"Analysis of Changes in the Percentage of \u0392 (CD19) and \u03a4 (CD3) Lymphocytes, Subsets CD4, CD8 and their Memory (CD45RO), and Naive (CD45RA) \u03a4 Cells in Children with Immune and Non-immune Thyroid Diseases","volume":"16","author":"Bossowski","year":"2003","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1146\/annurev-immunol-020711-074934","article-title":"Immune regulatory function of B cells","volume":"30","author":"Mauri","year":"2012","journal-title":"Annu. Rev. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Grubczak, K., Starosz, A., Sto\u017cek, K., Bossowski, F., Moniuszko, M., and Bossowski, A. (2021). Regulatory B Cells Involvement in Autoimmune Phenomena Occurring in Pediatric Graves\u2019 Disease Patients. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222010926"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.immuni.2015.04.005","article-title":"Regulatory B cells: Origin, phenotype, and function","volume":"42","author":"Rosser","year":"2015","journal-title":"Immunity"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1002\/JLB.MR0618-226R","article-title":"The multiple faces of CD5","volume":"105","author":"Soldevila","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1080\/08916934.2019.1697690","article-title":"Lower proportion of CD19(+)IL-10(+) and CD19(+)CD24(+)CD27(+) but not CD1d(+)CD5(+)CD19(+)CD24(+)CD27(+) IL-10(+) B cells in children with autoimmune thyroid diseases","volume":"53","author":"Grubczak","year":"2020","journal-title":"Autoimmunity"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Zha, B., Wang, L., Liu, X., Liu, J., Chen, Z., Xu, J., Sheng, L., Li, Y., and Chu, Y. (2012). Decrease in proportion of CD19+ CD24(hi) CD27+ B cells and impairment of their suppressive function in Graves\u2019 disease. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0049835"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Morandi, F., Airoldi, I., Marimpietri, D., Bracci, C., Faini, A.C., and Gramignoli, R. (2019). CD38, a Receptor with Multifunctional Activities: From Modulatory Functions on Regulatory Cell Subsets and Extracellular Vesicles, to a Target for Therapeutic Strategies. Cells, 8.","DOI":"10.3390\/cells8121527"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s13044-018-0046-9","article-title":"Role of the T and B lymphocytes in pathogenesis of autoimmune thyroid diseases","volume":"11","author":"Rydzewska","year":"2018","journal-title":"Thyroid Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1210\/jc.2006-2388","article-title":"B lymphocyte depletion with the monoclonal antibody rituximab in Graves\u2019 disease: A controlled pilot study","volume":"92","author":"Nielsen","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1530\/EJE-08-0084","article-title":"Rituximab in relapsing Graves\u2019 disease, a phase II study","volume":"159","author":"Heemstra","year":"2008","journal-title":"Eur. J. Endocrinol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1111\/ajt.14872","article-title":"Characterization of the in vitro and in vivo properties of CFZ533, a blocking and non-depleting anti-CD40 monoclonal antibody","volume":"18","author":"Ristov","year":"2018","journal-title":"Am. J. Transplant."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1210\/clinem\/dgab763","article-title":"Adjuvant Rituximab\u2014Exploratory Trial in Young People with Graves Disease","volume":"107","author":"Cheetham","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1007\/s12020-019-02180-9","article-title":"Practical applications of studies on the TSH receptor and TSH receptor autoantibodies","volume":"68","author":"Furmaniak","year":"2020","journal-title":"Endocrine"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3446","DOI":"10.1210\/en.2018-00306","article-title":"Immunotherapy with Apitopes Blocks the Immune Response to TSH Receptor in HLA-DR Transgenic Mice","volume":"159","author":"Jansson","year":"2018","journal-title":"Endocrinology"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1089\/thy.2019.0036","article-title":"Antigen-Specific Immunotherapy with Thyrotropin Receptor Peptides in Graves\u2019 Hyperthyroidism: A Phase I Study","volume":"29","author":"Pearce","year":"2019","journal-title":"Thyroid"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s13317-011-0025-9","article-title":"In vivo effects of a human thyroid-stimulating monoclonal autoantibody (M22) and a human thyroid-blocking autoantibody (K1-70)","volume":"3","author":"Furmaniak","year":"2012","journal-title":"Auto Immun. Highlights"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s13317-019-0121-9","article-title":"Preclinical studies on the toxicology, pharmacokinetics and safety of K1-70TM a human monoclonal autoantibody to the TSH receptor with TSH antagonist activity","volume":"10","author":"Furmaniak","year":"2019","journal-title":"Auto Immun. Highlights"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1111\/cen.14681","article-title":"TSH receptor specific monoclonal autoantibody K1-70(TM) targeting of the TSH receptor in subjects with Graves\u2019 disease and Graves\u2019 orbitopathy-Results from a phase I clinical trial","volume":"96","author":"Furmaniak","year":"2022","journal-title":"Clin. Endocrinol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/cyto.a.22348","article-title":"T helper cells plasticity in inflammation","volume":"85","author":"Cosmi","year":"2014","journal-title":"Cytom. A"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/j.1365-3083.2008.02118.x","article-title":"Neutralizing IL-21 and IL-15 inhibits pro-inflammatory cytokine production in rheumatoid arthritis","volume":"68","author":"Andersson","year":"2008","journal-title":"Scand. J. Immunol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1196\/annals.1423.063","article-title":"Treatment of BXSB-Yaa mice with IL-21R-Fc fusion protein minimally attenuates systemic lupus erythematosus","volume":"1110","author":"Bubier","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/7\/6835\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:11:04Z","timestamp":1760123464000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/7\/6835"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,6]]},"references-count":87,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24076835"],"URL":"https:\/\/doi.org\/10.3390\/ijms24076835","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,6]]}}}