{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T07:35:45Z","timestamp":1778657745805,"version":"3.51.4"},"reference-count":36,"publisher":"The Endocrine Society","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,12,1]]},"abstract":"<jats:sec>\n                    <jats:title>Context:<\/jats:title>\n                    <jats:p>It is well known that regulatory T cells (Tregs) are abnormal in Graves' disease (GD) and play crucial roles in the breakdown of immune tolerance and GD development. However, there are controversies about whether the quantity and\/or function of Tregs is aberrant in GD. The molecular mechanism of Tregs abnormality and its effects on GD development was still unclear, until now.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>MiRNAs play important roles in the function and development of the immune system including Tregs. To reveal the Tregs abnormality and its molecular mechanism in GD, we systematically studied the quantity and immunosuppressive function as well as the differential expression profiles of miRNA and mRNA of Tregs in newly diagnosed patients with GD using TaqMan miRNA array and mRNA microarray.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Our results showed that the quantity and immunosuppressive function of Tregs in initial patients with GD was significantly decreased. More importantly, the retinoic acid (RA) pathway was markedly suppressed and its agonist, all-trans retinoic acid, could notably improve the quantity and immunosuppressive function of Tregs from patients with GD in vitro. In addition, many other pathways including protein ubiquitination and circadian rhythm were also significantly regulated in Tregs of GD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>This integrative study first revealed the expression profiles of mRNA\/miRNA in Tregs of initial GD and RA pathway might play important roles in GD development. Our results implied that all-trans RA, which had been used for a long time in the clinical setting, had potential value in the treatment of GD and was worthy of additional study.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1210\/jc.2014-1883","type":"journal-article","created":{"date-parts":[[2014,9,18]],"date-time":"2014-09-18T11:47:02Z","timestamp":1411040822000},"page":"E2620-E2627","source":"Crossref","is-referenced-by-count":23,"title":["Integrative Analysis of mRNA and miRNA Array Data Reveals the Suppression of Retinoic Acid Pathway in Regulatory T Cells of Graves' Disease"],"prefix":"10.1210","volume":"99","author":[{"given":"Zhe","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism (Z.W., J.J.Z., R.R.Z., T.L., W.C.L.), Jinan 250021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaohua","family":"Fan","sequence":"additional","affiliation":[{"name":"Division of Rehabilitation Medicine (X.H.F.), Shandong Provincial Hospital affiliated to Shandong University, Jinan 250021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongrong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism (Z.W., J.J.Z., R.R.Z., T.L., W.C.L.), Jinan 250021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zongwei","family":"Lin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Ministry of Public Health (Q.Y.Z., Z.W.L), Qilu Hospital, Shandong University, Jinan 250100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism (Z.W., J.J.Z., R.R.Z., T.L., W.C.L.), Jinan 250021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Bai","sequence":"additional","affiliation":[{"name":"National Glycoengineering Research Center (X.B.), Shandong University, Jinan 250100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenchao","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism (Z.W., J.J.Z., R.R.Z., T.L., W.C.L.), Jinan 250021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiajun","family":"Zhao","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism (Z.W., J.J.Z., R.R.Z., T.L., W.C.L.), Jinan 250021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qunye","family":"Zhang","sequence":"additional","affiliation":[{"name":"Central Research Laboratory (Q.Y.Z.), The Second Hospital of Shandong University, Jinan 250033, China"},{"name":"Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Ministry of Public Health (Q.Y.Z., Z.W.L), Qilu Hospital, Shandong University, Jinan 250100, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"issue":"17","key":"2020071616554684900_B1","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1056\/NEJM200010263431707","article-title":"Graves' disease","volume":"343","author":"Weetman","year":"2000","journal-title":"N Engl J Med"},{"issue":"8","key":"2020071616554684900_B2","doi-asserted-by":"crossref","first-page":"4012","DOI":"10.1210\/jc.2009-2184","article-title":"Identification of outer membrane porin f protein of Yersinia enterocolitica recognized by antithyrotopin receptor antibodies in Graves' disease and determination of its epitope using mass spectrometry and bioinformatics tools","volume":"95","author":"Wang","year":"2010","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071616554684900_B3","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1146\/annurev-immunol-020711-075043","article-title":"Induced CD4+Foxp3+ regulatory T cells in immune tolerance","volume":"30","author":"Bilate","year":"2012","journal-title":"Annu Rev Immunol"},{"issue":"7129","key":"2020071616554684900_B4","doi-asserted-by":"crossref","first-page":"766","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"},{"issue":"7","key":"2020071616554684900_B5","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"},{"issue":"2","key":"2020071616554684900_B6","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1111\/imm.12065","article-title":"Transient depletion of CD4+ CD25+ regulatory T cells results in multiple autoimmune diseases in wild-type and B-cell-deficient NOD mice","volume":"139","author":"Ellis","year":"2013","journal-title":"Immunology"},{"issue":"8","key":"2020071616554684900_B7","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' disease","volume":"186","author":"Mao","year":"2011","journal-title":"J Immunol"},{"issue":"11","key":"2020071616554684900_B8","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1084\/jem.20061692","article-title":"A role for Dicer in immune regulation","volume":"203","author":"Cobb","year":"2006","journal-title":"J Exp Med"},{"issue":"5","key":"2020071616554684900_B9","doi-asserted-by":"crossref","first-page":"2578","DOI":"10.4049\/jimmunol.0803162","article-title":"Cutting edge: The Foxp3 target miR-155 contributes to the development of regulatory T cells","volume":"182","author":"Kohlhaas","year":"2009","journal-title":"J Immunol"},{"issue":"1\u20132","key":"2020071616554684900_B10","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.jneuroim.2010.06.009","article-title":"Altered miRNA expression in T regulatory cells in course of multiple sclerosis","volume":"226","author":"De Santis","year":"2010","journal-title":"J Neuroimmunol"},{"issue":"6","key":"2020071616554684900_B11","doi-asserted-by":"crossref","first-page":"E968","DOI":"10.1210\/jc.2011-2982","article-title":"Differential microRNA expression in peripheral blood mononuclear cells from Graves' disease patients","volume":"97","author":"Liu","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"2020071616554684900_B12","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1055\/s-0033-1361088","article-title":"microRNA Expressions in CD4+ and CD8+ T-cell Subsets in Autoimmune Thyroid Diseases","volume":"122","author":"Bernecker","year":"2014","journal-title":"Exp Clin Endocrinol Diabetes"},{"issue":"2","key":"2020071616554684900_B13","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1111\/cen.12432","article-title":"Circulating microRNAs in autoimmune thyroid diseases","volume":"81","author":"Yamada","year":"2014","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"12","key":"2020071616554684900_B14","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1089\/thy.2012.0277","article-title":"MicroRNAs miR-146a1, miR-155_2, and miR-200a1 are regulated in autoimmune thyroid diseases","volume":"22","author":"Bernecker","year":"2012","journal-title":"Thyroid"},{"issue":"10","key":"2020071616554684900_B15","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1111\/j.1432-2277.2010.01080.x","article-title":"Retinoic acid attenuates acute heart rejection by increasing regulatory T cell and repressing differentiation of Th17 cell in the presence of TGF-\u03b2","volume":"23","author":"Wang","year":"2010","journal-title":"Transpl Int"},{"issue":"16","key":"2020071616554684900_B16","doi-asserted-by":"crossref","first-page":"12697","DOI":"10.1074\/jbc.M011000200","article-title":"Selective roles of retinoic acid receptor and retinoid x receptor in the suppression of apoptosis by all-trans-retinoic acid","volume":"276","author":"Konta","year":"2001","journal-title":"J Biol Chem"},{"issue":"14","key":"2020071616554684900_B17","doi-asserted-by":"crossref","first-page":"3921","DOI":"10.1182\/blood-2010-10-311894","article-title":"Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation","volume":"117","author":"Di Ianni","year":"2011","journal-title":"Blood"},{"issue":"1","key":"2020071616554684900_B18","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1101\/gr.082701.108","article-title":"Most Mammalian mRNAs Are Conserved Targets of MicroRNAs","volume":"19","author":"Friedman","year":"2009","journal-title":"Genome Research"},{"issue":"7","key":"2020071616554684900_B19","doi-asserted-by":"crossref","first-page":"e264","DOI":"10.1371\/journal.pbio.0030264","article-title":"Human MicroRNA targets","volume":"3","author":"John","year":"2005","journal-title":"PLoS Biol"},{"key":"2020071616554684900_B20","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1038\/srep01860","article-title":"Transcriptome sequencing of neonatal thymic epithelial cells","volume":"3","author":"St-Pierre","year":"2013","journal-title":"Sci Rep"},{"issue":"8","key":"2020071616554684900_B21","first-page":"2138","article-title":"Clinical pharmacology of oral all-trans retinoic acid in patients with acute promyelocytic leukemia","volume":"52","author":"Muindi","year":"1992","journal-title":"Cancer Res"},{"issue":"4","key":"2020071616554684900_B22","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1530\/EJE-11-0879","article-title":"Function of regulatory T-cells improved by dexamethasone in Graves' disease","volume":"166","author":"Hu","year":"2012","journal-title":"Eur J Endocrinol"},{"issue":"9","key":"2020071616554684900_B23","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1210\/jc.2005-2337","article-title":"Regulatory T cells in human autoimmune thyroid disease","volume":"91","author":"Marazuela","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2020071616554684900_B24","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.immuni.2011.07.002","article-title":"The role of retinoic acid in tolerance and immunity","volume":"35","author":"Hall","year":"2011","journal-title":"Immunity"},{"issue":"8","key":"2020071616554684900_B25","doi-asserted-by":"crossref","first-page":"4170","DOI":"10.4049\/jimmunol.1101634","article-title":"A new look at immune privilege of the eye: Dual role for the vision-related molecule retinoic acid","volume":"187","author":"Zhou","year":"2011","journal-title":"J Immunol"},{"issue":"5835","key":"2020071616554684900_B26","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1126\/science.1145697","article-title":"Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid","volume":"317","author":"Mucida","year":"2007","journal-title":"Science"},{"issue":"10","key":"2020071616554684900_B27","doi-asserted-by":"crossref","first-page":"2131","DOI":"10.1084\/jem.20090639","article-title":"Retinoic acid can enhance conversion of naive into regulatory T cells independently of secreted cytokines","volume":"206","author":"Nolting","year":"2009","journal-title":"J Exp Med"},{"key":"2020071616554684900_B28","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1124\/mol.106.029579","article-title":"Cellular retinoic acid bioavailability determines epithelial integrity: Role of retinoic acid receptor alpha agonists in colitis","volume":"71","author":"Osanai","year":"2007","journal-title":"Mol Pharmacol"},{"key":"2020071616554684900_B29","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1093\/jn\/137.5.1216","article-title":"Diets rich in polyphenols and vitamin A inhibit the development of type I autoimmune diabetes in nonobese diabetic mice","volume":"137","author":"Zunino","year":"2007","journal-title":"J Nutr"},{"key":"2020071616554684900_B30","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1159\/000066783","article-title":"Effect of synthetic retinoid, TAC-101, on experimental autoimmune disease","volume":"67","author":"Miyagawa","year":"2003","journal-title":"Pharmacology"},{"key":"2020071616554684900_B31","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.1093\/jn\/132.9.2743","article-title":"Vitamin A deficiency exacerbates inflammation in a rat model of colitis through activation of nuclear factor-kappaB and collagen formation","volume":"132","author":"Reifen","year":"2002","journal-title":"J Nutr"},{"issue":"8","key":"2020071616554684900_B32","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1038\/leu.2012.57","article-title":"How to manage acute promyelocytic leukemia","volume":"26","author":"Mi","year":"2012","journal-title":"Leukemia"},{"issue":"13","key":"2020071616554684900_B33","doi-asserted-by":"crossref","first-page":"4323","DOI":"10.1016\/j.bmc.2006.02.041","article-title":"Retinoic acid metabolism blocking agents (RAMBAs) for treatment of cancer and dermatological diseases","volume":"14","author":"Njar","year":"2006","journal-title":"Bioorg Med Chem"},{"issue":"3","key":"2020071616554684900_B34","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.intimp.2013.01.023","article-title":"Ubiquitination signals critical to regulatory T cell development and function","volume":"16","author":"Chen","year":"2013","journal-title":"Int Immunopharmacol"},{"issue":"7","key":"2020071616554684900_B35","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1084\/jem.20100004","article-title":"Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells","volume":"207","author":"Harada","year":"2010","journal-title":"J Exp Med"},{"issue":"6159","key":"2020071616554684900_B36","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1126\/science.1243884","article-title":"TH17 cell differentiation is regulated by the circadian clock","volume":"342","author":"Yu","year":"2013","journal-title":"Science"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/99\/12\/E2620\/9083002\/jcem2620.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/jcem\/article-pdf\/99\/12\/E2620\/9083002\/jcem2620.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T23:25:53Z","timestamp":1594941953000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/99\/12\/E2620\/2833303"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,12,1]]},"references-count":36,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2014,12,1]]}},"URL":"https:\/\/doi.org\/10.1210\/jc.2014-1883","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.718880173.793500498","asserted-by":"object"}]},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12,1]]}}}