{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T13:40:26Z","timestamp":1780494026319,"version":"3.54.1"},"reference-count":38,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T00:00:00Z","timestamp":1744588800000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Int J of Rheum Dis"],"published-print":{"date-parts":[[2025,4]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n Granulocyte\u2013macrophage colony\u2010stimulating factor (GM\u2010CSF:\n CSF2<\/jats:italic>\n ) plays a crucial role in the pathogenesis of autoimmune diseases. The basic helix\u2013loop\u2013helix family member e40 (BHLHE40) gene is important for GM\u2010CSF production in CD4\n +<\/jats:sup>\n T cells. However, the relationship between the expression of these genes and rheumatoid arthritis (RA) remains unclear, particularly in interleukin\u20101 (IL\u20101)\u2010enriched inflammatory sites. Therefore, we investigated the expression of BHLHE40 and CSF2 in CD4\n +<\/jats:sup>\n T cells in RA.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We analyzed gene expression using previously deposited and publicly available databases containing peripheral blood (PB) and synovial fluid (SF) from patients with RA and healthy controls (HC). Comprehensive datasets, including single\u2010cell RNA\u2010sequencing (scRNA\u2010seq), RNA\u2010seq, and microarray data, were used for this analysis.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n BHLHE40<\/jats:italic>\n expression in PB CD4\n +<\/jats:sup>\n T cells from HC was higher in central memory, effector memory, Th17, and Th1\/17 cells than in naive CD4\n +<\/jats:sup>\n T cells. Furthermore,\n BHLHE40<\/jats:italic>\n and\n CSF2<\/jats:italic>\n expression in the CD45RA\n \u2010<\/jats:sup>\n CCR7\n +<\/jats:sup>\n \/\u2010<\/jats:sup>\n CD4\n +<\/jats:sup>\n T cell subset was significantly higher in the SF of patients with RA than in those with PB. scRNA\u2010seq revealed that\n BHLHE40<\/jats:italic>\n \u2010expressing cells showed higher\n CSF2<\/jats:italic>\n expression than those that did not. Additionally, scRNA\u2010seq showed higher\n BHLHE40<\/jats:italic>\n expression in PB CD4\n +<\/jats:sup>\n T cells from RA patients than in those from HC.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n We analyzed the gene expressions of\n BHLHE40<\/jats:italic>\n , which is crucial for GM\u2010CSF production,\n IL1R1<\/jats:italic>\n , which regulates\n BHLHE40<\/jats:italic>\n induction, and\n CSF2<\/jats:italic>\n , its resulting product, in CD4\n +<\/jats:sup>\n T cells. Their expression levels were compared across RA SF, PB, and HC. Notably, increased expression of these genes was identified in SF.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/1756-185x.70219","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T03:01:36Z","timestamp":1744599696000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of\n \n BHLHE40<\/i>\n <\/scp>\n \u2010Expressing\n CD4<\/scp>\n +<\/sup>\n T Cells Producing\n GM<\/scp>\n \u2010\n CSF<\/scp>\n in Rheumatoid Arthritis"],"prefix":"10.1111","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3100-9011","authenticated-orcid":false,"given":"Sho","family":"Ishigaki","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuya","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaru","family":"Takeshita","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2646-5765","authenticated-orcid":false,"given":"Yuko","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Internal Medicine Keio University School of Medicine Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxw006"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010immunol\u2010103019\u2010085803"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075\u2010019\u20101879\u2010x"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard\u20102023\u2010224482"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard\u20102023\u2010224449"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3008706"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/8880585"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590\u2010020\u20100622\u20108"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar318"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701484"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4551"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075\u2010024\u201003280\u20102"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.167881"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2020.09.002"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20122387"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20150568"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.4049\/immunohorizons.2300042"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201005044\u20104"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis\u20102018\u2010214885"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.08.036"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.4049\/immunohorizons.2000037"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.01.041"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010017\u201001771\u20102"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btz854"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4197"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059\u2010014\u20100550\u20108"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010020\u201076972\u20109"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1916897117"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20211191"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keh201"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1080\/25785826.2024.2430913"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.34477"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0092\u20108674(02)00767\u20105"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165\u20102478(91)90198\u2010j"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1993"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2017.12.006"}],"container-title":["International 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