{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T15:40:37Z","timestamp":1790005237494,"version":"4.0.1"},"reference-count":36,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2019,2,26]],"date-time":"2019-02-26T00:00:00Z","timestamp":1551139200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["#18K15827"],"award-info":[{"award-number":["#18K15827"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16K19330"],"award-info":[{"award-number":["16K19330"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Hepatology Research"],"published-print":{"date-parts":[[2019,6]]},"abstract":"<jats:sec><jats:title>Aim<\/jats:title><jats:p>Primary biliary cholangitis (PBC) is an autoimmune liver disease with unknown pathogenesis. In PBC, activation of T\u2010cell receptor (TCR) signaling is associated with inflammatory cytokine production through N\u2010Ras upregulation. Although the CD4<jats:sup>+<\/jats:sup> T cell TCR repertoire could be associated with PBC pathogenesis, it has not been evaluated. Thus, we analyzed the PBC\u2010CD4<jats:sup>+<\/jats:sup> T cell TCR repertoire using next generation sequencing (NGS).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Four PBC patients (one treatment\u2010na\u00efve and three receiving ursodeoxycholic acid) and three healthy individuals were enrolled. <jats:italic>NRAS<\/jats:italic> expression in CD4<jats:sup>+<\/jats:sup> T cells was assessed by quantitative reverse transcription\u2013polymerase chain reaction (qRT\u2010PCR). N\u2010Ras dynamics in CD4<jats:sup>+<\/jats:sup> T cells were assessed by qRT\u2010PCR and GTP\u2010N\u2010Ras activation assay. The TCR \u03b1\u2010 (TRA) and \u03b2\u2010chain (TRB) repertoires on CD4<jats:sup>+<\/jats:sup> T cells were analyzed by NGS and profiled using hierarchical analysis. Motif analysis was undertaken to elucidate the structure of PBC\u2010specific TCRs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>NRAS<\/jats:italic> was upregulated in PBC relative to control CD4<jats:sup>+<\/jats:sup> T cells (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05), and N\u2010Ras enhanced T cell activation in CD4<jats:sup>+<\/jats:sup> T cells. Among 2668 TRAs and 841 TRBs, 20 and 11, respectively, were differentially expressed in PBC compared to that in controls (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05, fold\u2010change &gt;2). Among them, TRAV29\/J22, TRBV6\u20135\/J2\u20136, and TRBV10\u20131\/J2\u20131 were expressed in PBC but the expression was negligible in the controls, with more mature and longer forms observed in PBC\u2010CD4<jats:sup>+<\/jats:sup> T cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>N\u2010Ras was upregulated in PBC\u2010CD4<jats:sup>+<\/jats:sup> T cells, and it enhanced TCR activation, indicating that PBC\u2010CD4<jats:sup>+<\/jats:sup> T cells were activated by N\u2010Ras upregulation with differentially expressed TCR repertoires on their surfaces.<\/jats:p><\/jats:sec>","DOI":"10.1111\/hepr.13318","type":"journal-article","created":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T03:33:10Z","timestamp":1548732790000},"page":"653-662","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["CD4<sup>+<\/sup> T cells from patients with primary biliary cholangitis show T cell activation and differentially expressed T\u2010cell receptor repertoires"],"prefix":"10.1111","volume":"49","author":[{"given":"Ryo","family":"Nakagawa","sequence":"first","affiliation":[{"name":"Division of Advanced Genome Medicine, Institute of Medical Science University of Tokyo  Tokyo Japan"},{"name":"Department of Gastroenterology and Hepatology Jikei University School of Medicine  Tokyo Japan"},{"name":"Department of Gastroenterology, Graduate School of Medicine Chiba University  Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Muroyama","sequence":"additional","affiliation":[{"name":"Division of Advanced Genome Medicine, Institute of Medical Science University of Tokyo  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chisato","family":"Saeki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology Jikei University School of Medicine  Tokyo 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