{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:12:32Z","timestamp":1788912752595,"version":"build-2803163510"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T00:00:00Z","timestamp":1716336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000194","name":"Nova Scotia Health Research Foundation","doi-asserted-by":"publisher","award":["1638"],"award-info":[{"award-number":["1638"]}],"id":[{"id":"10.13039\/501100000194","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009415","name":"IWK Health Centre","doi-asserted-by":"publisher","award":["20294"],"award-info":[{"award-number":["20294"]}],"id":[{"id":"10.13039\/501100009415","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Antigen-presenting dendritic cells (DCs) and monocytes play an essential role in rheumatoid arthritis (RA) pathogenesis, however, their tolerogenic potential remains unclear. Herein, the tolerogenic profiles of DCs are characterized in treatment-na\u00efve RA patients to determine their role to inflammatory arthritis management.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Thirty-six treatment-na\u00efve RA patients were enrolled, of which 62% were non-responders to methotrexate (MTX) monotherapy based on disease activity score (DAS) after 6-months of therapy. DC and monocyte subset frequencies, activation (CD40, CD86, CD209 expression), and tolerogenic profile (intracellular indoleamine-2,3-dioxygenase [IDO1] and cytotoxic T lymphocyte antigen 4 [CTLA-4] expression) were examined in the baseline peripheral blood by multicolor flow-cytometry. Soluble CTLA-4 (sCTLA-4) levels in plasma were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>DC subsets were decreased in RA compared to healthy controls (HC), and the frequency of conventional DCs (cDC) inversely correlated with inflammatory markers and improvement in disease activity. CD141<jats:sup>+<\/jats:sup> cDC1s were the major IDO1-expressing cells. IDO1<jats:sup>+<\/jats:sup>cDC1s were reduced in RA patients compared to HC. The baseline frequency of IDO1<jats:sup>+<\/jats:sup>cDC1s inversely correlated with improvement in disease activity. CTLA-4 expression in CD1c<jats:sup>+<\/jats:sup> cDC2s and monocytes was lower in RA patients compared to HC. Moreover, MTX-responders had a significantly lower frequency of IDO1<jats:sup>+<\/jats:sup>cDC1 cells and higher level of sCTLA-4 in the plasma compared to MTX non-responders. There was a strong predictive association of low IDO1<jats:sup>+<\/jats:sup>cDC1 cells, low sCTLA-4 and non-response to MTX.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our findings reveal altered DC and monocytes immunophenotypes that are associated with RA pathology and treatment response. The frequencies of tolerogenic IDO1<jats:sup>+<\/jats:sup>cDC1s and the low level of sCTLA-4 are strongly associated with MTX non-responsiveness and therapeutic outcome. These results suggest that investigation of the association IDO1<jats:sup>+<\/jats:sup>cDC1 and sCTLA-4 with response to treatment may be more generalizable to other autoimmune diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1352251","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T04:29:26Z","timestamp":1716352166000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Differences in IDO1+ dendritic cells and soluble CTLA-4 are associated with differential clinical responses to methotrexate treatment in rheumatoid arthritis"],"prefix":"10.3389","volume":"15","author":[{"given":"Anik\u00f3 E.","family":"Malik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drew","family":"Slauenwhite","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah M.","family":"McAlpine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Hanly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean S.","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas B.","family":"Issekutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"686","DOI":"10.3390\/ijms22020686","article-title":"From rheumatoid factor to anti-citrullinated protein antibodies and anti-carbamylated protein antibodies for diagnosis and prognosis prediction in patients with rheumatoid arthritis","volume":"22","author":"Wu","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.790122","article-title":"Molecular and cellular heterogeneity in rheumatoid arthritis: mechanisms and clinical implications","volume":"12","author":"Zhao","year":"2021","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1186\/s13075-022-02851-5","article-title":"Clinical predictors of response to methotrexate in patients with rheumatoid arthritis: a machine learning approach using clinical trial data","volume":"24","author":"Duong","year":"2022","journal-title":"Arthritis Res Ther"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1136\/ard-2022-223356corr1","article-title":"EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update","volume":"82","author":"Smolen","year":"2023","journal-title":"Ann Rheum Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/acr.24596","article-title":"2021 American college of rheumatology guideline for the treatment of rheumatoid arthritis","volume":"73","author":"Fraenkel","year":"2021","journal-title":"Arthritis Rheumatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/art.40810","article-title":"Maximizing Therapeutic Utility in Rheumatoid Arthritis Consortium tRSG, Hyrich K, et\u00a0al. 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