{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T03:11:05Z","timestamp":1778037065229,"version":"3.51.4"},"reference-count":50,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T00:00:00Z","timestamp":1600387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondo de Investigaci\u00f3n de la Seguridad Social, Instituto de Salud Carlos III","award":["PI18\/01726"],"award-info":[{"award-number":["PI18\/01726"]}]},{"name":"Programa de Actividades de I+D de la Comunidad de Madrid en Biomedicina","award":["S2017\/BMD-3804"],"award-info":[{"award-number":["S2017\/BMD-3804"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>CD4+T-lymphocytes are relevant in the pathogenesis of rheumatoid arthritis (RA), however, their potential involvement in early RA remains elusive. Methotrexate (MTX) is a commonly used disease-modifying antirheumatic drug (DMARD), but its mechanism has not been fully established. In 47 new-onset DMARD-na\u00efve RA patients, we investigated the pattern of IFN\u03b3, IL-4 and IL-17A expression by na\u00efve (TN), central (TCM), effector memory (TEM) and effector (TE) CD4+ subsets; their STAT-1, STAT-6 and STAT-3 transcription factors phosphorylation, and the circulating levels of IFN\u03b3, IL-4 and IL-17. We also studied the RA patients after 3 and 6 months of MTX treatment and according their clinical response. CD4+T-lymphocyte subsets and cytokine expression were measured using flow cytometry. New-onset DMARD-na\u00efve RA patients showed a significant expansion of IL-17A+, IFN\u03b3+ and IL-17A+IFN\u03b3+ CD4+T-lymphocyte subsets and increased intracellular STAT-1 and STAT-3 phosphorylation. Under basal conditions, nonresponder patients showed increased numbers of circulating IL-17A producing TN and TMC CD4+T-lymphocytes and IFN\u03b3 producing TN, TCM, TEM CD4+T-lymphocytes with respect to responders. After 6 months, the numbers of CD4+IL-17A+TN remained significantly increased in nonresponders. In conclusion, CD4+T-lymphocytes in new-onset DMARD-na\u00efve RA patients show IL-17A and IFN\u03b3 abnormalities in TN, indicating their relevant role in early disease pathogenesis. Different patterns of CD4+ modulation are identified in MTX responders and nonresponders.<\/jats:p>","DOI":"10.3390\/ijms21186847","type":"journal-article","created":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T07:27:33Z","timestamp":1600414053000},"page":"6847","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Methrotexate Treatment Inmunomodulates Abnormal Cytokine Expression by T CD4 Lymphocytes Present in DMARD-Na\u00efve Rheumatoid Arthritis Patients"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1775-4645","authenticated-orcid":false,"given":"Jorge","family":"Monserrat Sanz","sequence":"first","affiliation":[{"name":"Laboratory of Immune System Diseases, Department of Medicine, University Hospital \u201cPr\u00edncipe de Asturias\u201d, University of Alcal\u00e1, Alcal\u00e1 de Henares, 28871 Madrid, Spain"},{"name":"IRYCIS Unit, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria, 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Boh\u00f3rquez","sequence":"additional","affiliation":[{"name":"Immune System Diseases-Rheumatology Service, Department of Medicine, University Hospital \u201cPr\u00edncipe de Asturias\u201d, University of Alcal\u00e1, Alcal\u00e1 de Henares, 28805 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3981-5138","authenticated-orcid":false,"given":"Ana Maria","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Laboratory of Immune System Diseases, Department of Medicine, University Hospital \u201cPr\u00edncipe de Asturias\u201d, University of Alcal\u00e1, Alcal\u00e1 de Henares, 28871 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atusa","family":"Movasat","sequence":"additional","affiliation":[{"name":"Immune System Diseases-Rheumatology Service, Department of Medicine, University Hospital \u201cPr\u00edncipe de Asturias\u201d, University of Alcal\u00e1, Alcal\u00e1 de Henares, 28805 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"IRYCIS Unit, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria, 28034 Madrid, Spain"},{"name":"Immune System Diseases-Rheumatology Service, Department of Medicine, University Hospital \u201cPr\u00edncipe de Asturias\u201d, University of Alcal\u00e1, Alcal\u00e1 de Henares, 28805 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc\u00eda","family":"Ru\u00edz","sequence":"additional","affiliation":[{"name":"Immune System Diseases-Rheumatology Service, Department of Medicine, University Hospital \u201cPr\u00edncipe de Asturias\u201d, University of Alcal\u00e1, Alcal\u00e1 de Henares, 28805 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Diaz","sequence":"additional","affiliation":[{"name":"Laboratory of Immune System Diseases, Department of Medicine, University Hospital \u201cPr\u00edncipe de Asturias\u201d, University of Alcal\u00e1, Alcal\u00e1 de Henares, 28871 Madrid, Spain"},{"name":"IRYCIS Unit, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria, 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Isabel","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Immune System Diseases-Rheumatology Service, Department of Medicine, University Hospital \u201cPr\u00edncipe de Asturias\u201d, University of Alcal\u00e1, Alcal\u00e1 de Henares, 28805 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Albarr\u00e1n","sequence":"additional","affiliation":[{"name":"Immune System Diseases-Rheumatology Service, Department of Medicine, University Hospital \u201cPr\u00edncipe de Asturias\u201d, University of Alcal\u00e1, Alcal\u00e1 de Henares, 28805 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"Sanz","sequence":"additional","affiliation":[{"name":"Division of Immunology and Rheumatology, Department of Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melchor","family":"\u00c1lvarez-Mon","sequence":"additional","affiliation":[{"name":"Laboratory of Immune System Diseases, Department of Medicine, University Hospital \u201cPr\u00edncipe de Asturias\u201d, University of Alcal\u00e1, Alcal\u00e1 de Henares, 28871 Madrid, Spain"},{"name":"IRYCIS Unit, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria, 28034 Madrid, Spain"},{"name":"Immune System Diseases-Rheumatology Service, Department of Medicine, University Hospital \u201cPr\u00edncipe de Asturias\u201d, University of Alcal\u00e1, Alcal\u00e1 de Henares, 28805 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1016\/S0140-6736(10)60826-4","article-title":"Rheumatoid arthritis","volume":"376","author":"Scott","year":"2010","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0025-7125(05)70504-6","article-title":"Pathogenesis of rheumatoid arthritis","volume":"81","author":"Weyand","year":"1997","journal-title":"Med. 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